@article {pmid42712067, year = {2026}, author = {Baeza Robba, MJ and De Oliveira, G and Oropeza, T and Iriarte, E and Cianelli, R and Kim, K and De Santis, JP}, title = {"Support us, so we can rise": A qualitative exploration of Latinas' expectations of healthcare providers after intimate partner violence.}, journal = {Women's health (London, England)}, volume = {22}, number = {}, pages = {17455057261478478}, pmid = {42712067}, issn = {1745-5065}, mesh = {Humans ; Female ; *Hispanic or Latino/psychology ; *Intimate Partner Violence/psychology/ethnology ; Qualitative Research ; Adult ; *Survivors/psychology ; *Health Personnel/psychology ; *Help-Seeking Behavior ; *Patient Acceptance of Health Care/psychology ; Middle Aged ; Social Support ; Surveys and Questionnaires ; }, abstract = {BackgroundDue to multilevel factors, it is estimated that fewer than half of Latinas in the U.S who experience Intimate Partner Violence (IPV) access the resources they need. However, among those who do seek help, approximately 35% turn to a clinic or health center. This positions front-line healthcare providers (HCPs) as key actors in mitigating barriers to care. Delivering survivor-centered care, however, requires a nuanced understanding of Latina survivors' expectations of HCPs, grounded in their lived experiences and the structural contexts that shape their lives.ObjectivesThis study aimed to explore Latina survivors' expectations of healthcare providers during IPV disclosure and help-seeking.DesignA qualitative descriptive study guided by Liang et al.'s help-seeking theory.MethodsTwenty-five Latina IPV survivors living in South Florida were purposively recruited. Data collection included socio-demographic questionnaires and in-depth interviews (23 in Spanish, 2 in English/mixed). Interviews were transcribed and analyzed thematically in English by bilingual researchers. This study adheres to the SRQR Checklist.ResultsParticipants shared five key themes under the overarching concept "Support us, so we can rise", including 1) direct assessment, "If you ask us, we are going to tell"; 2) non-judgmental listening, "Create a supportive space"; 3) proactive referral and follow-up; 4) tailored support systems and social services; 5) delivery of educational interventions. Culturally responsive, empowering, and sustained provider engagement were seen as essential to fostering disclosure, resilience, and recovery.ConclusionFuture research should prioritize healthcare provider-led interventions and educational strategies that foster trust, safety, and empowerment while also facilitating a sustained help-seeking process. This includes proactive referrals and a thoughtful balance between follow-up care and respect for the survivor's autonomy. Incorporating a culturally specific perspective is critical to addressing the evolving needs of this population and advancing equity in care delivery.}, }
@article {pmid42712181, year = {2026}, author = {Mohajerin, B and Howard, R and Pincus, AL}, title = {A Response to Dimaggio et al.'s Commentary on Mohajerin et al. (2026).}, journal = {Clinical psychology & psychotherapy}, volume = {33}, number = {5}, pages = {e70332}, doi = {10.1002/cpp.70332}, pmid = {42712181}, issn = {1099-0879}, mesh = {Humans ; *Psychotherapy/methods ; Randomized Controlled Trials as Topic ; }, abstract = {Our randomized controlled trial comparing Unified Protocol (UP) and Schema-Focused Therapy (SFT) for grandiose and vulnerable presentations of narcissism has recently been critiqued in a commentary by Dimaggio et al. (2026). These authors raised concerns regarding the study's recruitment and subgroup classification, gender distribution, treatment response patterns, absence of dropouts, randomization, screening and recruitment procedures, trial registration, outcome assessment, supervision and treatment fidelity, treatment dose and duration, and disclosure of the NPD diagnosis. In this response, we clarify these methodological and procedural issues and provide additional information that was not fully described in the original article. We maintain that while both treatments were effective in ameliorating symptoms of narcissism, SFT was more effective in treating grandiose features, while UP was more effective in treating vulnerable features. Trial Registration: Iranian Registry of Clinical Trials identifier: IRCT20231106059970N3.}, }
@article {pmid42713005, year = {2026}, author = {Belaidi, AA and Furtado, DL and Alves, F and Nisbet, RM and Ayton, S and Bush, AI}, title = {Engineering mRNA-LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases.}, journal = {Exploration (Beijing, China)}, volume = {}, number = {}, pages = {70223}, pmid = {42713005}, issn = {2766-2098}, abstract = {Messenger RNA (mRNA) therapeutics delivered by lipid nanoparticles (LNPs) have advanced from concept to clinic at unprecedented speed, yet their promise for neurodegenerative diseases remains largely untapped. Currently intractable age-related proteinopathies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis demand new therapies that combine molecular precision with scalable manufacturing. This review surveys recent advances in engineering LNPs that traverse the blood-brain barrier (BBB), evade innate immune surveillance, and achieve cell-selective expression in the ageing brain. We highlight emerging chemistries, including BBB-shuttling ionizable lipids, peptide-functionalized shells, and liver-detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS-directed mRNA-LNP has yet reached clinical trials, first-in-human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID-19 mRNA vaccines and ongoing liver-targeted programmes, we outline a translational roadmap for brain applications. Major hurdles that are critically assessed include efficient endosomal escape in aged neurons, heterogeneity of the senescent BBB, chronic-dose immunogenicity, and large-scale synthesis of next-generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age-related BBB alterations. Together, these insights chart a path for engineering mRNA-LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.}, }
@article {pmid42713279, year = {2026}, author = {Kassubek, J and Müller, HP}, title = {Magnetic resonance imaging applications to amyotrophic lateral sclerosis beyond the central nervous system.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1849783}, pmid = {42713279}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; }, abstract = {Traditionally, in amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, the diagnostic and research focus in the domain of magnetic resonance imaging (MRI) has been targeted on the brain and spinal cord. Nevertheless, structures outside the central nervous system (CNS) are core structures of the pathological processes and are also assessible by imaging approaches. Advanced imaging of structures like bodyfat and muscles can considerably contribute to the pathophysiological understanding and disease monitoring of ALS. The multiparametric combination of MRI approaches that capture these changes could be very helpful in future studies, especially when machine learning algorithms are used. This review summarizes the current state of the art and the role of imaging beyond the CNS in ALS, examining its diagnostic and monitoring potential and how it might ultimately lead to improved management strategies for patients.}, }
@article {pmid42713950, year = {2026}, author = {Bernard, ME and Harrison, I}, title = {Dynamically biased microcanonical treatment of HCl dissociative chemisorption on Au(111) yields thermal associative desorption dynamics by detailed balance.}, journal = {The Journal of chemical physics}, volume = {165}, number = {10}, pages = {}, doi = {10.1063/5.0345352}, pmid = {42713950}, issn = {1089-7690}, abstract = {A dynamically biased microcanonical transition state theory model of HCl dissociative chemisorption on Au(111) was recently developed for Shirhatti et al.'s [J. Phys. Chem. Lett. 7, 1346 (2016)] non-equilibrium supersonic molecular beam experiments where normal translational energies varied over a 50-250 kJ/mol range. Model parameters include a relatively low threshold energy for reaction, E0 = 30.88 kJ/mol; an efficiency, εn = 0.26, for molecular normal translational energy to contribute to the active exchangeable energy capable of promoting reaction; and one surface oscillator, s = 1, involved in the local gas-surface collision complex wherein energy was taken as microcanonically exchangeable, although potentially subject to dynamical bias through efficiencies. To validate the model, detailed balance was used to predict the desorbing HCl product state distributions from thermal associative desorption of H(c) + Cl(c) on Au(111) that have been measured by Rettner and Auerbach [Science 263, 365 (1994)] while impinging a H atom beam onto a chlorinated Au(111) surface. Modeling of Rettner's [J. Chem. Phys. 101, 1529 (1994)] rovibrationally resolved HCl product state distributions allowed for the additional establishment of a rotational efficiency of εr = 0.23 that led to consistent prediction of both the thermal associative desorption and the supersonic molecular beam experimental results. The HCl(g) ⇄ H(c) + Cl(c) reactivity on Au(111) is thereby identified as a new benchmark system for gas-surface reactivity where highly detailed experimental data are available coming from both sides of the reaction barrier. The activation energy for thermal associative desorption was estimated as Ea,assoc = 5.6 ± 1.3 kJ/mol based on four independent kinds of measurement. The effect of dynamics on the thermal dissociative sticking coefficient, S(T), of interest in practical catalysis, was quantitatively assessed. As compared to a statistically behaving HCl/Au(111) system with Ea = 31 kJ/mol, dynamics reduced S(T) by a factor of 10 at 800 K, equivalent to an increase in activation energy of ΔEa = 15 kJ/mol.}, }
@article {pmid42716035, year = {2026}, author = {Hardiman, O}, title = {HIMALAYA: learning from another negative phase 2 trial in ALS.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {875-877}, doi = {10.1016/S1474-4422(26)00318-2}, pmid = {42716035}, issn = {1474-4465}, }
@article {pmid42716044, year = {2026}, author = {Cudkowicz, ME and Shefner, J and van den Berg, LH and Chio, A and Fan, D and Großkreutz, J and Lunetta, C and Tsai, RM and Li, Y and Wallstroem, E and Xiong, L and Chen, Y and Atassi, N and , }, title = {Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {900-910}, doi = {10.1016/S1474-4422(26)00277-2}, pmid = {42716044}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Middle Aged ; Male ; Female ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Treatment Outcome ; Adolescent ; }, abstract = {BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS.<br><br>METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early.<br><br>FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56&#xb7;9 years (SD 11&#xb7;5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6&#xb7;73 (95% CI -7&#xb7;48 to -5&#xb7;98) for SAR443820 group (n=169) and -6&#xb7;32 (-7&#xb7;36 to -5&#xb7;27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0&#xb7;41 [95% CI -1&#xb7;71 to 0&#xb7;88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820.<br><br>INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted.<br><br>FUNDING: Sanofi.}, }
@article {pmid42716045, year = {2026}, author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR}, title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {926-938}, doi = {10.1016/S1474-4422(26)00246-2}, pmid = {42716045}, issn = {1474-4465}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; }, abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.}, }
@article {pmid42716967, year = {2026}, author = {Mansour, SS and Mahmoud, AM and Moustafa, AA and Nashat, NW}, title = {"Green spectrophotometric determination of rupatadine, its toxic impurity, and methyl paraben: comparative AI-assisted univariate versus multivariate chemometrics".}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42716967}, issn = {2045-2322}, mesh = {*Parabens/analysis ; *Cyproheptadine/analogs &amp; derivatives/analysis/chemistry ; Loratadine/analogs &amp; derivatives/analysis ; Multivariate Analysis ; *Artificial Intelligence ; *Drug Contamination ; Spectrophotometry, Ultraviolet/methods ; Spectrophotometry/methods ; }, abstract = {Sensitive and selective green UV-spectrophotometric univariate and multivariate chemometric methods were developed to resolve the overlapped spectra of rupatadine fumarate (RUP), its impurity desloratadine (DES), and methyl paraben (MP). The univariate approach employed was the dual-wavelength (DW) method. Guided by artificial intelligence (AI) in the selection of the optimal wavelength pair, the determination of RUP was performed at 230 and 284.3 nm, and for MP at 236.6 and 253.8 nm. Among the multivariate methods, ANN demonstrated superior predictive accuracy (lowest RMSEP values), followed by PLS-1 and MCR-ALS, highlighting the power of machine learning for complex mixture resolution, particularly in the presence of the preservative MP. A three-factor, five-level experimental design was adopted to construct a calibration set comprising 25 mixtures with varying component ratios, along with 6 independent validation mixtures. The developed methods were successfully applied to pharmaceutical formulation containing the studied drug and were validated in accordance with International Conference of Harmonization (ICH) guidelines. The results obtained were reliable and reproducible, confirming the suitability of these methods for routine analysis and quality control in laboratories. Moreover, the GLANCE tool (Graphical Layout for Analytical Chemistry Evaluation) offered a clear visual summary of the twelve structured method attributes.}, }
@article {pmid42717683, year = {2026}, author = {Moody, L and Christoforidou, E and Joilin, G and Dilley, A and Hafezparast, M}, title = {Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.}, journal = {Disease models &amp; mechanisms}, volume = {}, number = {}, pages = {}, doi = {10.1242/dmm.052963}, pmid = {42717683}, issn = {1754-8411}, support = {Hafezparast/Oct19/897-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; Hafezparast/Apr21/880-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //Sussex Neuroscience PhD Programme/ ; DOD/14/30-PF12794//My Name'5 Doddie Foundation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.}, }
@article {pmid42717824, year = {2026}, author = {Zarco-Martín, MT and Andreo-López, MC and Yagui-Beltrán, MS and Fernández-Soto, ML}, title = {Appendicular Skeletal Muscle Mass and Sarcopenia as Prognostic Markers in Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {5}, pages = {e70378}, doi = {10.1002/jcsm.70378}, pmid = {42717824}, issn = {2190-6009}, support = {2024 Award for the Best Clinical Nutrition Research Project//Sociedad Espa&#xf1;ola de Nutrici&#xf3;n Cl&#xed;nica y Metabolismo/ ; 74-2022//Granada Biosanitary Research Institute (Ibs. Granada)/ ; }, mesh = {Humans ; *Sarcopenia/etiology/diagnosis/mortality/pathology ; *Amyotrophic Lateral Sclerosis/complications/mortality/diagnosis ; Female ; Prognosis ; *Muscle, Skeletal/pathology/physiopathology ; Male ; Aged ; Biomarkers ; Middle Aged ; Prospective Studies ; Hand Strength ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle wasting and functional decline. Prognostic assessment in clinical practice relies largely on functional scales and traditional anthropometric measures. The prognostic relevance of muscle mass, muscle strength and sarcopenia in ALS remains incompletely defined. This study evaluated the prognostic value of muscle mass, muscle function and sarcopenia in relation to mortality in patients with ALS.<br><br>METHODS: A prospective observational cohort study was conducted at the ALS Multidisciplinary Unit (UMELA), San Cecilio University Hospital in Granada. Sarcopenia was defined according to the European Working Group of Sarcopenia in Older People 2 (EWGSOP2) and malnutrition using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Muscle status was assessed using bioelectrical impedance vector analysis (BIVA)-derived parameters, muscle ultrasound, handgrip strength (HGS) and physical performance (SPPB). Differences between survivors and nonsurvivors were analysed and logistic regression explored potential predictors of mortality. Receiver operating characteristic (ROC) curves were constructed for significant predictors. Survival was analysed using the Kaplan-Meier and Cox proportional hazards regression.<br><br>RESULTS: A total of 42 patients with ALS were included (mean age 66.1&#x2009;&#xb1;&#x2009;10.3&#x2009;years, and 15 (36%) were female). During follow-up (mean survival 21.1&#x2009;&#xb1;&#x2009;10.5&#x2009;months), 45% died. Survivors showed higher appendicular skeletal muscle mass index (ASMI) (6.94&#x2009;&#xb1;&#x2009;0.91 vs. 5.80&#x2009;&#xb1;&#x2009;0.98&#x2009;kg/m[2], p&#x2009;=&#x2009;0.001), body cellular mass index (BCMI) (8.92&#x2009;&#xb1;&#x2009;1.59 vs. 7.64&#x2009;&#xb1;&#x2009;1.87&#x2009;kg/m[2], p&#x2009;=&#x2009;0.034) and HGS (25.45&#x2009;&#xb1;&#x2009;11.11 vs. 17.67&#x2009;&#xb1;&#x2009;8.83&#x2009;kg, p&#x2009;=&#x2009;0.032), while BMI did not differ (p&#x2009;=&#x2009;0.540). Sarcopenia was more prevalent in nonsurvivors (27.8% vs. 4.8%, p&#x2009;=&#x2009;0.047). In multivariable analysis, ASMI remained associated with mortality after adjustment for age, onset type and ALSFRS-R (OR 0.33, 95% CI 0.11-0.81, p&#x2009;=&#x2009;0.026), but this association was not statistically significant in the fully adjusted model including disease duration (p&#x2009;=&#x2009;0.093). ASMI showed the highest discriminative ability (AUC 0.81), compared to BCMI (AUC 0.70) and HGS (AUC 0.71). ROC-derived cut-offs (ASMI 6.74&#x2009;kg/m[2]; BCMI 7.2&#x2009;kg/m[2]; HGS 21&#x2009;kg) stratified survival. Higher ASMI (HR 7.53, p&#x2009;=&#x2009;0.008), BCMI (HR 4.18, p&#x2009;=&#x2009;0.005) and HGS (HR 4.02, p&#x2009;=&#x2009;0.019) were associated with longer survival, whereas sarcopenia increased mortality risk (HR 15.53, p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Beyond BMI, skeletal muscle mass-particularly ASMI-was associated with survival in ALS. Sarcopenia identifies a subgroup of patients at particularly high risk of death. Sarcopenia assessment may improve prognostic stratification and support clinical management in ALS.}, }
@article {pmid42719214, year = {2026}, author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP}, title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.}, journal = {3 Biotech}, volume = {16}, number = {10}, pages = {420}, pmid = {42719214}, issn = {2190-572X}, abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.}, }
@article {pmid42719350, year = {2026}, author = {Imashuku, S}, title = {Literature review of pediatric Erdheim-Chester disease (ECD) and mixed histiocytosis (Langerhans cell histiocytosis/ECD).}, journal = {Annals of translational medicine}, volume = {14}, number = {4}, pages = {53}, pmid = {42719350}, issn = {2305-5839}, abstract = {BACKGROUND AND OBJECTIVE: Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) are more commonly observed in childhood; however, Erdheim-Chester disease (ECD) predominantly affects adults, making pediatric ECD extremely rare. To find out the incidence and characteristics of ECD in children, a review article was prepared.<br><br>METHODS: A literature review was conducted to estimate the incidence of pediatric ECD and characterize its clinical features, using PubMed and Crossref, during 1990 to June 2026, with searched terms "Childhood or Pediatric", "Erdheim-Chester disease", "Mixed histiocytosis".<br><br>KEY CONTENT AND FINDINGS: A total of 28 pediatric ECD cases were collected, which compared with previously reported pediatric ECD case series (Pegoraro et al., n=21; Romano et al., n=16). Based on these reports, it was estimated that more than 30 pediatric ECD cases have been described to date. Pediatric ECD appears to be characterized by relatively high rates of central nervous system involvement (53-67%) and mixed histiocytosis (20-38%). In addition, ophthalmologic involvements in the Yeager et al.'s study in 45% (adult 30%) of pediatric ECD should be recognized as an important manifestation in the eyes even in children. Regarding prognosis, most pediatric patients with ECD were reported as alive with disease (AWD) at the time of publication, suggesting a more favorable outcome than that observed in adult cases.<br><br>CONCLUSIONS: Diagnosing ECD in children remains challenging; however, this rare entity should be considered in the differential diagnosis of pediatric histiocytosis, particularly in cases with central nervous system and ophthalmologic involvement.}, }
@article {pmid42706758, year = {2026}, author = {Zumbo, BD}, title = {Conditional Standard Error of Measurement as an Estimand of Individual Score Precision: Remarks on Pfadt et al. from an Operator-Theoretic Perspective.}, journal = {Psychometrika}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/psy.2026.10141}, pmid = {42706758}, issn = {1860-0980}, abstract = {This commentary supports Pfadt et al.'s (2026, Psychometrika, 2026, 1-35. https://doi.org/10.1017/psy.2026.10081) recommendation that individual score interpretation should rely on conditional standard errors of measurement rather than a single unconditional standard error. I argue, however, that this recommendation requires a sharper test-theoretic formulation. Conditional precision is not merely a computational refinement of the standard error of measurement; it is a different estimand, defined by the information structure relative to which score precision is interpreted. Using an operator-theoretic formulation of classical test theory, I treat the true score as a conditional expectation, the error score as a projection residual, and the standard error of measurement as the norm of that residual. From this perspective, conditional standard errors localize residual variation with respect to observed scores, score bands, persons, trait levels, or measurement contexts. This formulation clarifies why assumptions associated with particular estimation procedures should not be attributed to classical test theory itself, and why practices such as pooling sparse score groups change the estimand. The commentary concludes that responsible individual score interpretation requires identifying the relevant conditional-precision estimand before selecting an estimator or software procedure.}, }
@article {pmid42707250, year = {2026}, author = {Unuakhalu, R and Purcell, A and Jindal, I and Wu, Y and Arnold, M and Dominick, KC and Shillington, A}, title = {The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.}, journal = {Molecular genetics and metabolism reports}, volume = {48}, number = {}, pages = {101350}, pmid = {42707250}, issn = {2214-4269}, abstract = {Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood. We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20 years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6. Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype. This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.}, }
@article {pmid42707488, year = {2026}, author = {Feyissa, GD}, title = {Serial Bogota bag tightening: A pragmatic advance in open abdomen management for resource-limited settings.}, journal = {World journal of gastrointestinal pharmacology and therapeutics}, volume = {17}, number = {3}, pages = {120768}, pmid = {42707488}, issn = {2150-5349}, abstract = {Open abdomen management poses unique challenges in resource-limited settings, where costly dynamic fascial traction techniques remain inaccessible. Balhara et al's prospective randomized trial published on the World J Gastrointest Pharmacol Ther introduces serial Bogota bag tightening, a bedside, negligible-cost method using urine bags and sutures, as an effective dynamic fascial traction alternative, achieving skin-to-skin distance ≤ 5 cm in 9.94 days vs 13 days in controls (P = 0.0003) and shortening hospital stays without added morbidity. This editorial appraises the study's strengths, contextualizes it against negative pressure wound therapy/mesh systems, and advocates its scalability for low- and middle-income countries, urging multicenter validation of long-term fascial closure.}, }
@article {pmid42707600, year = {2026}, author = {Zhang, Z and Lu, Y and Yang, J and Li, M and Yang, M and Xu, Y and Ullah, MS and Wan, Q and Bao, B and Yu, W and Liu, X}, title = {Neurotoxic mechanisms of cadmium in neurodegenerative diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1899381}, pmid = {42707600}, issn = {2296-634X}, abstract = {Cadmium (Cd) is a highly toxic, bioaccumulative heavy metal increasingly implicated in the pathogenesis of neurodegenerative disorders. This review systemically characterizes the molecular mechanisms underlying Cd-induced neurotoxicity, with particular emphasis on oxidative stress-mediated pathways that initiate interconnected processes including ferroptosis, mitochondrial impairment, disruption of calcium homeostasis, and chronic neuroinflammation. Evidence indicates that Cd exerts both convergent and disease-specific effects in neurodegenerative conditions. In Alzheimer's disease (AD), Cd exposure has been associated with enhanced amyloid-β (Aβ) deposition and increased tau hyperphosphorylation. In Parkinson's disease (PD), Cd disrupts metabolic homeostasis via the gut-liver-brain axis and promotes aberrant conformational changes and aggregation of α-synuclein (α-Syn). Within the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum, Cd contributes to TDP-43 proteinopathy and impairs nucleocytoplasmic transport mechanisms. Therapeutic strategies targeting Cd-induced neurotoxicity are also explored, including upstream approaches like metal chelation and downstream interventions aimed at restoring autophagic flux, modulating the neuroimmune microenvironment, and enhancing neuronal repair. Although emerging platforms such as brain organoids provide valuable mechanistic insights, translating findings from in vitro models to real-world chronic exposure scenarios remains a significant challenge. This review provides a comprehensive framework for the development of early-warning systems and precision-based interventions for Cd-related neurodegeneration.}, }
@article {pmid42708447, year = {2026}, author = {Gazal, NG and Castellanos-Montiel, MJ and Bruno, G and Franco-Flores, AK and Lépine, S and Gursu, L and Haghi, G and Maussion, G and Reintsch, WE and Stefani, FD and Anastasía, A and Bisbal, M and Gorostiza, EA and Durcan, TM and Unsain, N}, title = {BetaII-spectrin gaps and patches emerge from the patterned assembly of the actin/spectrin membrane skeleton in human motor neuron axons.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42708447}, issn = {2050-084X}, support = {ANPCyT-PICT-2021-GRF-II-00048//Agencia Nacional de Promoci&#xf3;n de la Investigaci&#xf3;n, el Desarrollo Tecnol&#xf3;gico y la Innovaci&#xf3;n/ ; IBRO-Collaboration Grants 2021//International Brain Research Organization/ ; }, mesh = {Humans ; *Spectrin/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; *Actins/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Cytoskeleton/metabolism ; }, abstract = {The actin/spectrin membrane-associated periodic skeleton (MPS) is a cytoskeletal structure that supports axonal integrity and function. Lower spinal motor neurons (MNs) are characterized by exceptionally long axons and are particularly susceptible to degeneration in a wide range of hereditary neuromuscular disorders, including amyotrophic lateral sclerosis. Using confocal and super-resolution imaging, we characterized the spatial distribution of βII-spectrin and the assembly pattern of the MPS in human MN axons derived from induced pluripotent stem cells. We discovered a striking gap-and-patch pattern in the medial axon, where sharply demarcated βII-spectrin gaps alternate with patches containing a well-organized MPS. The pattern is acutely induced by the kinase inhibitor staurosporine and pharmacological inhibition of actin polymerization prevents patch formation, indicating a requirement for actin nucleation in MPS assembly. Our data supports a model in which spectrin incorporation into nascent MPS patches depletes neighboring regions, producing long-range gaps-and-patches patterns.}, }
@article {pmid42709165, year = {2026}, author = {Hamzeh, LH and Seyed, E and Elgendy, MA and Heib, D and Sadek, BI and Mohammed, COS and El Refaei, K and Soliman, YF and Eldmrdash, N and Abdelgalil, MS and Elsayed, MM}, title = {Efficacy and safety of memantine in adults with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42709165}, issn = {1435-1463}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.}, }
@article {pmid42709218, year = {2026}, author = {Sewell-Green, AR and Capstick, R and Holdom, CJ and Matthews-Rensch, K and Cameron, J and McCombe, PA and Henderson, RD and Ngo, ST and Steyn, FJ}, title = {Early weight loss predicts poorer prognosis and highlights limitations of predictive energy equations in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42709218}, issn = {1432-1459}, support = {2016-32//Wesley Medical Research/ ; CRG2025_01395//FightMND/ ; Higher Degree Research Scholarship//University of Queensland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/metabolism ; *Weight Loss/physiology ; Prognosis ; Female ; Male ; Middle Aged ; Case-Control Studies ; Prospective Studies ; Aged ; *Energy Intake/physiology ; }, abstract = {BACKGROUND: Weight loss and malnutrition are associated with poorer outcomes in people living with amyotrophic lateral sclerosis (plwALS). This study investigated the prognostic relevance of early weight loss in plwALS and assessed whether existing energy equations provide useful guidance for nutritional management.<br><br>METHODS: In this prospective case-control and within-case comparison study (March 2016October 2024), 170 plwALS and 173 non-neurodegenerative disease controls completed baseline anthropometric and metabolic assessment. Participants with ALS were classified according to weight change during the first six months following study inclusion as Weight Gain, Stable Weight, or Weight Loss. Weight-change groups were compared for subsequent changes in anthropometry, functional capacity, and survival. In a nested cohort of 82 plwALS with reported energy intake and repeat assessments, we assessed whether the relationship between reported intake and equation-derived energy requirements was concordant with subsequent weight change.<br><br>RESULTS: Early weight loss was associated with continued loss of body weight, fat mass, and fat-free mass, faster functional decline, and increased risk of earlier death relative to Weight Gain (HR=4.78 [95% CI 2.68-8.53], p<0.001). Concordance between equation-derived energy requirements, reported energy intake and observed weight trajectory was low (17.3-32.1%). The IBW30(30) equation showed the greatest concordance among participants with Weight Loss, but no equation performed consistently across weight-change groups.<br><br>CONCLUSIONS: Early weight loss identifies plwALS at increased risk of subsequent weight and body-composition loss, functional decline and earlier death. Existing energy equations proposed for use in ALS show limited concordance with observed weight trajectories, particularly when applied at a single time point. These findings support serial monitoring of nutritional risk and individualized, phenotype-informed dietetic care in ALS.}, }
@article {pmid42709229, year = {2026}, author = {Castro, J and Sá, V and Lopes, D and Alves, I and Oliveira Santos, M and de Carvalho, M}, title = {Phrenic nerve amplitude as an effort-independent prognostic biomarker of respiratory failure in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42709229}, issn = {1432-1459}, mesh = {Humans ; *Phrenic Nerve/physiopathology ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Female ; Male ; Prognosis ; *Respiratory Insufficiency/etiology/diagnosis/physiopathology/therapy ; Nerve Conduction Studies ; Middle Aged ; Aged ; Noninvasive Ventilation ; Action Potentials/physiology ; Cohort Studies ; Biomarkers ; }, abstract = {OBJECTIVE: In amyotrophic lateral sclerosis (ALS), the effort-dependent respiratory metrics used to determine the timing of non-invasive ventilation (NIV) lose reliability as bulbar and/or cognitive impairment progresses. We tested whether the effort-independent phrenic nerve compound muscle action potential (CMAP) amplitude predicts the timing of NIV independently of forced vital capacity (FVC) and the revised ALS Functional Rating Scale (ALSFRS-R).<br><br>METHODS: Pre-registered analysis of a single-centre ALS cohort (n = 1,486) contributing 2968 serial phrenic nerve conduction studies. Amplitude was expressed as percentage of an age- and sex-predicted value (per 10% decrease), and time to NIV initiation was the primary outcome (death competing). We used cause-specific Cox models, time-dependent and bootstrap-validated discrimination, and a Bayesian joint longitudinal-survival model.<br><br>RESULTS: Lower amplitude predicted earlier NIV (adjusted hazard ratio [HR] 1.22 per 10% decrease, 95% CI 1.16-1.27; likelihood-ratio &#x3c7;[2] = 77.6, p &#x2248; 10&#x207b;1&#x2078;). The association was concentrated in the first year (HR 1.31, 1.24-1.38) and attenuated thereafter. The optimism-corrected discrimination increment over the clinical model was +0.055 (0.034-0.073); below-normal amplitude approximately doubled 12-month NIV risk (62% vs 29%). In the joint model the current amplitude (HR 1.57, 1.46-1.69) and its rate of decline (HR 1.30, 1.20-1.44) were independently prognostic.<br><br>CONCLUSIONS: Phrenic nerve conduction studies, an effort-independent neurophysiological marker carried robust, near-term, incremental prognostic information for NIV beyond FVC and ALSFRS-R, establishing diaphragmatic motor amplitude as a candidate biomarker for objective respiratory prognostication in ALS. External validation and recalibration are required before clinical use.}, }
@article {pmid42709336, year = {2026}, author = {Colosimo, C}, title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {42709336}, issn = {1179-1918}, abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.}, }
@article {pmid42709471, year = {2026}, author = {Chin, N and Zhang, Q and Zou, J and Cheng, KC and Zheng, W and Ye, Y}, title = {Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.}, journal = {eLife}, volume = {15}, number = {}, pages = {}, pmid = {42709471}, issn = {2050-084X}, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; Humans ; *Phase Transition ; Phase Separation ; *Cytoplasm/metabolism ; Active Transport, Cell Nucleus ; *Protein Aggregates ; Cell Nucleus/metabolism ; }, abstract = {RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.}, }
@article {pmid42709996, year = {2026}, author = {Davies, BJ}, title = {The floor, not the ceiling: industry ties across the cancer ecosystem.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag208}, pmid = {42709996}, issn = {1460-2105}, abstract = {Industry financial ties to the US cancer ecosystem are everywhere. Kim et al.'s systematic review and meta-analysis finds that financial conflicts of interest exceed 50% prevalence across most oncology domains. These relationships are not always benign. A robust body of health services research, including a 2021 systematic review of 36 studies, demonstrates that 83% of analyses identify a positive association between industry payments and prescribing behavior. Even a single industry-sponsored meal costing <$20 has been linked to significantly higher odds of prescribing the promoted drug. As federal National Institute of Health (NIH) funding faces cuts, industry's role in shaping the research agenda will only expand. Current US policy responses such as the disclosure through the Sunshine Act and dollar thresholds for guideline panelists have had minimal effectiveness in curtailing the money flowing to oncologists. This editorial argues for stronger structural reforms, specifically mandatory cooling-off periods for guideline committee members modeled on existing federal ethics statutes. Disclosure alone is insufficient, and some evidence suggests it may paradoxically license conflicted behavior. Meaningful progress requires moving beyond transparency toward policies that prevent conflicts from influencing clinical decision making.}, }
@article {pmid42710492, year = {2026}, author = {Kage, F and Lee, M and Bramhe, S and McEwen, AG and Alpy, F and Higgs, HN}, title = {Phosphorylation-dependent interaction between VAP proteins and INF2 influences ER morphology.}, journal = {Current biology : CB}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cub.2026.08.031}, pmid = {42710492}, issn = {1879-0445}, abstract = {The endoplasmic reticulum (ER) interacts with virtually all other cellular organelles, and major players mediating these interactions are the ER-bound VAMP-associated protein (VAP) proteins VAPA and VAPB. Here, we show that VAP proteins interact with the actin polymerization factor INF2 in a phosphorylation-dependent manner. Similar to many other VAP-interacting proteins (the "VAPome"), an FFAT motif in INF2's C terminus interacts with the major sperm protein (MSP) domain of VAPs. Phosphorylation of a serine within the FFAT (S1100 in mouse; S1077 in human INF2) is necessary for high-affinity interaction both in cells and with purified proteins. The position of this phosphoserine, at position -1 of the FFAT consensus, is novel to the VAPome. Biochemical assays show that the phospho-FFAT binds both VAPA and VAPB, but not the related VAP family protein MOSPD2. Increased cytoplasmic calcium stimulates both INF2 phosphorylation and the INF2/VAP interaction. Amyotrophic lateral sclerosis (ALS)-associated mutations in the MSP disrupt the INF2/VAP interaction. Both major INF2 isoforms interact with VAPs: the INF2-CAAX isoform, which is constitutively ER-bound, and the INF2-nonCAAX isoform, which is predominantly cytosolic. For INF2-nonCAAX, VAP proteins cause ER recruitment in a phosphorylation-dependent manner. Disruption of INF2/VAP binding does not affect INF2-mediated actin polymerization but has a clear effect on ER morphology, causing the tubule/sheet balance to shift toward sheets. Cross-species evaluation suggests that only INF2 from placental mammals possesses an FFAT. These results suggest that interaction between VAP proteins and the actin polymerization factor INF2 plays a role in mediating ER morphology.}, }
@article {pmid42710553, year = {2026}, author = {Babu, D and Le, TH and Liu, H and Raji, D and Tran, NH and Lockhart, S and Tran, P and Eldalal, O and Tonoyan, L and Siraki, AG}, title = {Edaravone as an antioxidant adjuvant to attenuate clozapine toxicity in vitro.}, journal = {Toxicology letters}, volume = {}, number = {}, pages = {113188}, doi = {10.1016/j.toxlet.2026.113188}, pmid = {42710553}, issn = {1879-3169}, abstract = {Despite being the gold-standard therapy for treatment-resistant schizophrenia, clozapine use remains constrained by the risk of rare but serious adverse drug reactions, including severe neutropenia and agranulocytosis. Neutrophil myeloperoxidase (MPO)-mediated bioactivation of clozapine to reactive metabolites has long been implicated in agranulocytosis. Although clozapine is metabolized by MPO, there are numerous other compounds that can also be metabolized by this enzyme. Edaravone is a drug used to treat amyotrophic lateral sclerosis and has potent antioxidant activity; we have previously shown that edaravone is metabolized by MPO. Therefore, we hypothesized that edaravone can attenuate early toxicological events associated with clozapine through MPO modulation. Using purified human MPO, MPO-rich human promyelocytic leukemia (HL-60) cells, and isolated human neutrophils, we evaluated clozapine oxidation, competitive intracellular uptake, protein adduct formation, and cytotoxicity. UV-visible spectroscopy demonstrated concentration-dependent inhibition of MPO-catalyzed clozapine oxidation by edaravone, with 100µM edaravone producing suppression comparable to 100µM 4-aminobenzoic acid hydrazide. LC-MS analysis showed that MPO/H2O2 reduced clozapine levels to 26.7 ± 2.9% of control, whereas co-incubation with edaravone preserved clozapine to 67.9 ± 16.2%. Under the same conditions, edaravone was almost completely consumed (0.03 ± 0.02% remaining), consistent with its sacrificial antioxidant activity. In HL-60 cells, edaravone attenuated MPO activity and did not significantly alter clozapine uptake after 30minutes (97.2 ± 7.6% of clozapine alone). Immunoblotting revealed that edaravone reduced clozapine-protein adduct formation in purified MPO, HL-60 cells, and neutrophils. Clozapine (75µM) induced marked HL-60 cytotoxicity after 24hours, whereas edaravone concentration-dependently restored viability, with 200µM fully preventing toxicity. These findings provide proof-of-concept that edaravone mitigates multiple mechanistic events linked to clozapine-induced hematological toxicity and may represent a potential strategy to improve clozapine safety.}, }
@article {pmid42710846, year = {2026}, author = {Cunha, TA and Dourado, LC and Santana, GC and Yanagiura, MT and Galvão-Lima, LJ and Vale, SHL and Brandão-Neto, J and Dourado-Junior, MET and Leite-Lais, L}, title = {Evaluation of a self-administered version of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {9}, pages = {1-7}, doi = {10.1055/s-0046-1827063}, pmid = {42710846}, issn = {1678-4227}, support = {88887.824483/2023-00//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior (CAPES)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Reproducibility of Results ; Prospective Studies ; Female ; Middle Aged ; Male ; Severity of Illness Index ; Observer Variation ; Feasibility Studies ; Aged ; *Disability Evaluation ; Adult ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a standard tool for evaluating functional decline in patients with ALS. Despite its clinical value, administration by healthcare professionals can be time-consuming and resource intensive.<br><br>OBJECTIVE: To assess the reliability and feasibility of a self-administration version of the ALSFRS-R as an alternative for use in clinical and research settings.<br><br>METHODS: The present was an observational, analytical, prospective, single-center study involving ALS patients followed at the Neurology Outpatient Clinic of the Hospital Universit&#xe1;rio Onofre Lopes (HUOL). Three independent assessments of the ALSFRS-R were conducted: one self-administered version and two interviewer-administered versions performed by different researchers during face-to-face consultations. Interrater reliability was assessed using intraclass correlation coefficients (ICCs), and agreement among the three versions was analyzed using Bland-Altman plots.<br><br>RESULTS: A total of 43 participants were included in the study, with a mean age of 57&#x2009;&#xb1;&#x2009;11.67 years. The ICCs indicated high reliability for both the total ALSFRS-R score and its functional domains. Linear regression analyses demonstrated strong agreement between the two researchers (R[2]&#x2009;=&#x2009;0.98, p&#x2009;<&#x2009;0.001), as well as between each researcher and the self-administered version (R[2]&#x2009;=&#x2009;0.90 and 0.88, respectively). Bland-Altman analyses showed minimal bias and acceptable limits of agreement across all comparisons.<br><br>CONCLUSION: The self-administered version of the ALSFRS-R demonstrated high reliability and strong agreement with the researcher-administered versions, supporting its potential use for remote monitoring of ALS patients. Nonetheless, it should not replace professional assessments in clinical trial settings. Further research is warranted to validate its applicability in broader clinical contexts and diverse patient populations.}, }
@article {pmid42711836, year = {2026}, author = {Nischal, SA and Kale, KM and Tourigny, K and Abuelem, M and Greene, G and Walsh, R and Molnár, Z}, title = {Neuroanatomy education through the years: Revisiting the teaching slides used by Sir Wilfrid Edward Le Gros Clark.}, journal = {Journal of anatomy}, volume = {}, number = {}, pages = {}, doi = {10.1111/joa.70235}, pmid = {42711836}, issn = {1469-7580}, support = {//Wellcome Trust History of Neuroscience Grant/ ; //Federation of European Neuroscience Societies History of Science Grants/ ; MR/W029073/1/MRC_/Medical Research Council/United Kingdom ; BB/X008711/1//BBSRC/ ; }, abstract = {Sir Wilfrid Edward Le Gros Clark (1895-1971) was a pioneering British anatomist, physician, and evolutionary biologist whose legacy spans the foundational development of twentieth century neuroanatomy, primate biology, and medical education. From his formative experiences as a young medical officer in the First World War to his later academic ascendancy at the University of Oxford, Le Gros Clark exemplified a rare fusion of clinical insight, anatomical precision, and philosophical curiosity. His tenure in Borneo, where he studied primates in their natural habitats, enriched his evolutionary perspective, while his later role in debunking the Piltdown Man fraud cemented his place as a steadfast defender of scientific integrity. At Oxford, Le Gros Clark assembled a singular collection of neuroanatomical teaching specimens, many of which remain preserved today within the Department of Physiology, Anatomy &amp; Genetics, University of Oxford. Through detailed analysis of selected slides, including cases of tabes dorsalis, disseminated sclerosis, amyotrophic lateral sclerosis, syringomyelia, and the pineal gland's nervus conarii, we reflect on how Le Gros Clark's anatomical interpretations anticipated many of the concepts central to contemporary neuroscience, and on how his legacy has influenced generations of students and scientists. What emerges from these materials is that Le Gros Clark taught students not simply to memorize, but to observe, interpret, and understand the functional significance of anatomical structures in health and disease.}, }
@article {pmid42701529, year = {2026}, author = {Kadish, CB and Gage, CB and Powell, JR and Ulintz, AJ and Wang, HE and Gaw, CE and Muller, G and Panchal, AR}, title = {Practice variability of epinephrine administration in pediatric out-of-hospital cardiac arrest in the United States.}, journal = {Resuscitation plus}, volume = {31}, number = {}, pages = {101454}, pmid = {42701529}, issn = {2666-5204}, abstract = {BACKGROUND: Pediatric out-of-hospital cardiac arrests (pOHCA) are low frequency, high acuity events for Emergency Medical Services (EMS). The survival rate is low, with only 10% of children surviving, and few survivors having favorable neurologic outcomes. Optimal prehospital management of pOHCA includes rapid epinephrine administration, yet factors contributing to its administration are not well understood.<br><br>OBJECTIVE: Our study objective was to evaluate the frequency of epinephrine administration in pOHCA. Our secondary objective was to characterize the demographic and clinical characteristics associated with epinephrine administration in pediatric OHCA in the United States.<br><br>METHODS: In this retrospective, observational study, we analyzed data from the National Emergency Medical Services Information System (NEMSIS) dataset for the year 2021. We identified pediatric patients ages &#x2265;1 day-old to <18&#xa0;years-old from "9-1-1" activations that were treated by advanced life support (ALS) clinicians. OHCA events were identified by performance of cardiopulmonary resuscitation (CPR) or defibrillation. We used descriptive statistics to evaluate the frequency of epinephrine administration and assess demographic and clinical characteristics in this population. Multivariable logistic regression model was utilized to find characteristics associated with epinephrine administration.<br><br>RESULTS: In 2021, 8495 pOHCA events (median [IQR] age: 3.0 [0.3-13.0] years; 58.5% males) were managed by an ALS unit in the United States. Two out of every five (40.2%) pOHCA events did not receive epinephrine. Epinephrine use was more common in younger age groups (1&#xa0;day-1&#xa0;year OR, 1.25 [95% CI, 1.07-1.46]; 1-5&#xa0;years OR, 1.19 [95% CI, 1.00-1.38]; 6-12&#xa0;years OR, 1.59 [95% CI, 1.24-1.79]; referent: 13-17&#xa0;years), urban population settings (OR, 2.06 [95% CI: 1.79-2.38]), incidents with scene time >10&#xa0;min (OR, 1.41, [95% CI, 1.25-1.60]), advanced airway attempt(OR 8.33, [95% CI, 7.33-9.47]), and in those receiving defibrillation (OR 1.95, [95% CI, 1.61-2.37]). Odds of epinephrine administration were lower in public settings (OR 0.55, [95% CI, 0.47-0.65]) and in females (OR 0.83, [95% CI, 0.73-0.93]).<br><br>CONCLUSION: Epinephrine is not given in 2 of every 5 pOHCA events. Longer scene time and additional resuscitation interventions were associated with epinephrine administration. The low rate of administration has implications for further research and reforms in the prehospital care of critically ill children.}, }
@article {pmid42701881, year = {2026}, author = {Zhu, Y and Zhang, Y and Yan, T and Li, Y and Du, H and Zhang, S and Zhang, T and Zhou, W}, title = {The Role of overdose Folic Acid in Promoting Neuroinflammation, Oxidative Stress, and Apoptosis in SOD1-G93A Mice.}, journal = {Free radical research}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/10715762.2026.2729677}, pmid = {42701881}, issn = {1029-2470}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that involves the targeted degeneration of motor neurons. The precise pathogenetic mechanisms are still largely unclear. In this study, we utilized the SOD1-G93A mouse model of ALS to investigate the effects of folic acid (FA), an important factor involved in homocysteine metabolism. Our results indicated that a little FA prolong the lifespan of the SOD1-G93A mice and medium and high dose FA significantly shortened the lifespan of the SOD1-G93A mice. Furthermore, we observed that overdose FA significantly elevated inflammation levels in the cerebellum, as evidenced by increased concentrations of tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Cluster of Differentiation 68 (CD68), Cluster of Differentiation 86 (CD86), and Monocyte Chemoattractant Protein-1 (MCP-1), facilitating microglial activation. The low dose FA were the opposite of the overdose FA. Additionally, high dose FA increased the levels of phosphorylated p65 (p-p65)/p65, thereby promoting the NF-κB signaling pathway. Conversely, high dose FA inhibited the expression of total superoxide dismutase (T-SOD) while increasing the level of malondialdehyde (MDA) in the cerebellum; these effects were not observed in muscle tissue. Moreover, high dose FA elevated the levels of Bax2/Bcl-2. Concurrently, high dose FA induced increased apoptosis in SOD1-G93A mice, as demonstrated by TUNEL staining. Notably, the brain iron content of SOD1-G93A mice remained unchanged following FA treatment. These findings provide evidence that overdose FA supplementation may exert pro-inflammatory effects by promoting the NF-κB pathway, oxidative stress, and apoptosis in the context of ALS.}, }
@article {pmid42701950, year = {2026}, author = {Morgillo, F and Digennaro, V and Panciera, A and Benvenuti, L and Carbone, N and Ferri, R and Zielli, SO and Faldini, C}, title = {Torsional deformities and anterior knee pain: a systematic review and clinical approach to miserable malalignment syndrome.}, journal = {Musculoskeletal surgery}, volume = {}, number = {}, pages = {}, pmid = {42701950}, issn = {2035-5114}, abstract = {Despite advancements in understanding and treating anterior knee pain linked to lower limb torsional deformities, a definitive consensus on diagnostic criteria, clinical indications, and therapeutic strategies for "miserable malalignment syndrome" remains elusive. This systematic review synthesizes current research to unify understanding of this complex condition. Findings highlight varied definitions and surgical approaches, underscoring standardization challenges. This systematic review aimed to synthesize current research to provide a more unified understanding of this complex condition. While studies report favorable anatomical correction and symptomatic relief, inconsistent clinical outcome scores and limited long-term follow-up hinder robust comparisons. Conservative measures are often ineffective due to underlying mechanical imbalance; surgical interventions, primarily derotational osteotomies of the femur and/or tibia, offer the most direct anatomical correction. However, optimal level, extent, and timing of these osteotomies-whether single or double level, staged or simultaneous-are debated. Liße et al.'s proposed diagnostic criteria offer a valuable step towards standardized identification of true miserable malalignment syndrome. Future research, particularly robust multi-center studies with standardized outcome measures, is critically needed to establish clearer, evidence-based guidelines, ultimately improving patient care and long-term outcomes for this challenging condition.}, }
@article {pmid42702895, year = {2026}, author = {Uysal, SP and Dudley, KA and Sullivan, S and Brizzi, KT and Burke, KM and Hall, S and Pease, K and Goldstein, JN and Berry, JD and Ho, DT}, title = {Emergencies in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70398}, pmid = {42702895}, issn = {1097-4598}, abstract = {Emergencies are frequent in people living with amyotrophic lateral sclerosis (pALS), especially as the disease progresses, and can necessitate urgent evaluation and intervention. Progressive weakness in ALS inevitably increases fall risk, making discussion of fall prevention strategies integral to caring for pALS. Thromboembolic events and respiratory failure may present insidiously in ALS, requiring a high index of clinical suspicion, and management strategies differ from those for individuals without ALS. Bulbar impairment in ALS can give rise to aspiration, laryngospasm, and malnutrition leading to emergency department (ED) visits, underscoring the need for early consideration of gastrostomy tube placement. PALS face an increased risk of serious infections, making vigilant monitoring for any acute change essential. Tracheostomy and gastrostomy, although life-sustaining measures in ALS, may require ED care when complications arise. Proactive assessment and management are critical to prevent complications related to constipation, urinary dysfunction, cognitive and behavioral issues. Although serious adverse events from ALS treatments are very rare, potential immune-mediated neurologic complications are a consideration with tofersen use. Importantly, ALS emergencies should be viewed as potential indicators of disease progression, prompting timely serious illness discussions and reassessment of goals of care. Anticipation of potential complications and emergencies, combined with an understanding of appropriate evaluation and evidence-based management, constitute critical components of caring for pALS. Early recognition and proactive management of these emergencies can improve safety, reduce avoidable hospitalizations, and support goal-concordant, patient-centered care.}, }
@article {pmid42703939, year = {2026}, author = {Sun, J and Vocht, J and Laroy, M and Stam, D and Lien, CH and Lamaire, N and D'Hondt, A and Peeters, R and Sunaert, S and Van Damme, P and Vandenbulcke, M and Van den Stock, J}, title = {Tracking Socio-emotional Brain Changes in Premanifest C9orf72 Repeat Expansion Carriers: A Structural and Functional 2-Year Longitudinal Magnetic Resonance Imaging Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78355}, pmid = {42703939}, issn = {1531-8249}, support = {//Foundation Thierry Latran/ ; //Alzheimer Research Foundation/ ; //Sequoia Fund for Research on Ageing and Mental Health/ ; 12AQF24N//FWO-Vlaanderen/ ; G0C0319N//FWO-Vlaanderen/ ; G030025N//FWO-Vlaanderen/ ; G019625N//FWO-Vlaanderen/ ; //KU Leuven,/ ; C24/18/095//KU Leuven Research Council/ ; C24/18/095; IDN/21/010//KU Leuven Research Council/ ; J1990130-233837//King Baudouin Foundation/ ; }, abstract = {OBJECTIVES: The C9orf72 hexanucleotide repeat expansion (C9RE) is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Although structural alterations have been reported decades before symptom onset, the longitudinal evolution of socioemotional network dysfunction in premanifest C9RE carriers remains poorly understood.<br><br>METHODS: In this multimodal 2-year longitudinal study, we examined 21 premanifest C9RE carriers and 24 controls using structural magnetic resonance imaging (MRI), resting-state, and task-based functional MRI (fMRI), and multivariate pattern analysis. Participants completed facial emotion processing tasks during fMRI scanning, alongside behavioral assessments. We assessed regional activation, network connectivity, and voxel-wise structural integrity at baseline and follow up.<br><br>RESULTS: At baseline, premanifest C9RE carriers showed reduced emotion recognition efficiency, accompanied by bilateral thalamic atrophy, decreased activation in the anterior and posterior cingulate cortex, and increased activation in the posterior cerebellum, along with altered multivoxel activity patterns in the anterior cingulate and posterior cerebellum. Resting-state fMRI revealed decreased functional connectivity involving the thalamus, anterior, and posterior cingulate cortex. Longitudinal analyses indicated declining emotion-evoked responses in the posterior cingulate cortex and cerebellum, alongside further thalamic volume loss, whereas functional connectivity showed no significant change over time. Despite these progressive neural alterations, behavioral performance remained stable.<br><br>INTERPRETATION: Socioemotional circuit dysfunction emerges early in C9RE carriers and progresses over time, preceding overt clinical symptoms. Functional imaging, especially task-based fMRI combined with multivariate pattern analysis, captures early circuit-level alterations that may serve as sensitive biomarkers for premanifest neurodegeneration. ANN NEUROL 2026.}, }
@article {pmid42704422, year = {2026}, author = {Demir, BS and Cicek, SO and Houran, MA and Azizoglu, ZB and Asan, M and Bas, H and Cetin, BS and Gumus, H and Erdem, S and Canatan, H and Unal, E and Hsieh, EW and Kısaarslan, AP and Eken, A}, title = {Clinical and immunological characterization of a child with a homozygous TBK1 kinase-domain truncation.}, journal = {Immunologic research}, volume = {74}, number = {1}, pages = {}, pmid = {42704422}, issn = {1559-0755}, support = {TSG-2023-10935 and TYG-2023-13110//Erciyes University Research Council (BAP Grants)/ ; }, mesh = {Humans ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Homozygote ; *Arthritis, Juvenile/genetics/immunology/diagnosis ; *Encephalitis/genetics/immunology ; Cytokines/metabolism ; Mutation/genetics ; Phosphorylation ; Female ; Male ; Child ; }, abstract = {TBK1 is a serine-tyrosine kinase protein that transmits signals from pattern recognition receptors to the NF-κB pathway leading to production of Type 1 Interferons. Mutations in this protein have been associated with arthritis, vasculitis, herpes simplex encephalitis and amyotrophic lateral sclerosis. In the current study, we characterized the functional consequences of a TBK1-variant bearing a truncation in exon 4 and 5 in a patient with poly arthritis resembling juvenile idiopathic arthritis and necrotizing encephalitis. The truncation was associated with reduced TBK1 protein abundance and altered phosphorylation. The variant was associated with increased basal/and or Poly-I: C induced IL-6, TNFα, IL-1β and IL-18 and type 1 Interferon ex vivo. Our findings expand the phenotypic spectrum of TBK1 loss-of-function variants and may provide insight into the management of immune dysregulation in affected patients.}, }
@article {pmid42705614, year = {2026}, author = {Fritsch, J and Wiesner, S and Guthmann, F and Richter, MF}, title = {[Pulmonale Hämorrhagie bei Frühgeborenen &lt;1000 g (ELBW): Risikofaktoren und präventive Maßnahmen als Reaktion auf eine gestiegene Inzidenz].}, journal = {Klinische Padiatrie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2954-5687}, pmid = {42705614}, issn = {1439-3824}, }
@article {pmid42705992, year = {2026}, author = {Nie, W and Jing, Z and Cheng, L and Li, LL and Bai, Y and Xu, F and Li, S and Lin, L and Dong, X and Yu, L and Cai, L and Pan, B and Han, H and Cheng, H and Wang, X}, title = {ROMO1 loss in cholinergic neurons induces mitochondrial ultrastructural damage and ALS-like neuromuscular degeneration.}, journal = {Science bulletin}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.scib.2026.08.063}, pmid = {42705992}, issn = {2095-9281}, }
@article {pmid42706741, year = {2026}, author = {Grouls, A and Ubel, PA and Nguyen, M and Pathapati, N and Doerstling, S and Sloan, CE}, title = {Online Crowdfunding Campaigns for People Living With ALS Demonstrate Financial Burden and Unmet Needs.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70395}, pmid = {42706741}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: People living with amyotrophic lateral sclerosis (ALS; pALS) have extensive care needs, from wheelchairs to feeding tubes to caregiving support. The financial impact of these needs on pALS and their caregivers (cALS) has not been fully explored. We aimed to explore the types of expenses for which pALS and cALS crowdfund, and the financial circumstances that lead them to resort to crowdfunding.<br><br>METHODS: We randomly selected 320 ALS-related crowdfunding campaigns posted on the GoFundMe platform from 2010-2020. We conducted a summative content analysis to categorize the expenses for which campaigns requested money and descriptions of financial burden.<br><br>RESULTS: We included 266 campaigns. Most campaigns were written by people who were not the pALS or cALS, such as children or coworkers (85.3%). Most campaigns fundraised for medication and treatment costs (21.4%), equipment (25.2%), accessibility needs for home (24.0%), and transportation (19.5%), and in-home caregiving services (18%). Multiple campaigns (22.9%) requested assistance with nonmedical expenses ranging from rent and utilities to personal travel and hobby goals. Many campaign writers (47.7%) described financial burden related to the pALS' diagnosis, including medical debt (4.5%) and job loss of the pALS (30.5%) and/or cALS (6.8%).<br><br>DISCUSSION: Our analysis of ALS-related crowdfunding campaigns highlights the breadth of medical and nonmedical care needs and quality of life goals for which people request additional financial support throughout the disease course. These findings provide important insights for ALS care teams into the expenses of pALS.}, }
@article {pmid42694829, year = {2026}, author = {Chowdhury, S and Pramanik, S and Bhattacharjee, S and Billah, M}, title = {ALSGate: An Efficient Gated Mixture-of-Experts Model for Reliable ALS Detection Using EMG Signals.}, journal = {Healthcare technology letters}, volume = {13}, number = {1}, pages = {e70097}, pmid = {42694829}, issn = {2053-3713}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, resulting in neuromuscular weakness and paralysis. Electromyography (EMG) is of vital importance for the detection of ALS. In this paper, a refined mixture of experts is proposed that automatically discriminates ALS patients from non-ALS cases using clinical EMG signals from the N2001 EMGLAB open-access dataset. The architecture consists of a 1D convolutional neural network, a temporal convolutional network and a spectrogram-based CNN to collectively learn localised temporal, long-range temporal and spectral features from EMG activity. A gating mechanism dynamically weights expert contributions and performs significantly better than equal-weight fusion. Training with focal loss and exponential moving average stabilisation addresses class imbalance and improves convergence. The proposed approach reached an AUROC of 0.9992, an F1-score of 0.9903 and a balanced accuracy of 0.9905, demonstrating strong discriminative performance and potential for real-time clinical applications.}, }
@article {pmid42696048, year = {2026}, author = {de Bertier, S and Amador, MD and Guissart, C and Miki, T and Boillée, S and Lobsiger, CS and Bohl, D and Fauret-Amsellem, AL and Bohic, A and ,  and Giguet-Valard, AG and Bellance, R and Beauvais, K and Meininger, V and Bruneteau, G and Salachas, F and Vial, C and Camu, W and Esselin, F and de la Cruz, E and Bernard, E and Seilhean, D and Millecamps, S}, title = {Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42696048}, issn = {1432-0533}, support = {EQU202103012581//Fondation Recherche M&#xe9;dicale (FRM, France)/ ; #19466//Association Fran&#xe7;aise contre les Myopathies (AFM, France)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; France ; Female ; Male ; Middle Aged ; Cohort Studies ; Aged ; Adult ; DNA-Binding Proteins/metabolism ; *Genetic Predisposition to Disease ; Mutation/genetics ; Animals ; Brain/pathology ; }, abstract = {ARPP21 has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 ARPP21-linked patients. ARPP21 emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7% of familial cases (fALS) and 0.1% of sporadic cases. Age-dependent penetrance reached 45% by age 50 and increased only modestly thereafter, remaining incomplete even at advanced ages. In cellular models, the p.P713L mutant showed aggregation associated with protein hyperphosphorylation and colocalization with the autophagic marker p62. Neuropathological examination of tissue from a p.P529L carrier revealed typical cytoplasmic TDP-43 pathology, together with heterogeneous ARPP21-positive deposits. As ARPP21 antibody also stained granulovacuolar degenerations, ARPP21-positive deposits may reflect neuronal stress rather than mutant ARPP21-specific pathology. Nevertheless, together with previous studies, our findings support ARPP21 as an important ALS-associated gene, and indicate that both p.P529L/p.P563L and p.P713L/p.P747L should be considered pathogenic ALS-causing variants. Incorporating ARPP21 into the routine genetic testing panels for fALS could improve diagnostic yield.}, }
@article {pmid42696637, year = {2026}, author = {Guarino, AS and Wallace, J and Rohan, AM and Kroelinger, CD}, title = {Implementation Outcomes of 36 CDC-funded Statewide Perinatal Quality Collaboratives, 2023-2024.}, journal = {Journal of public health management and practice : JPHMP}, volume = {}, number = {}, pages = {}, pmid = {42696637}, issn = {1550-5022}, abstract = {CONTEXT: Maternal and infant morbidity and mortality remain high in the United States, and improving quality of clinical care is one strategy to improve outcomes. Perinatal Quality Collaboratives (PQCs) are statewide networks of teams working to improve maternal and infant health by supporting quality improvement (QI) initiatives. PQCs execute deliberate activities to support implementation of QI; implementation outcomes can be used to measure the execution of these activities.<br><br>OBJECTIVE: To examine PQC implementation outcomes to better understand implementation achievements.<br><br>DESIGN: We adapted Proctor et al.'s implementation outcomes framework to measure implementation outcomes using standardized annual PQC performance measures.<br><br>SETTING: US, October 2023 through September 2024.<br><br>PARTICIPANTS: Thirty-six Centers for Disease Control and Prevention-supported PQCs.<br><br>INTERVENTION: Developed implementation outcome definitions relevant for the standard PQC programmatic model and mapped outcomes to performance measures, assessing the execution of PQC activities. Descriptive PQC-reported data were summarized as counts and percentages.<br><br>MAIN OUTCOME MEASURE: Implementation outcomes (adoption, appropriateness, feasibility, fidelity, penetration, and sustainability).<br><br>RESULTS: PQCs reported moderate adoption, with an average of 67% of births in a state occurring in birthing hospitals that participated in PQC QI initiatives. PQCs also reported moderate appropriateness; among birthing hospitals serving populations most likely to experience adverse health outcomes, 67% participated with their PQC. An average of 85% of participating birthing hospitals submitted data to their PQC as required for QI initiatives (feasibility), and PQCs averaged 75% or higher on all fidelity measures (trainings, webinars, learning products, and convenings). For penetration, fewer than 50% of PQCs engaged in activities with community-based organizations, although 56% engaged with community members and 83% with patients/families. Most (78%) participating hospitals made lasting system changes (sustainability).<br><br>CONCLUSIONS: Findings suggest that PQCs implement QI initiatives with high feasibility, fidelity, and sustainability, moderate adoption and appropriateness, and varied penetration. Understanding PQC implementation outcomes can highlight areas of success and identify areas for PQC improvement.}, }
@article {pmid42697152, year = {2026}, author = {Fernández-Beltrán, LC and García-Toledo, I and Javaloyes García, K and Jiménez-Coca, I and Jiménez-Rodríguez, J and Fernández-Bernal, A and Godoy-Corchuelo, JM and Portero-Otín, M and Corrochano, S}, title = {Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1[G93A] mouse model of ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01062}, doi = {10.1016/j.neurot.2026.e01062}, pmid = {42697152}, issn = {1878-7479}, abstract = {Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1[G93A] mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.}, }
@article {pmid42697153, year = {2026}, author = {Lo'pez-Blanch, R and Salvador-Palmer, R and Oriol-Caballo, M and Moreno-Murciano, P and Dellinger, RW and Estrela, JM and Obrador, E}, title = {Corrigendum to 'Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice'.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01070}, doi = {10.1016/j.neurot.2026.e01070}, pmid = {42697153}, issn = {1878-7479}, }
@article {pmid42697379, year = {2026}, author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS}, title = {Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {116455}, doi = {10.1016/j.bbr.2026.116455}, pmid = {42697379}, issn = {1872-7549}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.}, }
@article {pmid42697520, year = {2026}, author = {Sharma, A and Jatana, N}, title = {Microbiota-derived metabolite-GPCR signalling in neurodegeneration.}, journal = {Neuroscience}, volume = {615}, number = {}, pages = {312-333}, doi = {10.1016/j.neuroscience.2026.09.001}, pmid = {42697520}, issn = {1873-7544}, abstract = {The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling pathways. There is growing evidence that metabolic alterations associated with dysbiosis contribute to the onset and progression of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In this context, G protein-coupled receptors (GPCRs) act as essential molecular transducers that link microbial metabolites to intracellular signalling networks. Aberrant GPCR activation, driven by altered metabolite profiles, modulates key downstream pathways including cAMP, MAPK, PI3K/Akt, NF-κB and Ca2 + signalling. This promotes neuroinflammation, oxidative stress, mitochondrial dysfunction and pathological protein aggregation - hallmark processes underlying neurodegeneration. By identifying convergent and disease-specific signalling pathways, the review highlights mechanistic nodes of therapeutic relevance and discusses GPCR-centric emerging and other microbiome-targeted strategies aimed at restoring metabolic and signalling homeostasis in neurodegenerative disorders.}, }
@article {pmid42697669, year = {2026}, author = {Zhang, P and Liu, Y and Tian, X and Wang, H and Liu, R and Wang, G and Wu, Y}, title = {Overexpression of the cytochrome P450 gene CYP99A3 likely mediates mesosulfuron-methyl resistance in Lolium multiflorum from China.}, journal = {Pesticide biochemistry and physiology}, volume = {223}, number = {}, pages = {107300}, doi = {10.1016/j.pestbp.2026.107300}, pmid = {42697669}, issn = {1095-9939}, mesh = {*Lolium/genetics/drug effects/enzymology/metabolism ; *Sulfonylurea Compounds/pharmacology ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; China ; *Plant Proteins/genetics/metabolism ; Acetolactate Synthase/genetics ; }, abstract = {Lolium multiflorum L. (Italian ryegrass) is a noxious weed causing severe yield losses in wheat production globally, and its rapid expansion across major wheat-producing regions in China poses an escalating agricultural threat. Recently, field-recommended doses of the acetolactate synthase (ALS) inhibitor mesosulfuron-methyl have failed to effectively control certain L. multiflorum populations. This study evaluated the resistance level and elucidated the underlying mechanisms in a suspected mesosulfuron-methyl-resistant L. multiflorum population (ZMHF-R) collected from China. Whole-plant bioassays demonstrated that the ZMHF-R population exhibited a high level of resistance (43.34-fold) to mesosulfuron-methyl. Replicate sequencing of the ALS gene revealed no known target-site mutations, thereby excluding target-site mutation-mediated resistance. Pretreatment with the cytochrome P450 inhibitors piperonyl butoxide (PBO) and malathion significantly synergized mesosulfuron-methyl toxicity in ZMHF-R, implicating P450 monooxygenases in the resistance phenotype. Comparative RNA-seq and RT-qPCR validation identified the constitutive overexpression of a specific P450 gene, LmCYP99A3, in the R population. Molecular docking simulations predicted favorable binding and potential metabolic activity of the LmCYP99A3 protein toward mesosulfuron-methyl. Furthermore, transgenic rice calli heterologously overexpressing LmCYP99A3 exhibited a distinct resistance phenotype against the herbicide. Taken together, this study functionally validates that LmCYP99A3 mediates mesosulfuron-methyl resistance in L. multiflorum, expanding our understanding of the metabolic basis of NTSR in this global weed species.}, }
@article {pmid42698124, year = {2026}, author = {Streicher, NS}, title = {Serum Neurofilament Light Chain and GFAP in Amyotrophic Lateral Sclerosis on a Commercial ECLIA Platform.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70397}, pmid = {42698124}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), SIMOA-based studies show that baseline serum neurofilament light chain (NfL) predicts the revised ALS Functional Rating Scale (ALSFRS-R) decline rate and survival. The Roche Elecsys electrochemiluminescence immunoassay (ECLIA) reports values approximately six-fold lower; cross-platform comparison confirms comparable performance, but serial clinical-practice data remain limited. We assessed whether ECLIA NfL correlates with the ALSFRS-R decline rate under the sampling conditions of clinical practice, and whether GFAP or S-100B adds prognostic or disease-specific information.<br><br>METHODS: We retrospectively analyzed 58 patients with medical-record-confirmed ALS at an academic center (2022-2026). Serum NfL, GFAP, and S-100B were measured on the Roche Elecsys ECLIA. The NfL-ALSFRS-R correlation was assessed within matching windows; serial NfL was examined in patients with repeat draws.<br><br>RESULTS: First-per-patient NfL median was 7.06&#x2009;pg/mL (IQR 4.06-17.30). NfL correlated strongly with the ALSFRS-R decline&#xa0;rate (Spearman r&#x2009;=&#x2009;0.704, n&#x2009;=&#x2009;31; r&#x2009;=&#x2009;0.809 within 90&#x2009;days, n&#x2009;=&#x2009;17; both p&#x2009;<&#x2009;0.0001). Fast progressors had 3.7-fold&#xa0;higher&#xa0;mean NfL than slow progressors (17.10 vs. 4.64&#x2009;pg/mL). NfL showed no correlation with King's clinical stage (r&#x2009;=&#x2009;0.00). GFAP correlated with age but not with progression rate or disease duration; S-100B showed no association with progression.<br><br>DISCUSSION: Serum NfL on a commercial ECLIA platform retained its strong correlation with progression rate despite unstructured sampling, replicating SIMOA-based findings at platform-specific values. NfL tracked the rate of decline rather than the accumulated disease state; GFAP and S-100B added no prognostic or disease-specific information.}, }
@article {pmid42698179, year = {2026}, author = {Dhar, A and Sharar, AD and Papisetty, S and Bydon, M and Moinuddin, FM}, title = {The Therapeutic Potential of Purmorphamine Across Disease Models.}, journal = {Journal of cellular and molecular medicine}, volume = {30}, number = {17}, pages = {e71349}, pmid = {42698179}, issn = {1582-4934}, mesh = {Humans ; Animals ; *Purines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Hedgehog Proteins/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Morpholines ; }, abstract = {Purmorphamine (PUR) is a trisubstituted purine compound that selectively activates Smoothened receptor, thereby initiating Sonic Hedgehog (Shh) signalling-a pathway critical for embryonic patterning, neuronal specification and tissue regeneration across multiple organ systems. Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI-mediated transcription and non-canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood-brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.}, }
@article {pmid42698276, year = {2026}, author = {Strong, MJ and Donison, N and Al-Chalabi, A and Boeve, B and Finger, EC and Holstege, H and Huey, ED and Lee, EB and Marzi, SJ and McHutchison, C and McMillan, CT and Otto, M and Petrucelli, L and Prudencio, M and Simuni, T and Tartaglia, MC and Turner, MR and Van Damme, P and Wolk, DA}, title = {Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag297}, pmid = {42698276}, issn = {1460-2156}, abstract = {Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.}, }
@article {pmid42698373, year = {2026}, author = {Pan, L and Hou, C and Seitz, C and Ingre, C and Hedman, &#xc5;K and Laffita, J and Vu, TN and Pawitan, Y and Ullgren, A and Yazdani, S and Andersson, J and Joyce, EE and Chourpiliadis, C and Lovik, A and Chen, Y and Lewandowski, SA and Fernandez-Capetillo, O and Barz, M and Samuelsson, K and Press, R and Piehl, F and Graff, C and Mälarstig, A and Fang, F}, title = {Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70741}, pmid = {42698373}, issn = {1468-1331}, support = {223077//&#xc5;hlen Stiftelse/ ; //Bjorklunds fund/ ; MegaALS, 802091//H2020 European Research Council/ ; //Bruno and Ilse Frick Foundation for Research on ALS/ ; FO2022-0233//Hj&#xe4;rnfonden/ ; 2021-01276//Karolinska Institutet/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; F2021-0116//Neuro Sweden/ ; 2023-02428//Swedish Research Council/ ; 2021-02605//Swedish Research Council/ ; FIB-ALS//Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; *Biomarkers/blood/cerebrospinal fluid ; Female ; Prognosis ; Male ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Plasma and cerebrospinal fluid (CSF) protein biomarkers in amyotrophic lateral sclerosis (ALS) may provide insight into disease mechanisms and yield clinically useful biomarkers.<br><br>METHODS: Overall, 363 proteins in plasma and CSF from 198 patients with ALS and 125 matched controls were profiled using Olink assays. Associations with disease status, survival, and functional decline, as well as longitudinal biomarker stability across the disease course were assessed, together with network and enrichment analyses. ALS risk-associated biomarkers were externally validated in the UK Biobank (UKB).<br><br>RESULTS: Overall, 125 proteins were significantly associated with at least one outcome (i.e., case status, risk, survival, or functional decline), and 21 were associated with three or more outcomes. NEFL was the most robust biomarker in plasma and CSF, alongside TNFRSF12A in plasma and CSF, EDA2R in plasma, and FABP4 in plasma and CSF. Most biomarkers remained stable longitudinally across the disease course. ALS risk-associated biomarkers were replicated in UKB, in which >&#x2009;3000 plasma proteins were measured in 52,990 participants, including 298 with ALS. Network and enrichment analyses highlighted their roles in immune response and extracellular-matrix remodeling, and their enrichments in the brain and T-cell subsets. Construction of an ALS risk-prediction model achieved an ROC-AUC of 0.72 in the UKB validation cohort.<br><br>CONCLUSIONS: These findings suggest candidate protein biomarkers for ALS risk stratification, early detection, and clinical therapeutic monitoring.}, }
@article {pmid42699326, year = {2026}, author = {Wang, J and Kissling, WD}, title = {LiDAR-derived dataset of extracted trees and shrubs from AHN4 airborne laser scanning in the Oostvaardersplassen wetland, the Netherlands.}, journal = {Data in brief}, volume = {68}, number = {}, pages = {113169}, pmid = {42699326}, issn = {2352-3409}, abstract = {This article describes a geospatial dataset of trees and shrubs extracted from the fourth Dutch national airborne laser scanning (ALS) survey (AHN4) covering the Oostvaardersplassen wetland in the Netherlands. The dataset was generated in the context of the MAMBO project, which focuses on automated workflows for deriving habitat condition metrics from LiDAR data for European habitat monitoring. The input data consist of nationally acquired AHN4 point clouds (2020-2022). A dedicated processing workflow was applied to classify and extract woody vegetation points in marsh and reedbed environments, where trees and shrubs co-occur with dense herbaceous vegetation. The workflow includes (i) pre-processing and segmentation of vegetation points, (ii) clustering of tree and shrub points using neighbourhood analysis and voxel-based aggregation, and (iii) delineation of individual woody elements through seed detection and connectivity analysis in three-dimensional space. Accuracy assessments were conducted using manually created ground truth datasets derived from ALS point clouds and by referencing 8 cm resolution aerial imagery for selected validation plots and patches. The dataset includes classified ALS point clouds (LAZ), extracted tree and shrub point clouds (LAZ), derived raster products (GeoTIFF), vector boundary files (ESRI Shapefile), processing scripts, and documentation. The dataset and associated processing workflow, source code, and metadata are publicly available through Zenodo, GitHub, and the LifeWatch Metadata Catalogue. The dataset can be reused for applications such as habitat structure mapping, woody vegetation monitoring in wetlands, LiDAR-based workflow benchmarking, training and validation of classification algorithms, and upscaling of tree extraction approaches to other airborne laser scanning datasets.}, }
@article {pmid42701411, year = {2026}, author = {Gonzo, P and Dunkl, S and Gatterbauer, M and Heider, S and Girsa, M and Krammel, M and Schnaubelt, S}, title = {Structured Evaluation and Treatment of cardiac arrest via the ABCDE approach (SETA) - Rethinking high-performance CPR and cause-finding during Advanced Life Support.}, journal = {Resuscitation plus}, volume = {31}, number = {}, pages = {101458}, pmid = {42701411}, issn = {2666-5204}, abstract = {The European Resuscitation Council (ERC) Guidelines 2025 continue to summarize the causes of cardiac arrest that should be sought during advanced life support (ALS) as "4Hs and 4Ts". While well established, this list-based mnemonic does not map onto the airway-breathing-circulation-disability-exposure (ABCDE) sequence that emergency teams use for every other patient assessment, and it excludes causes that are clinically treatable but not classically "reversible" in the prehospital phase. We present SETA (Structured Evaluation and Treatment of cardiac arrest via the ABCDE approach), a concept developed within the Emergency Medical Service Vienna that restructures both cause-finding during cardiopulmonary resuscitation (CPR) and evaluation of high-performance CPR around the ABCDE sequence, embeds protocol-linked actions at each step, and is designed to run within ongoing chest compressions without interrupting them. We outline its rationale, its relationship to existing pit-crew and ABCDE-based resuscitation models, and the prospective evaluation now needed before considered for wider use.}, }
@article {pmid42693185, year = {2026}, author = {Dalakas, MC and Lünemann, JD}, title = {Role of complement and complement-targeted therapeutics in neurological diseases.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42693185}, issn = {1759-4766}, abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.}, }
@article {pmid42693862, year = {2026}, author = {Ardakani, RH and Dashtaki, M and Mohamadi-Zarch, SM and Bagheri, SM}, title = {Cortisol Dysregulation as a Major Factor in the Development of Neurodegenerative Diseases, Drug Targets and Therapeutic Prospects: A Comprehensive Review.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273466502260813092749}, pmid = {42693862}, issn = {1996-3181}, abstract = {Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is critical for stress response, metabolism, and immune function. Its dysregulation is increasingly implicated in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). This review synthesizes evidence on cortisol's role in neurodegenerative disorders, exploring its mechanisms, clinical implications, and therapeutic potential. This study analyzed preclinical models, clinical studies, and biomarker data to elucidate cortisol's impact on neurodegeneration. Key mechanisms include glucocorticoid and mineralocorticoid receptor-mediated effects on synaptic plasticity, neuroinflammation, and oxidative stress. In AD, elevated cortisol accelerates cognitive decline, hippocampal atrophy, and amyloid-β accumulation. In PD, higher cortisol levels correlate with gait dysfunction and dopaminergic neuron loss. HD shows variable cortisol profiles, with early hypocortisolism shifting to hypercortisolism in later stages, linked to depression. In ALS, elevated cortisol hastens disease progression and neuroinflammation. In MS, HPA axis hyperactivity is associated with cognitive deficits and lesion activity, though it may support remyelination. Chronic stress exacerbates these effects across disorders, promoting neuronal vulnerability. Cortisol dysregulation is a significant contributor to neurodegenerative pathology, acting as both a biomarker and therapeutic target. Emerging interventions, including glucocorticoid receptor antagonists, cortisol synthesis inhibitors, and stress reduction strategies, show promise in mitigating neuronal damage. Personalized, stage-specific therapies and longitudinal studies are needed to optimize cortisol-targeted treatments for neurodegenerative diseases.}, }
@article {pmid42694267, year = {2026}, author = {Heffernan, &#xc1;B and Do, F and Carter, E and Al-Tameemi, F and Selvaraj, BT and Stavrou, M}, title = {Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1899307}, pmid = {42694267}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive loss of motor neurons. In addition to neurodegeneration, ALS is increasingly recognised as a disorder associated with widespread metabolic dysfunction, including hypermetabolism, weight loss, and dyslipidaemia, all of which correlate with disease progression and survival. Astrocytes play a central role in maintaining metabolic homeostasis in the central nervous system by supporting neuronal energy demands, regulating glutamate levels, buffering oxidative stress, and maintaining lipid balance. Emerging evidence suggests that disruption of these supportive astrocytic functions may contribute directly to motor neuron vulnerability in ALS. In this mini-review, we discuss how alterations in astrocyte metabolism may impair astrocyte-neuron metabolic coupling in ALS. We summarise work from human studies and experimental models demonstrating abnormalities in astrocytic glycolysis, mitochondrial function, lactate shuttling, lipid metabolism, and glutamate homeostasis. We highlight growing evidence implicating mitochondrial dysfunction and impaired lipid handling in astrocytes as important contributors to disease progression. We explore how these changes may deprive motor neurons of metabolic and antioxidant support while also promoting excitotoxicity, oxidative stress, and lipotoxicity. We also discuss how recent advances in human induced pluripotent stem cell models, metabolomics, and single-cell transcriptomics are improving our understanding of astrocyte dysfunction in ALS. Finally, we consider current and emerging therapeutic strategies aimed at restoring astrocytic metabolic function. Together, these findings support the idea that progressive failure of astrocyte-mediated metabolic support is an important component of ALS pathogenesis and may represent a promising therapeutic target.}, }
@article {pmid42694478, year = {2026}, author = {Cui, Q and Zheng, K and Liu, Q and Wang, L and Liu, Y and Bai, R and Zhang, W and Guo, J and Chang, X and Wang, J}, title = {From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1921079}, pmid = {42694478}, issn = {1662-5099}, abstract = {Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.}, }
@article {pmid42694654, year = {2026}, author = {Wu, Y and Duan, L and Zhang, L and Wang, S and Yan, H and He, M and Wang, T and Li, L and Gao, Y}, title = {TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1912989}, pmid = {42694654}, issn = {1664-3224}, mesh = {Humans ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Central Nervous System Diseases/metabolism/immunology/therapy ; Signal Transduction ; *Neuroimmunomodulation ; }, abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched immunoreceptor that functions as a central regulator of microglial adaptation by integrating immune surveillance, lipid sensing, metabolic reprogramming, and phagocytic responses in the central nervous system (CNS). Through association with the adaptor protein DAP12, TREM2 activates interconnected signaling networks involving the SYK pathway, PLCγ2-mediated Ca[2+] signaling, PI3K-AKT-mTOR signaling, NF-κB activation and inflammatory regulatory pathways, thereby shaping microglial survival, migration, clearance capacity, and interactions with surrounding neural and immune cells. Increasing evidence from genetic studies, single-cell transcriptomics, spatial analyses, and human-derived microglial models indicates that TREM2 dysfunction contributes to diverse CNS disorders; however, its biological consequences are highly dependent on disease stage, pathological substrate, cellular context, and microenvironmental cues. In Alzheimer's disease, TREM2 regulates amyloid-β-associated microglial responses, lipid metabolism, and synaptic remodeling, while its effects on tau-driven neurodegeneration remain controversial. In Parkinson's disease, stroke, epilepsy, and amyotrophic lateral sclerosis, TREM2 influences α-Syn clearance, inflammatory resolution, tissue repair, and microglial state transitions, but may exert beneficial or maladaptive effects depending on temporal dynamics and disease-specific stressors. Emerging clinical evidence, including TREM2 variants, soluble TREM2 (sTREM2) biomarkers, and human multi-omics studies, highlights both the translational potential and complexity of targeting this pathway. Herein, this review summarizes the molecular mechanisms, physiological functions, and disease-specific roles of TREM2 in CNS disorders, critically discusses unresolved controversies and species-specific challenges, and evaluates emerging therapeutic strategies toward biomarker-guided and stage-specific modulation of TREM2 signaling. Understanding how to restore appropriate microglial adaptability rather than simply enhance or suppress TREM2 activity may provide a foundation for precision therapies in CNS disorders.}, }
@article {pmid42689185, year = {2026}, author = {Sun, L and Yu, X and Yin, H and Bi, J and Lou, H and Pei, H}, title = {A recent review on ginseng's effects on neurodegenerative diseases: active ingredients, mechanisms of action, applications, and delivery strategies.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1912520}, pmid = {42689185}, issn = {2296-861X}, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose a major health challenge due to their high prevalence and the lack of effective treatments; ginseng, as medicine and food homology, has potential neuroprotective effects.<br><br>METHODS: This article provides a systematic review of research conducted over the past five years on the use of ginseng to treat NDDs, summarizing and analyzing the findings in four key areas: active components, mechanisms of action, clinical applications, and novel delivery strategies.<br><br>RESULTS: Ginsenosides are the core active ingredients in ginseng, while polysaccharides, essential oils, and peptides also exert synergistic effects through various pathways; their mechanisms of action include regulating A&#x3b2;/tau protein aggregation, inhibiting microglial activation, reducing glutamate excitotoxicity, and restoring mitochondrial function and antioxidant balance. In models of AD, PD, HD, and ALS, ginseng's active components have been shown to improve both behavioral and pathological indicators, while novel delivery strategies (nanoparticles, exosomes, and engineered cellular carriers) can significantly enhance blood-brain barrier permeability and brain-targeting efficiency.<br><br>CONCLUSION: Ginseng exhibits protective effects against NDDs through multiple mechanisms of action. However, current evidence is largely limited to preclinical studies, and future efforts should focus on advancing the clinical translation of safe and effective brain-targeted delivery systems.}, }
@article {pmid42690718, year = {2026}, author = {Nam, MK and Oh, Y and Choi, Y and Lee, J and Jeong, GH and Park, S and Yoo, SA and Kim, M and Kang, S and Rhim, H}, title = {Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {17}, pages = {3156-3168}, doi = {10.1021/acschemneuro.5c00977}, pmid = {42690718}, issn = {1948-7193}, support = {RS-2022-NR070495//National Research Foundation of Korea/ ; RS-2026-25504267//National Research Foundation of Korea/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Animals ; Mutation ; *Superoxide Dismutase/metabolism/genetics ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, with familial ALS (fALS) frequently caused by mutations in Cu/Zn superoxide dismutase (SOD1). The G93A mutation, one of the most aggressive forms, promotes the formation of cytotoxic protein aggregates through cross-β-sheet structures, leading to neuronal dysfunction and death. In this study, we investigated the therapeutic potential of NABi (natural Aβ binder and Aβ-aggregation inhibitor), a stable small engineered protein composed of the N-terminal 90 amino acids of SOD1, originally developed to target amyloid-β aggregation in Alzheimer's disease. Given the shared β-sheet-rich aggregation mechanisms between amyloid-β and mutant SOD1 proteins, we hypothesized that NABi could serve as a dual-action therapeutic for both diseases. Through an integrated approach involving structural, biochemical, and cellular analyses, we demonstrate that NABi exhibits a 4-fold greater binding affinity for SOD1G93A compared to SOD1WT, selectively targeting the mutant protein via specific hydrophobic interactions. Structural modeling using AlphaFold2 reveals that the G93A mutation exposes hydrophobic residues that create an optimal binding interface for NABi. Functionally, NABi effectively inhibits SOD1G93A aggregation, as demonstrated by filter trap assays and immunofluorescence microscopy, while maintaining the protein in a soluble, nontoxic state. Importantly, coexpression of NABi reduces SOD1G93A-induced cytotoxicity by approximately 4-fold, significantly enhancing neuronal survival. These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function. Our results support the development of NABi as an innovative pan-therapeutic approach targeting shared aggregation pathways across multiple neurodegenerative diseases.}, }
@article {pmid42691260, year = {2026}, author = {Aguirre-Urreta, M and Yamini, R and Rönkkö, M}, title = {Can formative latent variables represent psychological concepts? Replication and extension of MacKenzie et al. (2005).}, journal = {The Journal of applied psychology}, volume = {}, number = {}, pages = {}, doi = {10.1037/apl0001415}, pmid = {42691260}, issn = {1939-1854}, support = {//Research Council of Finland/ ; }, abstract = {We revisit MacKenzie et al.'s (2005) influential work on bias in path estimates arising from the misspecification of formative latent variable models as reflective ones. Using simulations, we demonstrate that the bias in unstandardized path coefficients reported by MacKenzie et al. is due to scaling differences rather than model misspecification. When these differences are taken into account, the bias nearly disappears. Building on their work, we also demonstrate that the formative indicators in their model are unnecessary. This is because the formative latent variables derive their identity from the reflective indicators added for model identification. Removing one or even all formative indicators is inconsequential for estimating the paths between latent variables. Our study reveals a fundamental problem with this approach: Formative latent variables (whether first or higher order) cannot represent psychological concepts as intended because their identity derives from downstream reflective indicators rather than the formative indicators. We conclude by discussing the implications for measurement and index construction. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42691539, year = {2026}, author = {Hsu, EC and Carder, P and Smith, L and Zhou, ZE and Yakusheva, O and Beeber, A and Jutkowitz, E and Thomas, KS}, title = {A Profile of Assisted Living Direct Care Workforce Training Requirements Across the United States.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {10}, pages = {106445}, doi = {10.1016/j.jamda.2026.106445}, pmid = {42691539}, issn = {1538-9375}, abstract = {OBJECTIVES: To characterize assisted living (AL) direct care worker (DCW) training requirements across the United States and how these regulations have changed over time. Specifically, we examine state-level profiles of training regulations, including duration, frequency, content, source of materials, evaluation, and changes in regulatory coverage.<br><br>DESIGN: Cross-sectional and longitudinal descriptive study using state policy data and AL directories from 2019, 2021, and 2023.<br><br>SETTING AND PARTICIPANTS: All US states' AL training-related regulations; all ALs and AL beds governed by those regulations.<br><br>METHODS: We used a mixed-methods approach with an explanatory sequential design (QUAN &#x2192; qual), first conducting health services regulatory analysis followed by qualitative content analysis.<br><br>RESULTS: In 2023, 43 states (90% of ALs, nationally) required DCW training, 29 states required annual training frequency, 28 states specified training hours (median 10 hours), 28 required dementia-specific content, and 29 required training to cover at least 5 topics when onboarding. Common training topics included resident rights, emergency response, infection control, and personal care; dementia-specific training topics included Alzheimer's disease, behavior, communication, and dignity of residents, with only 2 states requiring training that addressed DCWs' well-being. Ten states mandated use of professionally designed courses, and 5 states required DCWs to complete an exam. From 2019 to 2023, 6 states made changes to the scope of dementia-specific training.<br><br>CONCLUSIONS AND IMPLICATIONS: While most states mandate DCW training and over half require annual frequency, duration, and cover 5 topic areas, few states specify sources of training materials or require competency checks. Lack of specificity in training requirements requires AL operators to determine what constitutes adequate training for DCWs to be successful. To better prepare the AL workforce for growing resident complexity, policymakers should consider promoting specific training requirements that ensure both onboarding and continuous education for DCWs, particularly around dementia care and workforce well-being.}, }
@article {pmid42685707, year = {2026}, author = {Metelmann, C and Gräsner, JT and Jacobsen, N and Neuenfeldt, FJ}, title = {[European Resuscitation Council Guidelines 2025: Basic and Advanced Life Support].}, journal = {Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS}, volume = {61}, number = {9}, pages = {531-547}, doi = {10.1055/a-2931-2870}, pmid = {42685707}, issn = {1439-1074}, mesh = {Humans ; *Cardiopulmonary Resuscitation/standards/methods ; Europe ; *Advanced Cardiac Life Support/standards ; Heart Arrest/therapy ; *Practice Guidelines as Topic ; Emergency Medical Services/standards ; }, abstract = {The 2025 European Resuscitation Council (ERC) guidelines introduce updated recommendations for adult Basic Life Support (BLS) and Advanced Life Support (ALS), with a strong focus on early recognition, high-quality cardiopulmonary resuscitation (CPR), timely defibrillation, and physiologically guided resuscitation. This article summarizes the most relevant changes and practical implications for healthcare professionals and bystander.}, }
@article {pmid42686219, year = {2026}, author = {Liu, J and Lin, J and Liu, H and Soh, K and Ju, Q and Soh, K and Dong, X}, title = {Efficacy of Antimicrobial Lock Solutions on Central Line-Associated Bloodstream Infection and Catheter Survival in Hemodialysis Patients: A Systematic Review and Meta-Analysis.}, journal = {Seminars in dialysis}, volume = {}, number = {}, pages = {}, doi = {10.1111/sdi.70046}, pmid = {42686219}, issn = {1525-139X}, support = {202301A014//Chengde Science and Technology Program/ ; GJXH2021-126//Hebei Higher Education Association "14th Five-Year Plan" Research Project/ ; H2026406068//Hebei Natural Science Foundation/ ; 202307//Chengde Medical university Project/ ; 202404//Chengde Medical university Project/ ; }, abstract = {Hemodialysis (HD) catheters carry a high risk of life-threatening bloodstream infections and failure. Antimicrobial lock solutions (ALS) are used to reduce this risk, but their overall efficacy on key outcomes like infection rates and catheter survival requires comprehensive evaluation. This systematic review and meta-analysis assess the impact of ALS on preventing catheter-related bloodstream infections (including incidence and density) and on improving catheter survival. A systematic search was conducted across the databases of PubMed, Embase, Scopus, Cochrane Library, and Google Scholar. A meta-analysis was conducted using STATA software. A total of 1183 studies were screened based on title and abstract, and further 282 studies were evaluated in full text. Eventually, 14 studies with 15 treatment arms were included. Key outcomes including central line-associated bloodstream infection (CLABSI), exit infection, and catheter-free survival were conducted separately. ALS demonstrated statistically significant benefits on CLABSI infection and catheter-free survival compared to nonantimicrobial solutions, showing a reduction in CLABSI density with a pooled log odd ratio (logOR) of -1.29 (95% CI: -1.59 to -0.99), lower CLABSI rates (pooled logOR = -1.50, 95% CI: -1.85 to -1.15), and improved catheter-free survival with log hazard ratio (logHR) of -1.11 (95% CI: -1.41 to -0.8). Consistent treatment effects were observed across all lock types with no significant heterogeneity detected. ALS demonstrate statistically significant and clinically important efficacy in reducing CLABSI incidence and density while improving catheter survival in HD patients, establishing them as an essential preventive strategy in clinical practice.}, }
@article {pmid42687189, year = {2026}, author = {Keritam, O and Bormann, D and Haimberger, F and Gharib, D and Sener, M and Gruber, F and Antoniewicz, L and Fedak, I and Renner, A and Fasching, B and Ullrich, S and Paternostro, R and Dolak, W and Masel, EK and Schuhfried, O and Rath, J and Zulehner, G and Krenn, M and Zimprich, F and Cetin, H}, title = {Implementation of specialised care improves survival in patients with amyotrophic lateral sclerosis.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42687189}, issn = {2524-3489}, abstract = {OBJECTIVE: Access to multidisciplinary care influences survival in patients with amyotrophic lateral sclerosis (pwALS). However, real-world data comparing structured specialised care with general neurological management remain limited. We aimed to assess the influence of implementing a specialised outpatient clinic on survival in pwALS.<br><br>METHODS: This retrospective cohort study included pwALS meeting the Gold Coast criteria who were treated at the Department of Neurology of the Medical University of Vienna between January 2009 and July 2023. Demographic and clinical parameters and survival data were obtained from the local ALS registry, the Austrian Federation of Social Insurance databases, and the national mortality database of Statistik Austria. Data were censored in December 2024. Outcomes were compared between patients managed before (general care cohort) and after the establishment of a specialised ALS outpatient clinic in 2018 (specialised care cohort).<br><br>RESULTS: A total of 242 pwALS were included (47.5% female), of whom 43.8% received general neurological care and 56.2% specialised care. Spinal onset ALS was observed in 65.1% and 70.6%, respectively. Baseline demographic and clinical characteristics were comparable between both cohorts. Median survival time was 27.0 months (95% CI 23.0-35.0) in the general care cohort and 40.0 months (95% CI 32.0-47.0) in specialised care cohort (p&#x2009;=&#x2009;0.0173). This survival difference was driven by patients with spinal onset ALS, whereas no benefit was observed in those with bulbar onset disease.<br><br>CONCLUSIONS: Specialised care was associated with improved survival in this real-world ALS cohort, likely reflecting the cumulative effect of coordinated multidisciplinary management rather than individual interventions.}, }
@article {pmid42688548, year = {2026}, author = {Hassell, LA and Gallati, M and Thoma, M and Asfaw, S and Hart, AC}, title = {Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {42688548}, issn = {2578-9430}, support = {P40 OD010440/OD/NIH HHS/United States ; R21 NS116254/NS/NINDS NIH HHS/United States ; T32 GM149433/GM/NIGMS NIH HHS/United States ; T32 MH020068/MH/NIMH NIH HHS/United States ; }, abstract = {Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) overlap considerably in genetic origin and pathology. Multiple C. elegans models of ALS/FTD have been developed, but the integrity of glutamatergic neurons in these models has not been thoroughly evaluated. Here, we report degeneration of glutamatergic phasmid neurons in animals expressing either wild-type or disease variant V337M human tau, and mild degeneration in animals expressing disease variant M337V human TDP-43. Defects caused by ectopic expression of tau were suppressed by loss of the known modifier, spop-1 , suggesting that SPOP-1-dependent pathways are also involved in glutamatergic neuron degeneration.}, }
@article {pmid42688563, year = {2026}, author = {Gao, X and Wang, T and Chen, S and Ma, Y and Wei, Q and Li, C and Shang, H and Chen, X}, title = {Amyotrophic lateral sclerosis -plus patient with an intermediate-length CACNA1A allele: a Case Report.}, journal = {Frontiers in genetics}, volume = {17}, number = {}, pages = {1860828}, pmid = {42688563}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS), the most common type of motor neuron disease, primarily manifests as progressive weakness, atrophy, fasciculations, bulbar palsy, and pyramidal tract symptoms. Accumulating evidence indicates that the pathological spectrum of ALS extends beyond the pyramidal and neuromuscular motor systems, involving additional brain regions, manifesting as ALS-plus syndrome. We present a case of an elderly woman with bulbar-onset ALS accompanied by cerebellar manifestations and an intermediate-length CACNA1A allele. Based on the Gold Coast criteria, ALS diagnosis was made. Notably, the patient exhibited cognitive impairment and a positive Romberg sign, suggesting a broader phenotypic spectrum. Genetic analysis showed a CAG repeat genotype of 10/20 in the CACNA1A gene. The patient's son carried a 14/20 genotype and displayed isolated cerebellar ataxia without motor neuron features. We reviewed the literature on spinocerebellar ataxia (SCA) co-occurring with motor neuron disease and discussed the uncertain significance of the intermediate-length CACNA1A allele in this context, weighing coincidental co-occurrence against a potential causal link. To our knowledge, this case is the first reported instance of an intermediate-length CACNA1A allele co-occurring with ALS in Chinese population, although the association between the allele and ALS remains unclear.}, }
@article {pmid42680797, year = {2026}, author = {Lawandos, L and Sodhi, CP}, title = {Early CFTR modulation and clinical outcomes in preschool cystic fibrosis.}, journal = {Pediatric research}, volume = {}, number = {}, pages = {}, pmid = {42680797}, issn = {1530-0447}, abstract = {This commentary discusses Presti et al.'s multicenter prospective study evaluating lumacaftor/ivacaftor therapy in preschool children with cystic fibrosis homozygous for F508del. The findings provide important real-world evidence that early CFTR modulation improves biomarkers of CFTR function, pulmonary outcomes, and early lung physiology while maintaining an acceptable safety profile. These data support the broader concept that intervention during early childhood may offer an opportunity to modify disease progression before irreversible organ damage develops.}, }
@article {pmid42680877, year = {2026}, author = {Ren, Q}, title = {Plasma biomarkers for ALS.}, journal = {Nature neuroscience}, volume = {29}, number = {9}, pages = {2056}, doi = {10.1038/s41593-026-02440-8}, pmid = {42680877}, issn = {1546-1726}, }
@article {pmid42681595, year = {2026}, author = {Lehrer, S and Rheinstein, PH}, title = {Proteomic and Functional Signatures of Phenoconversion in Presymptomatic Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical neuromuscular disease}, volume = {28}, number = {1}, pages = {33-46}, doi = {10.1097/CND.0000000000000567}, pmid = {42681595}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Female ; Proteomics ; Male ; Middle Aged ; Biomarkers/blood ; C9orf72 Protein/genetics ; Aged ; Neurofilament Proteins/blood ; *Prodromal Symptoms ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) likely has a prolonged presymptomatic phase. Identifying blood biomarkers that predict phenoconversion is critical for early intervention.<br><br>METHODS: We analyzed baseline serum proteomics in 270 UK Biobank participants who later developed ALS. A prespecified 19-protein panel was evaluated in relation to time-to-diagnosis. C9orf72 risk was proxied using rs10757668 genotype.<br><br>RESULTS: Neurofilament light rose sharply in the 2-3 years preceding diagnosis (r = -0.37, P < 0.001). Muscle-stress markers, including EDA2R and MYL3, increased earlier, up to 4-6 years before onset. Higher EDA2R levels were associated with reduced grip strength at baseline. A combined 19-protein panel plus genotype predicted phenoconversion within 3 years with an area under the receiver operating characteristic curve of 0.77, outperforming neurofilament light alone.<br><br>CONCLUSIONS: ALS exhibits a measurable molecular prodrome detectable in blood years before diagnosis. Integrated proteomic and genetic profiling may support early identification and trial enrichment strategies.}, }
@article {pmid42681642, year = {2026}, author = {German, A and Grotemeyer, A and Koller, K and Eckstein, M and Wolff, H and Rampp, S and Süß, P and Müller, VC and Birnbacher, D and Winkler, J and Regensburger, M}, title = {Organ donation and brain preservation after assisted dying: case report and considerations for a potential pathway.}, journal = {BMC medical ethics}, volume = {27}, number = {1}, pages = {}, pmid = {42681642}, issn = {1472-6939}, mesh = {Humans ; *Tissue and Organ Procurement/ethics ; Germany ; *Suicide, Assisted/ethics ; *Organ Preservation/ethics ; *Brain ; Brain Death ; Cryopreservation ; }, abstract = {Protecting life and restoring health have been at the core of the conception of medical care since antiquity, for health professionals and the public alike. Assisted dying represents a practice that appears to challenge this traditional conception. In jurisdictions where assisted dying is condoned, the question remains as to whether the practice should be medicalized or deferred to non-medical actors. Irrespective of the divisive controversy surrounding assisted dying and its medicalization per se, the practice gives rise to high-stakes ethical, legal and organizational challenges when intersecting with organ transplantation, tissue banking, and Structural Brain Preservation or cryonics. In this narrative account, we describe the contextual framework and outline our experience and operational scope for addressing them at a university hospital in Germany. Based on this description we propose a structured pathway for increasing donation and preservation options for terminal patients while retaining ethical integrity and professional accountability.}, }
@article {pmid42681667, year = {2026}, author = {Sowoidnich, L and Norman, AL and Gerstner, F and Siemund, JK and Buettner, JM and Pagiazitis, JG and Dreilich, V and Pilz, K and Tian, D and Sumner, CJ and Paradis, A and Mentis, GZ and Simon, CM}, title = {A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42681667}, issn = {2051-5960}, mesh = {Animals ; Humans ; *Motor Neurons/pathology ; *Neurodegenerative Diseases/pathology ; *Spinal Cord/pathology ; Muscular Atrophy, Spinal/pathology ; Mice ; Disease Models, Animal ; }, abstract = {Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, for which spinal cord sampling emerged as a major contributor. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.}, }
@article {pmid42682425, year = {2026}, author = {Niu, X and Zhang, M and Huang, H and Shao, B and Wang, X and Cai, Z}, title = {Increased serum fibroblast growth factor 2 levels, altered peripheral blood inflammatory indicators and their ratios in amyotrophic lateral sclerosis: a clinical exploratory study.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1859903}, pmid = {42682425}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; Female ; *Fibroblast Growth Factor 2/blood ; Male ; Case-Control Studies ; Middle Aged ; Biomarkers/blood ; Prospective Studies ; Aged ; *Inflammation/blood ; Adult ; Disease Progression ; Neutrophils ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and ultimately respiratory failure. Previous research has highlighted the roles of neurotrophic factors and inflammatory responses in ALS pathogenesis; however, their interplay remains poorly understood. This exploratory study aims to elucidate the expression characteristics and correlations of fibroblast growth factor 2 (FGF2) and peripheral blood inflammatory indicators (PBIIs) such as derived neutrophil-to-lymphocyte ratio (dNLR) and systemic inflammatory response index (SIRI) in ALS patients.<br><br>METHODS: This was a prospective case-control study, involving ALS patients meeting Gold Coast diagnostic criteria and age- and sex-matched healthy controls (HCs). Serum FGF2 levels were measured using enzyme-linked immunosorbent assay (ELISA), and PBIIs were assessed through routine blood analysis. Statistical analysis was conducted mainly using intergroup comparison, correlation analysis, and multivariate linear regression.<br><br>RESULTS: The results showed significantly elevated levels of FGF2 and PBIIs in ALS patients compared to HCs, with strong correlations between FGF2, PBIIs, clinical staging, and disease progression rates. In multivariate linear regression analysis, PBIIs, especially SIRI, were significantly associated with disease severity and early disease progression. While serum FGF2 and FGF2 to dNLR ratio demonstrated potential as an auxiliary biomarker for later-stage disease.<br><br>DISCUSSION: These findings provide new insights into the molecular mechanisms underlying ALS and suggest practical diagnostic and prognostic tools, reinforcing the importance of targeting neurotrophic and inflammatory pathways in ALS management. This study holds significant promise for advancing both clinical practice and future research endeavors in the field.}, }
@article {pmid42682698, year = {2026}, author = {AlNujaidi, HY and Al-Rayes, SA and Alumran, A and Almukhadhib, OY and AlNujaidi, DY and Alhafid, IA and Alyousif, GF}, title = {Construct validation of HER-WELL: a bifactor exploratory structural equation modeling evaluation of an eight-domain wellness scale for women.}, journal = {Frontiers in global women's health}, volume = {7}, number = {}, pages = {1903478}, pmid = {42682698}, issn = {2673-5059}, abstract = {BACKGROUND: Wellness is a multidimensional latent construct whose valid assessment requires psychometrically robust, culturally adapted instruments; however, existing scales have been predominantly developed in Western contexts and remain inadequate for capturing the gendered and sociocultural dimensions of women's wellness in non-Western settings. This study aimed to develop and psychometrically validate the HER-WELL scale, a culturally adapted multidimensional measure of holistic wellness for Saudi women.<br><br>METHODS: Scale development followed Boateng et al.'s (2018) framework, and construct validity was tested in RStudio and Mplus by comparing six measurement models (final CFA, ESEM, second-order CFA, bifactor CFA, second-order ESEM, bifactor ESEM) estimated with robust WLSMV and TARGET rotation in a stratified community sample of Saudi women (N&#x2009;=&#x2009;1,068; 531 employed, 537 non-employed), with model fit (CFI, TLI, RMSEA, SRMR) evaluated against conventional and Dynamic Fit Index cutoffs.<br><br>RESULTS: HER-WELL items showed adequate variability, with the highest endorsement for Home Environment, social, and spiritual wellness and the lowest for physical wellness. Across employed, non-employed, and full samples, bifactor ESEM consistently provided the best representation of the data, with excellent fit (CFI &#x2248;.99, TLI &#x2248;.98, RMSEA &#x2248;.03, SRMR &#x2248;.02) that exceeded both conventional and DFI-tailored cutoffs. This structure supported a strong general women's wellness factor, with Physical, Financial, Mental, and Occupational wellness retaining sufficient domain-specific variance, while Emotional, Social, Spiritual, and Home Environmental wellness were more strongly saturated by the general factor and are best interpreted as expressions of overall wellness. Internal consistency was acceptable for most domains (&#x3c9; and &#x3b1; typically &#x2265;.80), with Home Environmental wellness showing the weakest reliability and specific-factor indices of any domain (&#x3c9; &#x2248;.77; AVE =.070-.122), and should be interpreted only via the total score.<br><br>CONCLUSION: ER-WELL demonstrates strong psychometric properties as a culturally validated measure of holistic wellness for Saudi women. The bifactor ESEM solution supports the simultaneous use of overall wellness scores alongside domain-specific profiles for Physical, Financial, Mental, and Occupational wellness for research, surveillance, and intervention evaluation in Saudi Arabia and similar Arab and Muslim-majority contexts.}, }
@article {pmid42682963, year = {2026}, author = {Albaji, M and Ashkboos, K and Bagherzadeh, K}, title = {Possible Paraneoplastic Amyotrophic Lateral Sclerosis Presenting as Respiratory Failure in a Breast Cancer Patient: A Case Report.}, journal = {Clinical case reports}, volume = {14}, number = {9}, pages = {e73447}, pmid = {42682963}, issn = {2050-0904}, abstract = {A 63-year-old female with metastatic breast cancer presented with acute hypercapnic respiratory failure secondary to severe diaphragmatic dysfunction and mixed upper and lower motor neuron signs. Serum onconeural and neural surface antibody panels were negative, and initial cerebrospinal fluid analysis revealed albuminocytologic dissociation. Immunotherapy with intravenous immunoglobulin (IVIG) produced no clinical improvement, necessitating invasive mechanical ventilation and gastrostomy. Applying the 2021 PNS-Care consensus criteria, the case fulfills criteria for possible paraneoplastic amyotrophic lateral sclerosis (ALS), although coincidental sporadic disease cannot be excluded. A markedly elevated erythrocyte sedimentation rate (ESR) was observed, largely attributable to skeletal metastases and localized pulmonary collapse. Clinicians must maintain a high index of suspicion for motor neuron disease in cancer patients with unexplained hypoventilation.}, }
@article {pmid42684486, year = {2026}, author = {Bencs, V and Hortobágyi, T and Nagy, AC and Kozák, M and Méhes, G and Oláh, L and Csiba, L}, title = {Establishment of a novel human nervous system tissue bank: University of Debrecen tissue bank-introduction and retrospective data analysis.}, journal = {Cell and tissue banking}, volume = {27}, number = {4}, pages = {}, pmid = {42684486}, issn = {1573-6814}, mesh = {Humans ; Female ; *Tissue Banks ; Male ; Retrospective Studies ; Middle Aged ; Aged ; *Brain/pathology ; Adult ; Aged, 80 and over ; Autopsy ; Adolescent ; Young Adult ; Paraffin Embedding ; Child ; }, abstract = {Human brain tissues obtained from autopsies, as well as muscle and nerve samples derived from biopsies, constitute indispensable resources for translational research investigating the pathomechanisms of neuropsychiatric disorders. In this study, we introduce the Nervous System Tissue Bank of University of Debrecen, which contains formalin-preserved and formalin-fixed paraffin-embedded (FFPE) brain samples, as well as frozen nerve and muscle biopsy specimens. Database was established containing clinical and pathological parameters. For autopsy cases, the following variables were recorded: sex, age, number of hospitalization days, admission diagnosis, comorbidities, cause of death, post-mortem interval, general autopsy findings, and macro- and microscopic brain pathology diagnoses. For biopsy samples, we recorded: sex, age, biopsy site, and microscopic and molecular genetic diagnoses. Based on the recorded parameters and their temporal changes, retrospective statistical analyses were performed. Formalin-fixed brain samples and FFPE blocks were available from 2425 deceased individuals, and nerve/muscle samples from 257 patients. The brain samples originate from the period between 1990 and 2012. The most frequent admission diagnoses included ischemic stroke (n = 1070), hemorrhagic stroke (n = 462), subarachnoid hemorrhage (n = 102), epilepsy (n = 103), brain metastasis (n = 70), primary brain tumor (n = 60), parkinsonism (n = 28), dementia (n = 21), and amyotrophic lateral sclerosis (n = 21). Prevalence of hypertension (67.6%) and diabetes mellitus (20.1%) showed a significant increase over time (p < 0.001), whereas the prevalence of malignancies, dementia, parkinsonism, and psychiatric disorders remained stable. Our tissue bank represents the largest nervous system collection in Hungary, providing well-characterized brain, muscle, and nerve samples linked to nearly three decades of clinical data. Samples are made available to researchers.}, }
@article {pmid42684942, year = {2026}, author = {Huang, D and Zhang, Z and Gong, X}, title = {Context-dependent roles of osteopontin in aging-related neurological disorders.}, journal = {The Journal of international medical research}, volume = {54}, number = {9}, pages = {3000605261476190}, pmid = {42684942}, issn = {1473-2300}, mesh = {Humans ; *Osteopontin/metabolism ; *Aging/pathology/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Brain/pathology/metabolism ; Alzheimer Disease ; Microglia/metabolism ; }, abstract = {Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.}, }
@article {pmid42685299, year = {2026}, author = {Benatar, M and Rothstein, JD and Snow, K and Sethi, N and Taylor, DM and Dave, KD and McDermott, CJ and Cochrane, TI}, title = {Repairing the Amyotrophic Lateral Sclerosis Trial Credibility Gap.}, journal = {Neurology}, volume = {107}, number = {7}, pages = {e218471}, doi = {10.1212/WNL.0000000000218471}, pmid = {42685299}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials as Topic/standards ; *Research Design/standards ; }, abstract = {There is a long history of early- and mid-phase amyotrophic lateral sclerosis (ALS) clinical trial data being used to make claims of clinical benefit that fail to translate into successful phase 3 outcomes. It is suggested that fallacious scientific reasoning is being encouraged by perverse incentives arising from a "clinical trial industrial complex" that greatly influences trial design, data interpretation, and results communication. Recurring fallacies include false premises underlying outcome comparisons, misuse and incorrect interpretation of biomarkers, mismatches between study design and stated objectives, selective reporting of outcomes, over-reliance on post hoc analyses and open-label extension data, and overly optimistic framing of inconclusive data. We argue that these practices, reinforced by misaligned incentives across industry and academia, lead to premature claims of therapeutic promise and tangible harm to patients. To address the resulting ALS clinical trial credibility gap, we call for rigorous adherence to established standards for reporting clinical trial results, clearer distinction between hypothesis generation and hypothesis testing, more measured description of trial results, and more disciplined triage of phase 2 programs. A cultural shift toward scientific skepticism and methodological rigor is essential to accelerate the development of genuinely effective ALS therapies.}, }
@article {pmid42685382, year = {2026}, author = {Ni, CC and Yu, CS and Wei, SY and Dai, JZ and Chang, CL and Ting, HC and Chang, CY and Chen, YC}, title = {UV-programmed gelatin methacryloyl hydrogel microenvironments reveal a bell-shaped vascularization window and enable compartmentalized neuromuscular disease modeling.}, journal = {Biomaterials}, volume = {338}, number = {Pt A}, pages = {124588}, doi = {10.1016/j.biomaterials.2026.124588}, pmid = {42685382}, issn = {1878-5905}, abstract = {Matrix mechanics and microarchitecture jointly regulate tissue morphogenesis and functional maturation; however, defining their combined effects remains challenging when microenvironmental tuning requires changes in material composition. Here, we establish a UV-programmable gelatin methacryloyl (GelMA) hydrogel system in which ultraviolet exposure coordinates changes in construct architecture, pore morphology, and apparent mechanical properties within a constant material formulation. This framework enables systematic mapping of biological responses to UV-programmed architectural-mechanical microenvironments without compositional confounders. In vivo subcutaneous implantation reveals a nonlinear, bell-shaped vascularization response to UV-programmed GelMA hydrogel properties, identifying a narrow microenvironmental window that supports blood-containing vessel formation, human-derived vascular structures, and host-perfused vascular integration. For neuromuscular modeling, a structurally stable UV-defined regime was selected to support long-term compartmentalized co-culture of human induced pluripotent stem cell-derived myoblasts and motor neuron spheroids. Within this same UV-defined compartmentalized neuromuscular microenvironment, amyotrophic lateral sclerosis (ALS)-derived constructs exhibit impaired myogenic maturation, reduced neuromuscular junction (NMJ)-like structural organization, and altered contractile responsiveness compared with gene-corrected Healthy controls. Pharmacological treatment with the FDA-approved drug Riluzole partially restores these disease-associated phenotypes. Together, these findings establish UV-programmed GelMA hydrogels as an adaptable architectural-mechanical platform for identifying vascularization-permissive microenvironments and supporting compartmentalized neuromuscular disease modeling.}, }
@article {pmid42685551, year = {2026}, author = {Kashif, M and Keating, ME and Byrne, HJ}, title = {Approaches to data mining reaction kinetics using Raman spectroscopic analysis of Claisen-Schmidt condensation as a model.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {365}, number = {}, pages = {128685}, doi = {10.1016/j.saa.2026.128685}, pmid = {42685551}, issn = {1873-3557}, abstract = {Raman spectroscopy provides a powerful, non-destructive tool for real-time monitoring of multicomponent kinetics. However, extraction of reliable kinetic information from kinetically evolving Raman data can be challenging, due to the degree of spectral overlap of constituent signatures, rank deficiency, and rotational ambiguity. In this work, as a model reaction, solvent-free, base-catalysed Claisen-Schmidt condensation between benzaldehyde and acetone at room temperature was monitored using Raman microspectroscopy, in-situ, over a timescale of 1000 min. The resulting multicomponent dataset was analysed using problem-based nonlinear least squares (NLS) fitting of the weighted sums of the spectra of the reaction components, and multivariate curve resolution-alternating least squares (MCR-ALS) analysis. Three and four-components models were explored within the NLS framework, while a mechanistically constrained model (A + B → C, C + A → D) was implemented for MCR-ALS hard modelling. Conventional soft and hard MCR-ALS approaches failed to identify the correct reaction components and resolve chemically meaningful profiles, whereas seeded MCR-ALS, with 10,000× optimized seed weightings, successfully overcame these failings and yielded physically consistent spectra and concentration profiles. Reaction kinetics were evaluated by fitting the resolved concentration profiles to a kinetic model (A → C → D). The seeded MCR-ALS approach provided the most reliable kinetic description, while, in comparison, NLS based approaches using resolved and pure components spectra exhibited lower fitting accuracy. Quantitatively, the seeded MCR-ALS model showed superior performance, co-efficient of determination (R[2]) = 0.935, residual sum of squares (RSS) = 0.156, relative residual error (RRE) = 0.70% relative to NLS using resolved spectra (R[2] = 0.782, RSS = 0.524, RRE = 2.34%) and NLS using pure spectra (R[2] = 0.783, RSS = 0.408, RRE = 2.33%). These results demonstrate that seeded MCR-ALS, combined with constrained exponential kinetic modelling provides a robust and physically consistent framework for resolving spectroscopic data and extracting reliable mechanistic and kinetic insights. The proposed methodology is broadly applicable to complex multicomponent systems, including metabolomics, process analytics, and pharma kinetics, in which severe spectral overlap and rank deficiency limit conventional analytical approaches.}, }
@article {pmid42677900, year = {2026}, author = {Chan, KH and Ha, Y and Islegen-Wojdyla, A and Leon, S and Garces, M and McReynolds, D and Chong, X and Sriramoju, RV and Mahl, J and Guenzing, D and Koepp, W and Hexemer, A and Hellert, T and Chavez, T}, title = {Orchestrating agentic systems at ALS beamline 5.3.1 with Osprey and Bluesky.}, journal = {Journal of synchrotron radiation}, volume = {}, number = {}, pages = {}, doi = {10.1107/S1600577526007836}, pmid = {42677900}, issn = {1600-5775}, support = {107514//US Department of Energy, Office of Science/ ; DE-AC02-05CH11231//US Department of Energy, Office of Science/ ; }, abstract = {Modern synchrotron beamlines support increasingly complex experiments, but their operation remains strongly dependent on facility-specific control interfaces and workflows. This reliance creates a significant barrier to entry for new users and limits the portability of experimental procedures across beamlines. Here, we present a minimal, agent-agnostic orchestration architecture for AI-assisted beamline operation, deployed at Advanced Light Source beamline 5.3.1. The approach introduces a capability-based abstraction layer that exposes beamline functionality as a set of predefined operations. Within this framework, AI agents translate natural-language user requests into structured experimental plans composed of these capabilities. All plans are executed through the Bluesky Queue Server, ensuring deterministic operation within existing control and safety constraints without modification of the underlying beamline control system. The framework is defined by three key elements: (i) a portable capability layer that decouples user intent from beamline-specific implementation, (ii) a hybrid interaction framework combining AI-assisted workflow composition with graphical user interface (GUI)-based monitoring and control, and (iii) constrained execution that restricts all actions to predefined capabilities and requires user approval prior to execution. We demonstrate the architecture using grazing-incidence scattering (GISAXS), multi-edge X-ray absorption spectroscopy (XANES), and cross-beamline deployment scenarios. In each case, the system generates physically meaningful experimental plan, adapts to local hardware constraints, and preserves experimental intent across different instruments. These results demonstrate a practical and scalable approach for integrating AI into synchrotron experimentation, enabling intent-driven, portable, and safe beamline operation.}, }
@article {pmid42678414, year = {2026}, author = {Henne, C and Sigfridsson, I and Brännström, T and Forsberg, KME and Marklund, SL and Zetterström, P and Andersen, PM}, title = {Seeds from ALS patients homozygous for the SOD1 D90A mutation transmit two types of SOD1 aggregation and motor neuron disease.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42678414}, issn = {1432-0533}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; *Mutation/genetics ; Homozygote ; Mice ; Spinal Cord/pathology/metabolism ; Disease Models, Animal ; Female ; Male ; Motor Neurons/pathology ; *Protein Aggregation, Pathological/genetics/pathology ; Middle Aged ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most prevalent mutation, D90A, disease primarily develops in homozygotes. Increasing evidence suggests that prion-like propagation of SOD1 aggregation is the central pathogenic mechanism. Two structurally different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic (Tg) mouse models of ALS. Strain A is formed by most mutants including hSOD1[G85R] and homozygous hSOD1[WT] Tg mice, whereas homozygous hSOD1[D90A] Tg mice form a distinct strain B, but also A. Inoculation of strain A and B seed preparations from Tg mice into lumbar spinal cord of adult hSOD1[G85R] mice induced templated spreading hSOD1 aggregation and premature ALS-like disease. Seeds from an ALS patient carrying the hSOD1[G127X] truncation mutation likewise transmitted strain A aggregation and disease. In the present study, we investigated whether seeds prepared from spinal ventral horns from six patients homozygous for the hSOD1[D90A] mutation could transmit aggregation and disease to adult hSOD1[G85R] Tg mice. Despite the extensive degeneration and loss of motor neurons in the long-lived D90A patients, two of the seeds significantly shortened the survival of the Tg mice, one transmitting A and the other B-pattern hSOD1 aggregation. Nine different preparations from four human controls lacked effects. The results demonstrate that two distinct aggregate strains can arise and propagate in homozygous hSOD1[D90A] ALS patients, further supporting the hypothesis that prion-like transmission of hSOD1 aggregation is the primary pathogenic mechanism in SOD1-linked ALS.}, }
@article {pmid42678590, year = {2026}, author = {Ahmad, R and Naeem, M and Houlden, H}, title = {Whole-exome sequencing reveals a novel frameshift and a recurrent nonsense SPG11 variant causing rare familial amyotrophic lateral sclerosis type 5 in two consanguineous Pakistani families.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42678590}, issn = {1573-4978}, mesh = {Humans ; Pakistan ; Female ; Male ; Exome Sequencing/methods ; Pedigree ; *Amyotrophic Lateral Sclerosis/genetics ; Consanguinity ; Adult ; Frameshift Mutation/genetics ; Codon, Nonsense/genetics ; *Proteins/genetics ; Homozygote ; Phenotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. METHODS: We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes.<br><br>RESULTS: Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity.<br><br>CONCLUSION: Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.}, }
@article {pmid42679713, year = {2026}, author = {Özbey, H and Beşiktaş, S and Bayat, M}, title = {Validation of the Turkish caring professional scale among mothers of hospitalized neonates: A psychometric study based on Swanson's theory of caring.}, journal = {Journal of pediatric nursing}, volume = {91}, number = {}, pages = {546-553}, doi = {10.1016/j.pedn.2026.08.055}, pmid = {42679713}, issn = {1532-8449}, abstract = {INTRODUCTION: The aim is to adapt the CPS into Turkish and evaluate its psychometric properties specifically among mothers of hospitalized neonates.<br><br>METHODS: This cross-sectional study included 149 mothers at a university hospital NICU. Cross-cultural adaptation followed Beaton et al.'s five-stage framework. Psychometric evaluation included internal consistency (Cronbach's &#x3b1; and McDonald's &#x3c9;), confirmatory factor analysis (CFA) using both maximum likelihood on Pearson correlations and unweighted least squares on polychoric correlations, convergent and discriminant validity, and criterion-related validity with the Barrett-Lennard Relationship Inventory empathy subscale.<br><br>RESULTS: The Turkish CPS demonstrated excellent internal consistency (&#x3b1;&#xa0;=&#xa0;0.961, &#x3c9;&#xa0;=&#xa0;0.911). The two-factor model showed excellent fit under polychoric-ULS estimation (CFI&#xa0;=&#xa0;0.99, RMSEA&#xa0;=&#xa0;0.001, SRMR&#xa0;=&#xa0;0.046), and all standardized factor loadings exceeded 0.75. However, the one-factor and two-factor models showed almost identical fit, and the two subscales were highly overlapping, indicating that discriminant validity between them was not established. Significant positive correlations with empathy scores provided support for criterion validity.<br><br>CONCLUSION: The Turkish CPS demonstrates strong internal consistency and provides initial evidence for model fit in the NICU; however, discriminant validity between the two subscales was not supported, and the total score may be more appropriate than subscale-level interpretation. The findings support the cross-cultural applicability of Swanson's Theory of Caring and emphasize the necessity of using polychoric-based CFA methods for ordinal nursing data.<br><br>IMPLICATIONS TO PRACTICE: The Turkish CPS provides pediatric nurses and researchers with a brief, theory-based tool to assess maternal perceptions of professional caring in the NICU.}, }
@article {pmid42680205, year = {2026}, author = {Hines, TJ and Funke, JR and Pratt, SL and Rice, AD and Twiss, JL and Burgess, RW}, title = {A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.}, journal = {Human molecular genetics}, volume = {35}, number = {18}, pages = {}, doi = {10.1093/hmg/ddag084}, pmid = {42680205}, issn = {1460-2083}, support = {R01 NS068933//National Institute of Neurological Diseases and Stroke/ ; R37 NS054154//National Institute of Neurological Diseases and Stroke/ ; K99 NS130151//National Institute of Neurological Diseases and Stroke/ ; }, mesh = {Animals ; Disease Models, Animal ; Mice ; Male ; *Spinocerebellar Ataxias/genetics/pathology ; *Muscle Spasticity/genetics/pathology ; *Muscular Diseases/genetics/pathology ; *Tubulin/genetics ; Humans ; *Intellectual Disability/genetics/pathology ; *Optic Atrophy/genetics/pathology ; Mice, Inbred C57BL ; Mutation, Missense ; Polymorphism, Single Nucleotide ; Mutation ; Genes, Dominant ; Female ; Protein Serine-Threonine Kinases/genetics ; Muscle, Skeletal/pathology ; }, abstract = {Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6 J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6 J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have overt ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.}, }
@article {pmid42680415, year = {2026}, author = {Wu, H and Zhou, Q and Fan, Z and Lao, Y and Pu, J and Wang, C and Chen, J and Huang, L and Song, S and Zhong, Y and Li, M and Pan, K and Ma, J}, title = {High carbon dioxide and silicon-aluminum interactions remodel cell walls: Surface architecture and adhesion in the marine diatom Phaeodactylum tricornutum.}, journal = {Journal of environmental sciences (China)}, volume = {168}, number = {}, pages = {571-578}, doi = {10.1016/j.jes.2026.01.023}, pmid = {42680415}, issn = {1001-0742}, mesh = {*Diatoms/physiology/drug effects ; *Silicon/chemistry/metabolism ; *Carbon Dioxide/toxicity ; *Aluminum/chemistry/toxicity ; *Cell Wall ; }, abstract = {Anthropogenic carbon dioxide (CO2) elevation increases pressure on ocean ecosystems. As the key primary producers in marine ecosystems, diatoms rely heavily on silicon (Si) to form their cell walls, while aluminum (Al) can compete with or modulate Si uptake. Nevertheless, the interactions among CO2, Si, and Al in marine diatoms remain unclear. This study elucidates how CO2, Si, and Al influence the model marine diatom Phaeodactylum tricornutum through single-element (C, Si, Al) and combined treatments (+Si+CO2, +Al+CO2). Multilevel indicators from growth rate to surface nano structures and elemental composition were characterized using interdisciplinary methods-such as atomic force microscopy and X-ray photoelectron spectroscopy. Results demonstrate that elevated CO2 and exogenous Si synergistically increased the growth rate of diatoms by 53 %, but the cell size significantly decreased by 5.4 %. Critically, this co-stimulation concurrently increased surface roughness and enhanced silicate polymerization via higher silanol groups (Si-OH) ratio in cell walls, thereby accelerating the sinking velocity. Al's impact emerged only under elevated CO2, promoting organic groups synthesis such as elevated amide-N functional groups on cell surfaces. These findings demonstrate that rising CO2, interacting with Si/Al availability, alters diatom adaptability and thereby potentially impacts diatom-mediated C-Si-Al biogeochemical cycles.}, }
@article {pmid42680774, year = {2026}, author = {Ren, K and Cheng, M and Luo, Q and Zhang, B and Zhang, H and Li, Z and Liu, Y and Wang, Y and Kang, T and Dai, X and Chen, J and Cheng, Y and Huang, L}, title = {YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42680774}, issn = {2041-1723}, support = {32300651//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82370182//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics/metabolism/chemistry ; Humans ; *Molecular Chaperones/metabolism/genetics ; Animals ; Mutation ; Protein Aggregates ; Protein Folding ; Protein Aggregation, Pathological/genetics/metabolism ; *Nerve Tissue Proteins/metabolism/genetics ; Neurons/metabolism ; }, abstract = {Proteostasis failure drives multiple neurodegenerative disorders (NDs), and ATP-independent chaperone pathways that support neuronal proteostasis remain poorly defined. Here, we identify the N6-methyladenosine (m[6]A)-binding protein YTHDC1 as an ATP-independent molecular chaperone, whose activity is mediated by a highly acidic polyaspartate/glutamate (polyD/E) segment. YTHDC1 prevents protein misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Deletion of the polyD/E segment abolishes these activities, whereas aromatic-cage mutants retain chaperone activity, demonstrating independence from m[6]A recognition. We identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein hnRNPA1 as a YTHDC1 client. YTHDC1 maintains liquid-like hnRNPA1 condensates, delays fibrillization of disease-associated mutants, and limits stress-granule sequestration, while mitigating mutant hnRNPA1-induced neurite growth defects in primary neurons. These findings define a proteostatic function of YTHDC1 and highlight its chaperone activity as a potential target for mitigating protein aggregation in ALS-related NDs.}, }
@article {pmid42669933, year = {2026}, author = {Milella, G and Vacchiano, V and Velucci, V and Zoccolella, S and Liguori, R and Defazio, G}, title = {Data-Driven SuStaIn Model of Disability Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42669933}, issn = {2328-9503}, abstract = {OBJECTIVE: To determine whether ordinal Subtype and Stage Inference (SuStaIn) applied to routine ALSFRS-R item scores can identify reproducible disability progression patterns in amyotrophic lateral sclerosis (ALS) and provide clinically meaningful staging.<br><br>METHODS: We analysed baseline ALSFRS-R item responses from 866 PRO-ACT participants. Ordinal SuStaIn inferred subtype-specific sequences of functional deterioration and assigned each participant to a subtype and a SuStaIn-derived functional stage. Longitudinal stability was assessed across 3625 consecutive follow-up visit pairs from 697 participants. Structural reproducibility was evaluated in an independent cohort of 301 consecutive ALS patients. Associations of baseline subtype and stage with survival and subsequent ALSFRS-R decline were examined using Cox and piecewise-linear models.<br><br>RESULTS: A three-subtype solution identified fine motor-, gross motor- and bulbar-predominant patterns of early disability. Within each subtype, SuStaIn reconstructed ordered multidomain sequences of functional deterioration and assigned each participant a SuStaIn-derived stage. Subtype assignment was stable across 90.4% of consecutive visit pairs, and stage was non-decreasing in 98.8%. Subtype-specific event ordering was reproduced in the validation cohort. Higher baseline stage was associated with increased mortality risk in the fine motor- and gross motor-predominant subtypes, but not clearly in the bulbar-predominant subtype. Baseline stage showed subtype-dependent, non-linear associations with subsequent functional decline, with acceleration up to mid-stage breakpoints in the fine motor- and gross motor-predominant subtypes and less evident stage-dependent acceleration in the bulbar-predominant subtype.<br><br>INTERPRETATION: Routine ALSFRS-R item-level data can define clinically interpretable ALS progression subtypes and latent SuStaIn-derived functional stages. Joint subtype-stage modelling may refine prognostic stratification and support prognosis-informed trial enrichment.}, }
@article {pmid42670527, year = {2026}, author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L}, title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.}, journal = {International journal of nanomedicine}, volume = {21}, number = {}, pages = {628071}, pmid = {42670527}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; }, abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.}, }
@article {pmid42670631, year = {2026}, author = {Bischoff, KE and Leavell, YL and Besbris, JM and Lero, C and Noble, K and Grouls, A and Kurent, J and Kluger, BM and Pantilat, SZ and Mehta, AK and , }, title = {Priorities for Advancing Palliative Care for Amyotrophic Lateral Sclerosis: A Consensus Report From a Palliative Care for ALS Working Group in the United States.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70381}, pmid = {42670631}, issn = {1097-4598}, abstract = {Until there is a cure for amyotrophic lateral sclerosis (ALS), it is imperative that everyone facing this devastating illness receives care to alleviate symptoms and suffering and improve quality of life. Emerging evidence has demonstrated benefits of palliative care for people with ALS, but palliative care is not yet widely available or accessed by people with ALS throughout the disease course. The Palliative Care for ALS Working Group was formed within the International Neuropalliative Care Society, consisting of interprofessional ALS and palliative care clinicians, researchers, advocates, and patients and care partner representatives who are committed to improving palliative care for people living with ALS. The group engaged in a strategic planning process to determine what is needed to advance palliative care for people with ALS over the next 3-5 years. This report outlines the core recommendations from that strategic planning process. Recommendations are divided into five sections: (1) clinician education, (2) clinical service expansion, (3) research, (4) public awareness, and (5) policy change. The aim of this report is to provide ALS and palliative care clinicians, researchers, ALS advocacy organizations, and funders with a road map of priority areas where dedicated focus could significantly advance palliative care for people facing ALS, with the goals of relieving suffering and improving quality of life. The Palliative Care for ALS Working Group is making concrete steps toward these priority areas and will continue to serve as a convening and coordinating body for this work.}, }
@article {pmid42670660, year = {2026}, author = {Basualdo Allende, AL}, title = {Comment on: 'Living in a world that's not about us': The impact of everyday life on the health and wellbeing of autistic women and gender diverse people.}, journal = {Women's health (London, England)}, volume = {22}, number = {}, pages = {17455057261484826}, pmid = {42670660}, issn = {1745-5065}, mesh = {Humans ; Female ; *Oral Health ; *Autistic Disorder/psychology ; *Women's Health ; Gender-Nonconforming Persons ; }, abstract = {This correspondence comments on Grove et al.'s autistic-led qualitative study on the health and wellbeing of autistic women and gender-diverse people. It argues that oral health should be considered within autism-aware women's healthcare because toothbrushing, dental attendance, oral pain, sensory distress, and communication barriers may affect daily living, access to care, and overall wellbeing. The letter proposes a practical integration pathway based on simple oral-health screening, autism-aware dental referral, sensory and communication adaptations, and collaboration with primary care, mental health, and women's health services. This approach does not imply causality, but supports more holistic, person-centred care.}, }
@article {pmid42671301, year = {2026}, author = {Burke, S and Skedros, SA and Carroll, BT}, title = {Comment on Dowdle et al.'s "National Trends in Repair Type Selection After Mohs Micrographic Surgery: A Benchmark Analysis Using TriNetX.".}, journal = {Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]}, volume = {}, number = {}, pages = {}, doi = {10.1097/DSS.0000000000005334}, pmid = {42671301}, issn = {1524-4725}, }
@article {pmid42671791, year = {2026}, author = {Thomasen, MS and Brams, PH and Værbak, N and Cox, CMM and Parsons, CE}, title = {Daily emotion in fathers and mothers: Little evidence for greater paternal well-being during infant care.}, journal = {Emotion (Washington, D.C.)}, volume = {}, number = {}, pages = {}, doi = {10.1037/emo0001734}, pmid = {42671791}, issn = {1931-1516}, support = {//Carlsbergfondet/ ; }, abstract = {Parents' daily experience of childcare has garnered considerable attention following Kahneman et al.'s (2004) finding that childcare ranked among the least enjoyable daily activities. Subsequent studies have generally found that fathers report more positive valence during childcare compared to mothers. Here, we used experience sampling to examine daily experiences of first-time parents in Denmark between 2022 and 2024, where parental leave policies aim to promote involvement of fathers in infant care. Parents responded to 7 days of prompts during maternity and paternity leave, assessing valence (0-100 scale), sleepiness (Karolinska Sleepiness Scale), and current activities, including direct infant care, indirect care, and play (N = 227). Data were analyzed using Bayesian multilevel beta regression models. We found no credible evidence for the previously documented father advantage in valence during childcare. Mothers showed less positive valence during caregiving activities relative to other activities; effects for fathers were uncertain, and valence patterns differed across maternity and paternity leave. Sleepiness was strongly associated with less positive valence for both parents, with mothers showing steeper declines compared to fathers. Sleepiness moderated activity-valence associations in gender-specific ways: attenuating negative associations with direct care for mothers while reducing positive associations with play for fathers. In a country where paternal caregiving is supported through paid leave policies, mothers and fathers report largely similar valence patterns during infant care. The robust association between sleepiness and less positive valence points to sleep disruption as impacting parental emotion experiences, with mothers showing more vulnerability to its negative effects. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42672036, year = {2026}, author = {Krumina, M and Fernandes, S and Vilne, B and Baczyk, M}, title = {Computational Insights into Neuromodulation: How Electric Fields Shape Motor Neuron Excitability.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2026.3729166}, pmid = {42672036}, issn = {1558-0210}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by the selective loss of spinal motor neurons (MN). Trans-spinal direct current stimulation (tsDCS) has emerged as a promising noninvasive neuromodulation technique that could provide neuroprotection and slow down disease progression. However, the mechanisms by which tsDCS affects individual MNs remain poorly understood. This study uses computational modeling to explore how low-intensity extracellular electric fields (EEFs), generated by tsDCS, influence the electrophysiological behavior of MNs. Morphologically realistic, multi-compartment models of neonate mouse alpha-MNs were developed in the NEURON simulation environment. Simulations were conducted under different EEF magnitudes, polarities and orientations. At the population level, consistent directional effects on excitability-related properties were limited and depended on stimulation condition. However, analyses of response magnitude showed that EEFs could modulate several properties, including resting membrane potential and rheobase, even when the direction of change varied across neurons. This heterogeneity was associated with neuronal morphology and its alignment with the applied field, with dendritic length and asymmetry affecting sensitivity. Overall, the results suggest that low-intensity EEFs produce modest, morphology-dependent modulation of MN electrophysiological properties, and that variability in neuronal structure and orientation may help explain discrepancies across previous experimental and modeling studies.}, }
@article {pmid42673727, year = {2026}, author = {Aladwan, S and Jasim, A and Qassem, TA and Gajjar, TB and Hanumanthayya, M and Tripathi, V and Maharana, L and Bainsal, N}, title = {Human health risk assessment of toxic and non-toxic elements in various oily, cream, and powder cosmetics in Arab countries- A systematic literature review.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {97}, number = {}, pages = {127946}, doi = {10.1016/j.jtemb.2026.127946}, pmid = {42673727}, issn = {1878-3252}, abstract = {Oily, cream, and powder cosmetics (OCPCs) are widely used worldwide, especially in Arab nations, highlighting the need for ongoing heavy metal (HM) monitoring. This systematic review examined 16 HM concentrations in 14 OCPC product categories across 11 of the 22 Arab countries, selected countries based on predefined inclusion and exclusion criteria, and evaluated their associated health risks for only 9 of the 14 OCPCs for which sufficient data were available. The analysis included 24 papers published between June 1, 2007, and January 30, 2026, selected according to prescribed inclusion and exclusion criteria. International authorities like the WHO and the EU set acceptable limits (ALs) for HM levels. According to EPA criteria, all detected HMs underwent a health risk assessment (HRA). Saudi Arabia and Jordan had the highest HM detection rates in OCPCs among the 11 Arab countries analyzed, underscoring the need for stronger regulation. Moisturizing creams, toners, cosmetic masks, and oils were mostly contaminated with non-toxic HMs, whereas facial foundation and face cream samples were contaminated with toxic HMs. Despite exceedances of WHO and EU ALs for several elements, the EPA-based dermal risk indices remained below acceptable thresholds, reflecting the distinction between concentration-based regulatory limits and exposure-based health risk assessment. Arab regulatory agencies should establish monitoring systems to limit HMs in OCPCs, in line with WHO and EU guidelines on HM ALs in cosmetics, before market access.}, }
@article {pmid42674126, year = {2026}, author = {Raffaele, S and Bonifacino, T and Mannella, FC and Nguyen, N and Torazza, C and Marangon, D and Chinosi, EM and Schrøder, HD and Hejbøl, EK and Madsen, K and Marchetti, L and Trincavelli, ML and Milanese, M and Lecca, D and Lambertsen, KL and Bonanno, G and Abbracchio, MP and Fumagalli, M}, title = {Selective targeting of the oligodendroglial GPR17 receptor improves myelin integrity and motor function in female SOD1[G93A] mice.}, journal = {Pharmacological research}, volume = {232}, number = {}, pages = {108424}, doi = {10.1016/j.phrs.2026.108424}, pmid = {42674126}, issn = {1096-1186}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no definitive disease-modifying therapies available, underscoring the urgent need to identify novel druggable targets. The G protein-coupled receptor GPR17 is a critical regulator of oligodendrocyte maturation and has emerged as a candidate target in ALS, yet its relevance to human disease and its therapeutic potential remain unclear. Here, we demonstrate that pathological GPR17 upregulation defines a conserved, pathologically immature oligodendroglial state in human ALS that can be pharmacologically leveraged to restore myelin integrity and improve functional outcome in vivo. Publicly available transcriptomics datasets and histological analyses revealed an increased abundance of GPR17-expressing immature oligodendrocytes in post-mortem human spinal cord tissue from ALS cases. Moreover, sustained activation of GPR17 with a selective agonist induced GPR17 internalization in heterologous expression systems and promoted the differentiation of primary oligodendrocyte precursors derived from SOD1[G93A] mice. Translating these findings in vivo, chronic treatment with a brain-penetrant GPR17 agonist derived from the same pharmacological class significantly extended survival, delayed body weight loss, and improved motor performance in female SOD1[G93A] mice, whereas male mice showed no therapeutic benefit. These effects were associated with restored oligodendrocyte maturation, preserved myelin integrity, motor neuron survival, and attenuated reactive gliosis in the spinal cord of female SOD1[G93A] mice, while milder effects were observed in males. Together, these findings establish oligodendroglial GPR17 as a conserved and pharmacologically actionable target in ALS and show that sustained in vivo GPR17 agonism can reprogram altered oligodendroglial states and slow disease progression in a sex-dependent manner.}, }
@article {pmid42675240, year = {2026}, author = {Ma, S and Luo, S and Zhong, H}, title = {Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {42675240}, issn = {2193-8253}, support = {Open research fund: gect-2025-Z01//Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases/ ; }, abstract = {Neuromuscular diseases (NMDs) encompass over 800 distinct entities affecting approximately one in 1000 individuals worldwide, with progressive muscle weakness, atrophy, and motor impairment as primary clinical manifestations. The rarity of most NMDs creates fundamental challenges for artificial intelligence (AI) and machine learning (ML) applications that typically require large-scale datasets. In this narrative review we synthesize the literature published between 2018 and 2025 on AI applications across the NMD spectrum, organized by clinical application domain. We examine how AI has advanced diagnostic capabilities through genetic variant interpretation, muscle magnetic resonance imaging analysis, electromyography-based classification, and computational pathology. In disease monitoring and prognosis, wearable-derived digital biomarkers have achieved regulatory qualification (US Food and Drug Administration [FDA] and European Medicines Agency [EMA]) as clinical trial endpoints for Duchenne muscular dystrophy, while AI-driven survival models for amyotrophic lateral sclerosis (ALS) have been validated across 14 European centers. Proteomic and multi-omics analyses using ML have identified diagnostic panels for ALS. However, most reported models were developed and internally validated on single-center datasets, and few have undergone external or prospective validation or clinical implementation. Despite these achievements, research intensity varies dramatically across NMD subtypes, with ALS and Duchenne muscular dystrophy dominating while myotonic dystrophy, congenital myopathies, and metabolic myopathies remain virtually unexplored. Critical gaps persist in computational pathology, multi-center validation, and clinical translation. In this review, we discuss how federated learning, international collaborative networks (TREAT-NMD, Solve-RD, EURO-NMD), and foundation models can address these challenges, and propose directions for future AI-enhanced clinical studies in this data-scarce field.}, }
@article {pmid42676114, year = {2026}, author = {Xu, J and Wu, X and Zhang, B and Wu, K}, title = {Ba4Al4SnS12: balancing bandgap and nonlinear optical performance in thioaluminate via multifunctional group engineering.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6dt01763k}, pmid = {42676114}, issn = {1477-9234}, abstract = {The exploration of infrared nonlinear optical (IR NLO) crystals with excellent performance has attracted increasing attention in view of the inherent drawbacks (low laser damage threshold (LDT) or harmful two-photon absorption (TPA)) of commercial NLO crystals. However, the critical performances (wide bandgap (>3.0 eV) and good nonlinearity (>0.5 × AgGaS2)) show an inverse relationship in IR NLO crystals; thus, the judicious selection and combination of functional motifs are critical, as performance is fundamentally governed by structure. For that reason, we propose a multifunctional group engineering strategy incorporating [AlS4] for a wide bandgap and [SnS4] for large nonlinearity to design a new NLO chalcogenide that affords the successful synthesis of thioaluminate, Ba4Al4SnS12. Experimental study shows that Ba4Al4SnS12 achieves an optimal performance balance between a wide bandgap (3.06 eV) and a moderate second-harmonic generation (SHG) response (0.56 × AgGaS2) with requisite phase-matching behavior (Δn = 0.042), further indicating that Ba4Al4SnS12 could be regarded as a potential IR NLO candidate. Theoretical analysis demonstrates the respective contributions of distinct tetrahedral groups to the bandgap and NLO coefficient and validates the feasibility of multifunctional group engineering. Therefore, this study provides a principle for selecting excellent functional groups and research systems, illuminating a feasible pathway toward future NLO crystals with superior performance.}, }
@article {pmid42676195, year = {2026}, author = {Arbuzova, EE and Seksyaev, NE and Karakulova, YV and Selyanina, NV and Danilova, MA}, title = {[Atypical forms of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {126}, number = {8}, pages = {13-20}, doi = {10.17116/jnevro202612608113}, pmid = {42676195}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Phenotype ; Diagnosis, Differential ; Disease Progression ; Motor Neurons/pathology ; }, abstract = {This article provides a comprehensive overview of contemporary concepts regarding the classical and atypical phenotypes of amyotrophic lateral sclerosis (ALS), with a particular focus on critical diagnostic challenges. The classical variant of the disease is characterized by the progressive involvement of both upper and lower motor neurons, typically presenting with an asymmetric onset and a predictable progression. However, several atypical phenotypes are identified, including syndromes predominantly affecting the lower motor neurons, such as the «hanging hands» and «hanging legs» syndromes, isolated bulbar paralysis, ALS with respiratory onset, and forms with a predominance of upper motor neuron involvement. These atypical variants often mimic other neurological conditions-such as cervical myelopathy, multifocal motor neuropathy, and myasthenia gravis-which can result in significant delays in the accurate diagnosis of ALS. Atypical forms of ALS represent a major source of diagnostic errors in clinical practice. Enhancing healthcare professionals' understanding of the spectrum of phenotypic presentations, alongside the application of contemporary diagnostic criteria, facilitates more timely diagnoses, optimized patient care pathways, and the prompt initiation of pathogenetic therapies, ultimately improving both survival rates and quality of life for affected individuals.}, }
@article {pmid42677779, year = {2026}, author = {Ali, A and Arif, M and Ashraf, U and Elahi, S and Mustafa, A and Yasir, MB and Sarfraz, W and Ansari, AU and Masood, HMY and Shabbir, MA and Abdullah, A and Sharma, MK}, title = {CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.}, journal = {Brain and behavior}, volume = {16}, number = {9}, pages = {e71740}, pmid = {42677779}, issn = {2162-3279}, mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications ; Biomarkers/cerebrospinal fluid ; *Frontotemporal Dementia/cerebrospinal fluid/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/etiology ; }, abstract = {INTRODUCTION: Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous.<br><br>METHODS: This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework.<br><br>RESULTS: Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (&#x3b2; = -0.03, p = 0.006) and memory performance (&#x3b2; = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower A&#x3b2;42/A&#x3b2;40 was associated with poorer memory performance (&#x3b2; = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (&#xb1; evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis.<br><br>CONCLUSIONS: The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and A&#x3b2;42/A&#x3b2;40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.}, }
@article {pmid42677823, year = {2026}, author = {Chandran, D and Agrawal, U and Damayanthi, D and Nair, DT and Mandagini, G and Nair, SS and Narasimhaiah, D and Fernandez, FB and Thakur, P and Raghavan, CT and Krishnan, S and Gopala, S and Urulangodi, M}, title = {Cofilin 1 Is an Extracellular Vesicle-Associated Plasma Biomarker of Parkinson's Disease in Humans.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78348}, pmid = {42677823}, issn = {1531-8249}, abstract = {OBJECTIVE: Parkinson's disease (PD) lacks reliable, minimally invasive biomarkers for diagnosis. This study aimed to identify and validate PD-specific plasma extracellular vesicle (EV)-associated proteins.<br><br>METHODS: Plasma EVs were isolated by ultracentrifugation and characterized. Proteomic profiling of total plasma EVs from PD patients and healthy controls was performed, and a candidate protein identified after analysis was validated by enzyme-linked immunosorbent assay. Diagnostic accuracy was evaluated using receiver operating characteristic and precision-recall curve analysis. Disease specificity was examined in progressive supranuclear palsy and amyotrophic lateral sclerosis. Histochemical and immunofluorescence analyses were conducted in human and mouse PD brain tissue.<br><br>RESULTS: Proteomic analysis identified distinct PD-specific EV proteins, including cofilin 1 (CFL1), which was significantly enriched in EVs isolated from PD. EV-CFL1 levels were significantly elevated in PD compared with healthy controls (p&#x2009;<&#x2009;0.0001). Receiver operating characteristic analysis showed strong diagnostic performance for EV-CFL1 (area under the curve 0.87). Also, EV CFL1 levels could distinguish PD from progressive supranuclear palsy patients (area under the curve 0.914). CFL1 was enriched in L1 cell adhesion molecule-positive EVs, indicating a possible neuronal origin. CFL1 was detected in both human and mouse PD brain sections. Importantly, EV-CFL1 levels were independent of age, disease stage, and motor severity.<br><br>INTERPRETATION: EV-associated CFL1 represents a PD-specific, blood-based marker with strong diagnostic accuracy and can distinguish PD from atypical parkinsonism. The presence of CFL1 was confirmed in human and mouse PD brain tissue, and its accumulation in PD brain suggests a possible role in disease pathogenesis. ANN NEUROL 2026.}, }
@article {pmid42677831, year = {2026}, author = {Basak, B and Riley, JF and Nataraj, NM and Holzbaur, EL}, title = {Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {17}, pages = {}, pmid = {42677831}, issn = {1558-8238}, mesh = {Humans ; *Mitophagy ; Animals ; *Neurons/pathology/metabolism ; *Mitochondria/pathology/metabolism/genetics ; PTEN-Induced Putative Kinase ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Protein Kinases/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Signal Transduction ; }, abstract = {Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.}, }
@article {pmid42665659, year = {2026}, author = {Shi, P and Melillo, B and McHenry, MW and Camara, CM and Yang, K and Njomen, E and Godes, M and Pazyra-Murphy, MF and Branch, MR and Tesar, B and Segal, RA and Rubin, LL and Cameron, MD and Bird, GH and Wales, TE and Gygi, SP and Cravatt, BF and Walensky, LD}, title = {An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo.}, journal = {Nature chemical biology}, volume = {}, number = {}, pages = {}, pmid = {42665659}, issn = {1552-4469}, support = {R35CA197583//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R50CA211399//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R35CA231991//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can activate or inhibit its function. Here, we report enantioselective covalent BAX inhibitors that site-specifically react with C126 and confer cytoprotection across multiple cell types. These ligands constrain BAX conformation and suppress apoptosis in a strictly BAX-dependent manner. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), an analog with pharmacokinetics suitable for in vivo studies. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 reduced hepatocyte apoptosis and preserved liver histology and survival. CBI-3 also conferred cytoprotection of motor neurons derived from human induced pluripotent stem cells of healthy and amyotrophic lateral sclerosis donors. These findings establish covalent BAX inhibition as a therapeutic strategy to directly block pathologic cell death.}, }
@article {pmid42666334, year = {2026}, author = {Garbey, M and Lesport, Q and Öztosun, G and Heidebrecht, M and Pirouz, K and Bayat, E}, title = {Feasibility study on a noninvasive assessment of ALS patient emotional state.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1886561}, pmid = {42666334}, issn = {2673-253X}, abstract = {INTRODUCTION: Objective assessment of emotional responsiveness in Amyotrophic Lateral Sclerosis (ALS) remains limited despite its importance for personalized care. This study investigated whether non-invasive speech analysis could identify digital biomarkers associated with emotional coping behaviors in ALS patients.<br><br>METHODS: We analyzed 28 ALS patient visits using clinician-rated emotional concern scores, ALS Functional Rating Scale-Revised (ALS-FRS-R), forced vital capacity (FVC), and speech acoustic features. We also evaluated the reliability of large language models (LLMs), including ChatGPT, Gemini, and Claude, for automated concern assessment. Patients were classified relative to functional impairment as congruent, muted, or excessive responders.<br><br>RESULTS: LLMs failed to provide reliable or reproducible assessments of patient concern without expert clinical supervision. Subjective concern levels also showed discordance with objective respiratory measures such as FVC. Excessive responders were predominantly male and required significantly greater clinician interaction time, while muted responders were predominantly female. Acoustic analysis revealed distinct vocal profiles between groups. Muted responders demonstrated high loudness and sharpness with low roughness and fluctuation, whereas excessive responders showed the opposite profile. These findings suggest that dysarthria may function as an acoustic filter modulating emotional expression.<br><br>DISCUSSION: Speech-derived acoustic biomarkers may enable objective identification of emotional coping phenotypes in ALS and support earlier, personalized psychosocial interventions. The findings also highlight important limitations of current LLM-based clinical interpretation tools in unsupervised settings.}, }
@article {pmid42666355, year = {2026}, author = {Wei, Y and Wang, J and Ji, Y and Shang, T and Shen, Y and Sun, H and Cai, Y}, title = {Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {626069}, pmid = {42666355}, issn = {1177-8881}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Precision Medicine ; Animals ; *Clinical Trials as Topic ; *Neuroprotective Agents/therapeutic use ; *Research Design ; Genetic Therapy ; Drug Development ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all" approach toward "precisely stratified" medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.}, }
@article {pmid42666931, year = {2026}, author = {Laffita-Mesa, JM and Paucar, M and Svenningsson, P}, title = {ATXN2 Spectrum Disorders: Genetic Complexity Beyond Dominant Inheritance.}, journal = {Neurology. Genetics}, volume = {12}, number = {5}, pages = {e200428}, pmid = {42666931}, issn = {2376-7839}, abstract = {The genetic complexity of ATXN2 challenges conventional paradigms in neurodegeneration. While initially linked to autosomal dominant spinocerebellar ataxia type 2, ATXN2 CAG expansions have emerged as a major risk factor for amyotrophic lateral sclerosis. In a recent article, Saucier et al. describe an Acadian family with a recessive inheritance pattern of ATXN2-related disease, challenging the long-held assumption of a predominantly autosomal dominant, gain-of-function-driven mechanism. Here, we analyze how ATXN2's inheritance mode may shift based on repeat interruptions, somatic mosaicism, and gene dosage, suggesting that loss-of-function mechanisms contribute to pathogenesis in certain contexts. We discuss implications for disease classification, genetic counseling, and therapeutic strategies, emphasizing the need for genetic stratification.}, }
@article {pmid42667453, year = {2026}, author = {Liu, C and Zhang, Y}, title = {Ginsenosides: potential therapeutic implications in neurodegenerative diseases by inhibiting ferroptosis.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42667453}, issn = {1573-4978}, mesh = {Humans ; *Ginsenosides/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Ferroptosis/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {A positive correlation exists between the accelerating pace of population aging and the increasing prevalence of neurodegenerative diseases. Conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) profoundly compromise patient quality of life, yet efficacious clinical interventions remain notably limited. The prevention and management of neurodegenerative diseases represent a critical global public health imperative. A comprehensive literature search was performed across PubMed, Web of Science, and Scopus to identify studies on the biological functions, molecular mechanisms, and clinical implications of ginsenosides. The search strategy incorporated MeSH terms and free-text keywords, encompassing "neurodegenerative disease", "ferroptosis", "ginsenosides", "Parkinson's disease", "Alzheimer's disease", "amyotrophic lateral sclerosis", "Huntington's disease" and "multiple sclerosis". From an initial pool of over 400 papers (1998-2026), 107 were selected in this narrative review. Ferroptosis is intricately linked to the pathogenesis of neurodegenerative diseases. Ginsenosides constitute the principal bioactive triterpenoid saponins extracted from plants of the Panax genus, demonstrating broad-spectrum pharmacological efficacy encompassing antitumor, immunomodulatory, anti‑inflammatory, anti‑allergic, anti‑atherosclerotic, antihypertensive, antidiabetic, antistress, and neuroprotective activities. Ginsenosides exert their neuroprotective effects against AD, PD, and ALS predominantly through the modulation of ferroptosis. Herein, this article provides a review of the molecular mechanisms, genetic determinants, signaling cascades, and functional implications of ferroptosis. Ginsenosides represent promising therapeutic agents in neurodegenerative diseases via modulation of iron homeostasis; this paper elucidates mechanistic insights into disease pathogenesis and evaluates their translational therapeutic potential. This narrative review highlights emerging insights that provide novel therapeutic perspectives for neurodegenerative diseases.}, }
@article {pmid42667624, year = {2026}, author = {Bues, B and Sasmita, AO and Mao, S and Komarek, L and O'Mahony, K and Burk, K}, title = {Axonal pathology and impaired axo-glial crosstalk as early drivers of neurodegeneration.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-26-00462}, pmid = {42667624}, issn = {1673-5374}, abstract = {Axonal dysfunction is a critical event in neurodegenerative diseases, which can precede neuronal loss. For instance, in multiple sclerosis, chronic demyelination leads to axonal transection and downstream neurological deficits, yet in other neurodegenerative conditions, the causal relationship between axonal pathology and disease progression remains elusive. While defects in axonal transport, cytoskeletal integrity, and organelle trafficking are observed in Alzheimer's disease and the frontotemporal dementia-amyotrophic lateral sclerosis spectrum, a question remains: Are axonal defects merely downstream consequences of somatic neurodegeneration, or do they actively drive pathogenesis? Emerging evidence suggests that early axonal dysfunction may accelerate disease progression through disrupted connectivity, retrograde degeneration, and neuroinflammation. Here, we highlight current evidence on axonal pathophysiology across Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis. We first outline the makeup of the mature axonal compartment, as well as the processes related to axonal maintenance, which include myelination, glial support, and microtubule-dependent transport mechanisms. We further compare axonal perturbations in Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis, exploring commonalities as potential convergent mechanisms. Therapeutic strategies to stabilize axons by maintaining microtubule dynamics, restoring energetics, or modulating glial support could therefore theoretically offer neuroprotection if performed selectively on vulnerable neuronal subsets and early in the disease course. Ultimately, by reframing axonal pathology as a primary driver rather than an epiphenomenon, this review underscores the importance of targeting axonal health in neurodegenerative diseases.}, }
@article {pmid42667698, year = {2026}, author = {Rey, V and Feijoó, MEG and Vittar, EE and Morales, JMN and Fernández, JM and Morán Vieyra, FE and Tuttolomondo, ME and Borsarelli, CD}, title = {Photoreductive synthesis and analytical performance of silver nanoparticles stabilized with humic acids for selective and sensitive colorimetric detection of mercury (II) ions.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {269}, number = {}, pages = {116112}, doi = {10.1016/j.colsurfb.2026.116112}, pmid = {42667698}, issn = {1873-4367}, abstract = {This study presents the one-step photoreductive synthesis and characterization of humic acid-stabilized silver nanoparticles (AgNP@HA) via the reduction of Ag[+] ions by ketyl radicals generated by UVA-light using the water-soluble photoinitiator Irgacure® 2959 (I-2959) as a function of pH and HA concentration. The formation and properties of the AgNP@HA were characterized by several techniques, including UV-Vis, FTIR, and Raman spectroscopies, as well as transmission electron microscopy (TEM) and dynamic light scattering (DLS). The UV-Vis absorption spectrum changes occurring during the formation of the AgNP@HA were modeled with the multivariate curve fitting using alternating least squares (MCR-ALS) method. The kinetic profiles of each observed species suggested that AgNP@HA are produced through a mechanism of nucleation and aggregation. The AgNP@HA solutions were evaluated as colorimetric sensors for the selective detection of Hg[2+] ions at different pH. The changes in the surface plasmon band absorbance of AgNP@HA induced by Hg[2+], irrespective of the presence of other interfering ions and pH, indicated that AgNP@HA specifically interacts with Hg[2+] to form an amalgam with silver, with remarkable analytical performance, detecting Hg[2+] in the sub ppm range. These results indicate that AgNP@HA prepared by photoreduction with I-2959 can be used as a suitable, simple, economical, and environmentally friendly plasmonic sensor for the detection of mercury in water samples.}, }
@article {pmid42667936, year = {2026}, author = {Zhu, J and Zhang, Y and Yang, B and Xiang, Q and Hu, S and Wei, W and Zhou, H and Yang, G and Zhang, H}, title = {Associations of cumulative exposure and longitudinal trajectories of neurofilament light chain with 1-year adverse events in amyotrophic lateral sclerosis: A prospective cohort study.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107584}, doi = {10.1016/j.nbd.2026.107584}, pmid = {42667936}, issn = {1095-953X}, abstract = {BACKGROUND: Baseline neurofilament light chain (NFL) predicts amyotrophic lateral sclerosis (ALS) outcomes, but it does not summarize early repeated biomarker information. We evaluated whether cumulative NFL exposure (cuNFL), calculated over an early monitoring window, and longitudinal NFL trajectory groups were associated with subsequent adverse events in a prospective cohort.<br><br>METHODS: This prospective study enrolled patients with ALS from 32 provinces in China between January 2024 and January 2025. Plasma NFL was measured at baseline, month 1, and month 2. We used K-means clustering to describe longitudinal NFL patterns and multivariable survival models to evaluate prognostic associations. Inverse-probability weighting and causal-forest analyses were used as exploratory, confounding-adjusted analyses of high versus low cuNFL.<br><br>RESULTS: K-means clustering identified three longitudinal NFL groups: Low-Stable (n&#x202f;=&#x202f;183), Moderate (n&#x202f;=&#x202f;225), and High-Progressive (n&#x202f;=&#x202f;100). The High-Progressive group had the shortest event-free survival (P&#x202f;<&#x202f;0.001). Each 1-SD increment in cuNFL was associated with higher odds of adverse events (adjusted OR 1.99; 95% CI 1.52-2.60; P&#x202f;<&#x202f;0.001). Using the manuscript-defined 127-event outcome, apparent discrimination was AUC 0.730 for cuNFL and 0.717 for baseline NFL. The paired DeLong comparison was not statistically significant (P&#x202f;=&#x202f;0.084). Exploratory machine-learning analyses suggested heterogeneity in the association of high cuNFL with outcome by age and respiratory function.<br><br>CONCLUSION: Early repeated NFL measurements summarized as cuNFL and longitudinal trajectory groups were associated with short-term adverse events in this cohort. These findings support further external validation of longitudinal NFL-based risk stratification. They do not establish a causal biological effect or a basis for routine repeated measurement.}, }
@article {pmid42668676, year = {2026}, author = {Varon-Vega, F and Franco Parra, CE and Adame Ochoa, DF and Uricoechea, N and Tuta-Quintero, E and Martinez Ayala, MC}, title = {Use of High-Flow Nasal Cannula in Amyotrophic Lateral Sclerosis Patients Intolerant to Non-Invasive Ventilation: A Case Series.}, journal = {Respirology case reports}, volume = {14}, number = {9}, pages = {e70744}, pmid = {42668676}, issn = {2051-3380}, abstract = {Non-invasive ventilation (NIV) is standard respiratory support for amyotrophic lateral sclerosis (ALS), but intolerance may limit its use. High-flow nasal cannula (HFNC) has emerged as a potential alternative in selected patients, but evidence regarding its use remains scarce. We describe 18 ALS patients' management with HFNC between 2014 and 2024 after documented intolerance to NIV. Mean age at HFNC initiation was 65.1 ± 12.5 years, and 66.7% of patients were female. Partial NIV intolerance occurred in 38.9% of cases, while 33.3% tolerated intermittent combined NIV and HFNC. During follow-up, 50.0% of patients required hospitalization, 33.3% experienced respiratory infections, and 27.8% died. Arterial blood gas parameters remained stable, including PaCO2 (p = 0.314). Functional status declined significantly, with Barthel Index decreasing (35.0 ± 20.5 vs. 11.7 ± 11.3; p < 0.001), whereas respiratory muscle strength remained unchanged. HFNC was feasible as home-based support in ALS patients intolerant to NIV, warranting prospective comparative evaluation.}, }
@article {pmid42669596, year = {2026}, author = {Horton, DK and Raymond, J and Larson, T and Weisskopf, MG and Howard, I and Mehta, P}, title = {Military Service and Survival Among Persons With ALS in the U.S. National ALS Registry, 2011-2023.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70390}, pmid = {42669596}, issn = {1097-4598}, support = {//CDC/ATSDR National ALS Registry/ ; }, abstract = {INTRODUCTION/AIMS: Military service has been associated with increased risk of amyotrophic lateral sclerosis (ALS) but less is known about survival after diagnosis. We evaluated the association between military service and survival after ALS diagnosis among U.S. National ALS Registry participants.<br><br>METHODS: Participants who completed the Registry's Military History Survey between 2011 and 2023 and had valid ALS diagnosis and mortality follow-up information were eligible. Military service was classified as veteran or nonveteran. Mortality was ascertained through National Death Index linkage. Kaplan-Meier methods evaluated survival distributions, and Cox proportional hazards models estimated adjusted mortality associations.<br><br>RESULTS: Among 8643 participants, 1735 (20.1%) were veterans and 6908 (79.9%) were nonveterans. Veterans were older at diagnosis and reported greater smoking and alcohol use. The median observed time from ALS diagnosis to death or censoring was 3.77&#x2009;years among veterans and 4.79&#x2009;years among nonveterans, an approximate 1-year difference; Kaplan-Meier estimated 5-year survival was 47.1% and 57.4%, respectively. Veterans experienced significantly poorer survival than nonveterans (log-rank &#x3c7;[2]&#x2009;=&#x2009;113.45, p&#x2009;<&#x2009;0.0001). In the primary adjusted Cox model, military service remained associated with increased mortality (HR 1.25, 95% CI 1.15-1.35; p&#x2009;<&#x2009;0.0001). Findings were consistent across sensitivity analyses accounting for disease severity, symptom onset site, and delayed Registry entry.<br><br>DISCUSSION: Military service was associated with poorer survival after ALS diagnosis. Veterans had lower 5-year survival and higher mortality hazards than nonveterans, suggesting military history may be an important prognostic factor in ALS.}, }
@article {pmid42669806, year = {2026}, author = {Rogala, O and Tarach, KA and Kordek, A and Shu, Y and Gilson, JP and Lakiss, L and Góra-Marek, K}, title = {Commercial Fluid Catalytic Cracking Catalysts for Polymers Chemical Recycling.}, journal = {ChemSusChem}, volume = {19}, number = {17}, pages = {e71002}, doi = {10.1002/cssc.71002}, pmid = {42669806}, issn = {1864-564X}, support = {2021/43/B/ST4/00307//Narodowe Centrum Nauki/ ; 2023/49/B/ST4/02340//Narodowe Centrum Nauki/ ; }, abstract = {Commercial FCC catalysts (fresh and equilibrated) and laboratory made catalysts from Y type zeolite and γ-Al2O3 are characterized by standard techniques and evaluated in the cracking of pure PP, LDPE, and PS polymers as well as coprocessing PP/LDPE mixture in TGA (light-off curves) and a unique operando FTIR &amp; GC-MS set-up. Conversions, products selectivities as well as coke deposition and removal are studied as a function of temperature. In spectroscopic operando investigations, MCR-ALS analysis provides significant insight into the observed results. The equilibrium FCC catalyst (Cat-Eq800) differs markedly from its fresh counterpart (Cat-F800) in product selectivity. Regardless of the polyolefin feed, Cat-Eq800 exhibits higher olefinicity in the C4 fraction. In both commercial catalysts, coke precursor formation proceeds predominantly via paraffin consumption. In situ FTIR analysis revealed valuable information regarding reactant diffusion and catalyst acidity. Despite undergoing severe deactivation treatments, the equilibrium catalyst displays the highest Brønsted-to-Lewis acid site ratio while maintaining efficient mass transport through its hierarchical pore structure. Important information to better design FCC catalysts can be derived, as the exact composition of these important catalysts are often tailored for specific families of heavy oil fractions.}, }
@article {pmid42669892, year = {2026}, author = {Zanovello, M and Serani, F and Bebeti, A and Paredi, F and Quadrio, G and Fortuna, A and Minicuci, GM and Pegoraro, E and Cagnin, A and Cecchin, D and Sorarù, G}, title = {Metabolic and Fluid Biomarkers Support Microglia Activation in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42669892}, issn = {2328-9503}, abstract = {Amyotrophic lateral sclerosis is an incurable neurodegenerative disease involving motor neuron degeneration and metabolic and immune dysfunction. We combined clinical data, cerebrospinal fluid biomarkers and fluorodeoxyglucose positron emission tomography with magnetic resonance imaging to investigate the role of reactive microglia in disease pathogenesis. Patients showed increased cerebrospinal fluid levels of neurofilament light chain and chitinases, along with hypermetabolism in the medulla oblongata. Chitinase levels correlated with brainstem metabolism and clinical severity. These findings suggest a link between microglial activation, brainstem hypermetabolism and disease progression in amyotrophic lateral sclerosis, supporting a central role for neuroinflammation in disease pathogenesis.}, }
@article {pmid42661070, year = {2026}, author = {Abel Jopaul, VP and Lingaraj, M}, title = {Comment on "Artificial intelligence construction: a review of the bridge between CT imaging features of lung ground-glass nodules adenocarcinoma and carcinogenic driver genes".}, journal = {Journal of cancer research and clinical oncology}, volume = {152}, number = {8}, pages = {}, pmid = {42661070}, issn = {1432-1335}, mesh = {Humans ; *Tomography, X-Ray Computed/methods ; *Lung Neoplasms/genetics/diagnostic imaging/pathology ; *Adenocarcinoma of Lung/genetics/diagnostic imaging/pathology ; *Artificial Intelligence ; }, abstract = {Xue and Chen et al.'s review connects AI-derived CT features of lung ground-glass nodule adenocarcinoma to driver gene status. Three aspects are missing. There is no stated search strategy no databases, date range, or inclusion criteria despite drawing on more than 150 references, so readers cannot tell whether weaker or null results were sought out or just left aside. Individual studies are cited by their best accuracy or AUC figures, from approximately 0.64 to above 0.95, with no attempt to weigh them by sample size, design, or validation status. The framing does not match the evidence the review cites: the text calls AI transformative, but a systematic review it references reports a mean AUC of only ~0.64 for driver gene prediction from imaging. None of this undercuts the review's usefulness as a starting map of the field, but a stated search process, some quality-weighting of the cited numbers, and framing that matches the aggregate evidence would make it more reliable.}, }
@article {pmid42661170, year = {2026}, author = {Wolf, J and Safer, A and Stefenelli, U and Woehrle, JC and Maschke, M and Nix, WA and Grau, AJ}, title = {Long-term survival in amyotrophic lateral sclerosis - data from a population-based registry in Rhineland-Palatinate, Germany.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {42661170}, issn = {1471-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/diagnosis ; Female ; Germany/epidemiology ; Male ; Registries ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Kaplan-Meier Estimate ; Disease Progression ; Prospective Studies ; }, abstract = {BACKGROUND: Data on long-term survival in amyotrophic lateral sclerosis (ALS) is scarce. In a population-based ALS cohort in Germany we evaluated long-term survival and assessed key factors influencing long-term survival, including demographic and clinical variables that are available at an early stage of the disease.<br><br>METHODS: Data from patients in the prospective, population-based ALS-registry Rhineland-Palatinate were analyzed. Survival was evaluated separately for time from symptom onset and time from diagnosis. Patient demographic and disease-related variables were analyzed in relation to survival probability using the Kaplan-Meier method and Cox proportional hazards regression.<br><br>RESULTS: Data from 200 incident ALS patients (106 men and 94 women) were included in the study. The median age of the patients was 68&#xa0;years (range 23-85&#xa0;years; mean age 65.8&#xa0;years; standard deviation 10.5&#xa0;years). The median survival time was 2.5&#xa0;years from symptom onset and 1.5&#xa0;years from diagnosis. 12% of the patients survived for at least ten years from first manifestation of symptoms. Multivariate statistics revealed that younger age, a low progression rate, the absence of frontotemporal dementia and a long interval between symptom onset and diagnosis were predictors of long survival.<br><br>CONCLUSIONS: 12% of ALS patients are still alive ten years after the onset of symptoms, which is important for advance planning of patient care. In our analysis demographic and clinical variables available at an early stage of the disease have emerged as valuable predictive factors.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov (NCT01955369; registered retrospectively 28/09/2013).}, }
@article {pmid42661580, year = {2026}, author = {O'Farrell, S and Holland, MC and Peelo, C and McLaughlin, R and Heverin, M and Hardiman, O and Costello, E and Pender, N}, title = {Cognitive and behavioral manifestations of the C9orf72 mutation in Amyotrophic Lateral Sclerosis: an age, education, and gender-matched cohort study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2721333}, pmid = {42661580}, issn = {2167-9223}, abstract = {OBJECTIVES: The presence of a hexanucleotide expansion in the gene C9orf72 confers a higher risk of developing ALS and FTD with associated cognitive and behavioral change, although penetrance is incomplete, and many gene carriers never exhibit any clinical signs during their lifetime. To date, there have been few studies investigating additional factors such as age, years of education, gender, and their influence on cognition and behavior in people with ALS (pwALS), particularly those with a hexanucleotide expansion in the gene C9orf72.<br><br>METHODS: We selected 104 consenting pwALS from the Irish ALS register, comprising 52 C9orf72 positive participants and 52 C9orf72 negative controls matched on age, years of education, and gender. Cognitive functioning was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), while behavioral changes were examined using the Beaumont Behavioral Inventory (BBI).<br><br>RESULTS: No significant differences in ECAS performance were observed across the two groups, with the exception of visuospatial performance, which was more impaired in those carrying the C9orf72 repeat expansion (p = .001). Similarly, there was no difference in behavoural scores between the 2 groups.<br><br>CONCLUSIONS: These findings suggest that the presence of the C9orf72 repeat expansion does not presage the development of significant cognitive or behavioral impairment early in the disease stage when controlled for age, years of education, and gender. When interpreting these results, it is important to consider the relatively small sample size, and the exclusion criteria of previous clinically significant comorbidities.}, }
@article {pmid42661656, year = {2026}, author = {Praharaj, S and Chakraborty, E and Mahalingam, G}, title = {Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1909393}, pmid = {42661656}, issn = {1662-5102}, abstract = {Ultraviolet radiation exhibits a complex, often contradictory link to neurodegeneration risk/progression, spanning clinically diagnosed diseases [Parkinson's Disease (PD), Alzheimer's Disease (AD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS)] or intermediate phenotypes (decreased neurogenesis, loss of hippocampal volume). The aim of this review is to highlight the dual impact of UV radiation by collecting and synthesizing experimental (preclinical and translational) evidence as well as epidemiological evidence. Current literature exhibits a clear dichotomy: while Vitamin D is capable of exerting a potent neuroprotective effect via anti-oxidant and anti-inflammatory pathways, chronic and intense UV radiation exposure actually hastens the progression or even drives neurodegeneration via a variety of mechanisms. UV radiation exerts its effects through various interconnected pathways: DNA damage pathways, ROS mediated pathways, vitamin D signaling and the skin-brain axis, which unifies both protective and degenerative effects of UV radiation. Owing to the increasing occurrence of neurodegenerative diseases in the general population, these pathways and mechanisms must be leveraged in future research to develop novel therapeutic and preventive strategies. Investigation of biomarkers linked to certain genetic and environmental factors that could provide a link to predisposition toward neurodegeneration and standardization of UV radiation dosimetry (exposure dose/duration) across experimental or pre-clinical studies must also be prioritized.}, }
@article {pmid42662266, year = {2026}, author = {Dresel, FC and Michaelis, M and Gourlay, CW}, title = {The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.}, journal = {International journal of cell biology}, volume = {2026}, number = {}, pages = {3022967}, pmid = {42662266}, issn = {1687-8876}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota-derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS-related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1[G85R]. Mechanistically, NaB recapitulated the effects of the pan-HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1[A4V], Sod1[G85R] or Sod1[G37R] in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.}, }
@article {pmid42663687, year = {2026}, author = {Hu, N and Zhang, L and Tian, H and Ding, J and Shen, D and Yang, X and Cui, L and Niu, J and Liu, M}, title = {Exploration of reliable assessment of respiratory function in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {9}, pages = {}, pmid = {42663687}, issn = {1590-3478}, support = {CIFMS 2021-I2M-1-003//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; 2022-PUMCH-B-017, 2022-PUMCH-D-002//National High Level Hospital Clinical Research Funding/ ; 2022ZD0118003//National Key Transform Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; Phrenic Nerve/physiopathology ; Ultrasonography ; Diaphragm/diagnostic imaging/physiopathology ; *Respiration Disorders/etiology/diagnosis/physiopathology ; Respiratory Function Tests ; Nerve Conduction Studies ; Fasciculation/physiopathology/etiology/diagnostic imaging ; }, abstract = {OBJECTIVE: To identify potentially useful objective indicators for early assessment of respiratory dysfunction in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Forty ALS patients were enrolled and followed every 3 months for one year. Baseline assessments included dyspnea complaints, ALSFRS-R, the ALS Respiratory Symptom Score (ARES), physical examination (including lower lung mobility), phrenic nerve conduction studies, diaphragm ultrasound, and multi-region ultrasound fasciculation detection. Forced vital capacity (FVC%) was also measured. Logistic regression (binary outcomes) and linear regression (continuous outcomes) were used to identify predictors of respiratory decline at 6 and 12 months.<br><br>RESULTS: At 6 months, decreased right lower lung mobility (&#x3b2;&#x2009;=&#x2009;1.771, 95%CI:1.047-2.495, p&#x2009;=&#x2009;0.038), bulbar fasciculations (OR&#x2009;=&#x2009;2.198, 95%CI:1.527-2.868, p&#x2009;=&#x2009;0.001), and lumbosacral fasciculations (OR&#x2009;=&#x2009;2.117, 95%CI:1.516-2.839, p&#x2009;=&#x2009;0.001) independently predicted a higher post-progression rate. At 12 months, cervical fasciculations predicted a higher post-progression rate (OR&#x2009;=&#x2009;1.644, 95%CI:1.130-2.157, p&#x2009;=&#x2009;0.017). Traditional measures (FVC%, diaphragm ultrasound, phrenic CMAP) showed limited short-term predictive value.<br><br>CONCLUSION: Lower lung mobility on physical examination and ultrasound-detected fasciculations in bulbar, cervical, and lumbosacral regions are potentially valuable objective markers for predicting disease progression in ALS. These exploratory findings suggest they may complement conventional pulmonary function tests, but require validation in larger independent cohorts.}, }
@article {pmid42664170, year = {2026}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O Apos Connell, C}, title = {Associations between level of urbanization and greenness and the development of amyotrophic lateral sclerosis: A matched case-control study.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1}, doi = {10.1159/ned/adwag011}, pmid = {42664170}, issn = {1423-0208}, abstract = {INTRODUCTION: Previous studies have considered level of urbanization when evaluating the role of place of residence in ALS. However, these studies have been subject to recall bias regarding previous exposures to urban characteristics owing to a lack of historical geospatial measures on urban form indicators.<br><br>METHODS: Thus, we created a robust database from multiple sources and conducted a matched case-control study in New Brunswick, Canada to investigate the association between long-term exposure to various local climate zones, as well as greenness, at place of residence and the development of ALS.<br><br>RESULTS: Odds of ALS were not significantly associated with the dense urban (1.1, 0.6 - 2.0 [95% CI]), open urban (0.5, 0.2 - 1.3 [95% CI]), residential (1.0, 0.9 - 1.1 [95% CI]), industrial (0.8, 0.6 - 1.2 [95% CI]), natural (1.0, 0.9 - 1.1 [95% CI]), or water (1.0, 0.9 - 1.1 [95% CI]) local climate zone classification categories per ten percentage increase in influence in the adjusted regression models. Exposure to greenness (1.7, 0.5 - 6.2 [95% CI]) was also not significantly associated to ALS in the adjusted regression models.<br><br>CONCLUSION: While not significantly associated to ALS, urban influence and greenness need to be further explored. Future studies should consider traffic-related pollutants as it pertains to urban density, while considering vegetation type and industry practices, such as farming and spraying, alongside greenness exposure measures.}, }
@article {pmid42664377, year = {2026}, author = {Escobar-Villegas, PA and Realpe-Camelo, AI and Arana-Salas, DA and Velásquez, JG and Paulo, M and Martínez-Cajas, CH and Amaya-Sanchez, S and Gómez-Mesa, JE}, title = {Endodontic status of patients with coronary atherosclerosis: A cross-sectional study.}, journal = {Dental and medical problems}, volume = {63}, number = {4}, pages = {885-891}, doi = {10.17219/dmp/205472}, pmid = {42664377}, issn = {2300-9020}, mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Coronary Artery Disease/epidemiology/complications/diagnostic imaging ; Middle Aged ; Colombia/epidemiology ; Aged ; *Root Canal Therapy ; Adult ; Prevalence ; Coronary Angiography ; }, abstract = {BACKGROUND: There are no studies in the Colombian population assessing the prevalence and severity of apical lesions (ALs), or the relationship between the frequency and quality of endodontic treatment (ET) obturation and the presence of ALs in patients with coronary atherosclerosis (CA).<br><br>OBJECTIVES: The present study aimed to estimate the frequency of ALs and ET in Colombian patients with CA, and to identify a possible association between the frequency and severity of ALs and CA.<br><br>MATERIAL AND METHODS: The study had a cross-sectional design. We included patients with the evidence of CA diagnosed by coronary angiography. The main outcome variables were the number of compromised coronary arteries and their degree of obstruction, as well as ET, including ALs and previously treated teeth (PTT). The periapical index (PAI) was assessed using periapical radiographs.<br><br>RESULTS: A total of 1,394 teeth from 69 patients were evaluated (&#x3b4; = 20.2 teeth/patient). The frequency of ALs and ET was 5.7% and 10.1%, respectively, considering all teeth evaluated, with a greater presence in the maxilla (50.6% and 51.4%, respectively). Apical lesions were most frequently observed in premolars and molars (35.4%), whereas ET was more frequent in molars (38.6%). Among teeth with ALs, PAI 3 was the most frequent score. Apical lesions were present in 40.0% of endodontically treated teeth; 79.2% of these teeth had inadequate obturation, of which 40 (39.2%) had ALs (p = 0.021).<br><br>CONCLUSIONS: In patients with CA, a high incidence of ALs and ET was observed, with no evidence of an association between the frequency of ALs, the severity of coronary vessel occlusion, and the number of coronary arteries affected. More ALs were observed in teeth with inadequate ET. However, as we did not have a control group for comparison, these findings should be interpreted with caution.}, }
@article {pmid42664852, year = {2026}, author = {Rogayan, DV and Tamoria, FV and Jaballa, JA and Andres, KP and Dantic, MJP and Tamoria, JR and Sahagun, RLA}, title = {TikTok for HIV prevention among Filipino youth: A behavioral economics approach.}, journal = {Patient education and counseling}, volume = {152}, number = {}, pages = {109833}, doi = {10.1016/j.pec.2026.109833}, pmid = {42664852}, issn = {1873-5134}, abstract = {This correspondence responds to Guss et al.'s study on using behavioral economics and TikTok for HIV pre-exposure prophylaxis (PrEP) education among youth. It expands the discourse to the Philippine context, where limited health literacy and rising HIV cases remain pressing concerns. With over 62 million TikTok users, the Philippines presents a critical opportunity to promote PrEP through gain-framed, authentic messaging. The commentary highlights the potential of social media as a tool for health education and calls for culturally relevant, youth-centered strategies to strengthen HIV prevention efforts among Filipino adolescents and young adults.}, }
@article {pmid42665553, year = {2026}, author = {Zhu, CW and Curtis, G and Joseph, J and Wecht, JM and Galea, MD and Harel, NY}, title = {Factors Affecting Disease Progression, Survival, and Caregiver Burden in United States Veterans at a Multidisciplinary Veterans Affairs ALS Center.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70385}, pmid = {42665553}, issn = {1097-4598}, support = {24-TC-705//ALS Association/ ; }, abstract = {INTRODUCTION/AIMS: Though studies of Veterans with ALS have reported survival rates, scant literature reports longitudinal symptom progression in Veterans using the ALS Functional Rating Scale-revised (ALSFRS-R). In the absence of an existing national database tracking disease progression in Veterans, we sought to use local medical records to characterize a cohort of Veterans with ALS treated at our VA ALS clinic.<br><br>METHODS: We examined demographic and clinical factors of 216 Veterans with ALS treated at the James J. Peters VA Medical Center (2012-2025) including race, ethnicity, region of symptom onset, and medication use as predictors of diagnostic delay, functional decline (ALS Functional Rating Scale-Revised (ALSFRS-R)), survival, and caregiver burden (Zarit Caregiver Burden Interview). Joint linear mixed modeling estimated longitudinal functional trajectories and survival simultaneously.<br><br>RESULTS: The cohort was 96.8% male and 74.5% White. Median age at symptom onset was 69.3&#x2009;years. Mean baseline ALSFRS-R was 30.7. Median survival from symptom onset was 4.4&#x2009;years. Median age at symptom onset was younger for Black (60.8&#x2009;years) and Hispanic (62.5&#x2009;years) Veterans than Whites (70.1&#x2009;years). Blacks had faster initial ALSFRS-R progression than Whites (mean 1.9 vs. 0.9 points per month). Blacks and Hispanics had 2.8-fold and 2.3-fold higher adjusted mortality hazard than Whites, respectively. Forty-nine percent of caregivers reported high caregiver burden at first assessment, rising to 66.2% at subsequent assessments.<br><br>DISCUSSION: Racial and ethnic disparities in ALS progression and survival are pronounced in this single-site Veteran cohort. Standardized ALS-specific data collection across the VHA is needed to enable system-wide analyses.}, }
@article {pmid42665653, year = {2026}, author = {Shaji, V and Jain, R and Puthumadathil, N and Jana, K and T S, V and Kleinekathöfer, U and Chattopadhyay, K and Mahendran, KR}, title = {A self-assembled peptide forms α-helical nanopores for ultrasensitive biomarker profiling.}, journal = {Nature nanotechnology}, volume = {}, number = {}, pages = {}, pmid = {42665653}, issn = {1748-3395}, support = {BT/PR53613/BMS/85/242/2024//Department of Biotechnology, Ministry of Science and Technology (DBT)/ ; IIRPIG-2024-01-00131//Indian Council of Medical Research (ICMR)/ ; IIRPSG-2024-01-01188//Indian Council of Medical Research (ICMR)/ ; INST 676/7-1 FUGG//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; OLP-120//Council of Scientific and Industrial Research (CSIR)/ ; }, abstract = {α-Helical nanopores are attractive molecular sensors, yet their rational design and assembly remain challenging. Here we show that the single peptide pPorA, derived from porin PorACj, self-assembles into flexible α-helical nanopores, inserts in lipid membranes and exists in distinct small- and large-conductance states. By strategically incorporating unnatural amino acids, we engineered small- and large-diameter pores exhibiting single-channel conductances of 2.4 nS and 3.5 nS in 1 M KCl, respectively, while retaining a common octameric architecture. These nanopores enabled the detection of sugars, peptide enantiomers and intrinsically disordered disease proteins that form dynamic, heterogeneous assemblies. The large pores detected multiple α-synuclein (α-syn) variants, including a pathogenic Parkinson's disease-associated C-terminal deletion mutant with nanomolar affinity (KD ≈ 20 nM). Selective electrostatic trapping of the α-syn N-terminus enabled charge-resolved identification of individual α-syn species within heterogeneous mixtures. The nanopores further resolved time-dependent and inhibitor-modulated α-syn aggregation pathways from monomers to toxic oligomers and fibrils. The small pores detected humanin and superoxide dismutase peptides associated with apoptosis and amyotrophic lateral sclerosis, demonstrating tunable sensing through pore-size control. These conformationally programmable α-helical nanopores provide a versatile platform for ultrasensitive profiling of disease biomarkers.}, }
@article {pmid42657487, year = {2026}, author = {da Silva, AA and Pupe, CCB and Dos Santos, JCC}, title = {High-dose methylcobalamin in amyotrophic lateral sclerosis: mechanistic rationale, translational evidence, and clinical implications.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/17582024.2026.2713755}, pmid = {42657487}, issn = {1758-2032}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons, driven by converging mechanisms including glutamatergic excitotoxicity, mitochondrial dysfunction, oxidative stress, calcium dyshomeostasis, impaired RNA metabolism, and neuroinflammation. In the absence of effective disease-modifying therapies, high-dose methylcobalamin has emerged as a candidate intervention based on its pleiotropic neurobiological effects. A structured literature search was conducted in PubMed/MEDLINE and ScienceDirect to identify peer-reviewed studies published between January 2017 and December 2025 addressing the mechanistic, preclinical, and clinical effects of methylcobalamin in ALS. Preclinical evidence suggests that methylcobalamin modulates homocysteine metabolism, supports S-adenosylmethionine-dependent methylation pathways, preserves mitochondrial integrity, attenuates oxidative stress, and promotes axonal regeneration. Experimental and translational findings further indicate that its therapeutic effects may be strongly dose dependent, particularly under ultra-high-dose regimens capable of overcoming limitations in central nervous system delivery. Clinical trials evaluating ultra-high-dose methylcobalamin demonstrate a potential attenuation of functional decline in patients treated during early disease stages, although effects on survival and respiratory outcomes remain inconsistent. This narrative review integrates molecular mechanisms, experimental evidence, biomarker research, and clinical trial data to examine the translational relevance, stage dependency, and therapeutic implications of high-dose methylcobalamin in ALS.}, }
@article {pmid42658841, year = {2026}, author = {Carbayo, &#xc1; and Turon-Sans, J and Alcolea, D and Cortés-Vicente, E and Cabezas-Torres, M and Alvarez-Sanchez, E and Muñoz, L and Rubio-Guerra, S and García-Castro, J and Selma-González, J and Bernal, S and Gonzalez-Quereda, L and Bejanin, A and Aranha, MR and Santos-Santos, M and Belbin, O and Vesperinas-Castro, A and Collet-Vidiella, R and Caballero-Ávila, M and Llansó, L and Querol, L and Lleó, A and Fortea, J and Gelpí, E and Dols-Icardo, O and Illán-Gala, I and Rojas-Garcia, R}, title = {Methodological insights and clinical outcomes in ALS and FTLD: lessons from the SPIN cohort.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71777}, pmid = {42658841}, issn = {1552-5279}, support = {//Fundaci&#xf3; V&#xed;ctor Gr&#xed;fols i Lucas/ ; PI17/01019//Instituto de Salud Carlos III/ ; PMPER24/0017//Instituto de Salud Carlos III/ ; PI18/00435//Instituto de Salud Carlos III/ ; 044412//Fundaci&#xf3; la Marat&#xf3; de TV3/ ; 20142610//Fundaci&#xf3; la Marat&#xf3; de TV3/ ; PI19/01543//Instituto de Salud Carlos III/ ; FISEC08/00077//Instituto de Salud Carlos III/ ; PI22/00758//Instituto de Salud Carlos III/ ; INT21/00073//Instituto de Salud Carlos III/ ; INT19/00016//Instituto de Salud Carlos III/ ; PI22/00611//Instituto de Salud Carlos III/ ; AC19/00103//Instituto de Salud Carlos III/ ; R21 AG056974/AG/NIA NIH HHS/United States ; PI18/00335//Instituto de Salud Carlos III/ ; ICI23/00032//Instituto de Salud Carlos III/ ; PI14/01126//Instituto de Salud Carlos III/ ; DABNIproject//Fundaci&#xf3; Bancaria "La Caixa"/ ; PI13/00772//Instituto de Salud Carlos III/ ; PI15/01618//Instituto de Salud Carlos III/ ; PI23/01786//Instituto de Salud Carlos III/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; //Fondo Europeo de Desarrollo Regional (FEDER)/ ; RF1 AG061566/AG/NIA NIH HHS/United States ; //Fundaci&#xf3;n HNA/ ; PI23/00845//Instituto de Salud Carlos III/ ; RF1 AG056850/AG/NIA NIH HHS/United States ; AACSF-21-850193/ALZ/Alzheimer's Association/United States ; PI20/01473//Instituto de Salud Carlos III/ ; PI19/00882//Instituto de Salud Carlos III/ ; PI17/01896//Instituto de Salud Carlos III/ ; PI21/00791//Instituto de Salud Carlos III/ ; PI22/00307//Instituto de Salud Carlos III/ ; 201437.10;20141210//Fundaci&#xf3; la Marat&#xf3; de TV3/ ; INT23/00048//Instituto de Salud Carlos III/ ; AUL2025.1//Fundaci&#xf3;n Luz&#xf3;n/ ; //FUNDELA/ ; //Fundaci&#xf3; Catalana S&#xed;ndrome de Down/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/genetics/pathology/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cohort Studies ; Neuroimaging ; Male ; Female ; Longitudinal Studies ; Precision Medicine ; Aged ; Middle Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) constitute a clinico-genetic-neuropathological continuum with marked heterogeneity. Reliable in vivo biomarkers of the disease are lacking. Large, multimodal cohorts are needed to advance biomarker discovery and precision medicine.<br><br>METHODS: We describe the structure and results derived from the Sant Pau Initiative on Neurodegeneration (SPIN)-ALS-FTLD subcohort, a longitudinal, multimodal platform that integrates clinical, cognitive, genetic, biofluid, neuroimaging, and neuropathological data within a unified framework embedded in routine care.<br><br>RESULTS: The cohort includes over 1000 participants, 800 blood, 400 CSF, and 800 DNA samples, neuroimaging in over 250 cases, and 66 neuropathological studies. Harmonized longitudinal data and biospecimen collection have enabled substantial clinical, molecular, and translational research output.<br><br>DISCUSSION: SPIN-ALS-FTLD extends the original SPIN framework to the ALS-FTLD continuum, enabling deep phenotyping and multimodal biomarker discovery. This scalable model supports patient stratification, longitudinal monitoring, and the development of precision medicine approaches in neurodegenerative diseases.}, }
@article {pmid42652600, year = {2026}, author = {Davies, A and Bentley, A and Bikov, A}, title = {The Role of Neurofilaments in Diagnosis and Monitoring of Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {16}, pages = {}, pmid = {42652600}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease (MND), is a devastating diagnosis that often leads to mortality within 2-5 years of symptom onset. Respiratory failure and aspiration pneumonia both associated with respiratory muscle weakness are the most common causes of death. Difficult to diagnose and devastating in its prognosis, much research has aimed to identify a reliable biomarker to diagnose ALS, prognosticate and improve enrolment into clinical trials to further research efforts. Over the last few decades, neurofilaments (NFs) have emerged as promising biomarkers, especially neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). This review aims to summarise the current evidence for use of NFs as biomarkers in ALS. Current Evidence: Higher levels of NFL and pNFH are measured in CSF than in serum, and levels in CSF and serum are correlated. High CSF NFL, serum NFL and CSF pNFH levels could differentiate patients with ALS from healthy controls, other neurological disease, neurodegenerative controls (without MND), other MND subtypes and ALS disease mimics; however, studies reported a high degree of heterogeneity irrespective of which media or NFs have been used. The number of studies examining NFs to predict respiratory failure in patients with ALS is low. Conclusions and Future Directions: Despite numerous studies consistently reporting higher NF levels in ALS compared to various controls, their clinical value is limited due to high heterogeneity of the results and inconsistencies in proving its prognostic value. Further understanding the relationship between NF levels and respiratory failure is paramount to improve the quality of life of patients with ALS and increase survival.}, }
@article {pmid42652767, year = {2026}, author = {Friebel, J and Manni, M and Gozdowsky, SC and Brettschneider, P and Grün, D and Baumann, AM and Spielmann, E}, title = {Reorganisation of the Basic Life Support Segment in a Physician-Led Emergency Medical Service: A Retrospective Evaluation of Operational and Clinical Characteristics.}, journal = {Journal of clinical medicine}, volume = {15}, number = {16}, pages = {}, pmid = {42652767}, issn = {2077-0383}, abstract = {Background: Increasing demand for emergency medical services (EMS) challenges prehospital resource availability, particularly for time-critical emergencies requiring advanced life support (ALS). Although tiered BLS and ALS response models are established in many non-physician-led EMS systems, evidence regarding qualification-based dispatch stratification within physician-led EMS systems remains limited. This study evaluated the clinical and operational characteristics of an expanded BLS dispatch segment in Berlin EMS. Methods: A retrospective observational study analysed 2,132,246 EMS missions in Berlin, Germany, between 2020 and 2024. Missions were retrospectively classified according to dispatch codes included in the expanded BLS segment, designed to allocate incidents with lower expected requirements for ALS-level interventions to appropriately qualified EMS personnel. Analyses included dispatch characteristics, clinical findings from electronic patient care records, observed safety-related indicators, and ALS response intervals. Results: Overall, 28.7% of EMS missions were classified within the expanded BLS segment. Traumatic and psychiatric presentations represented the most frequent diagnostic groups. Based on predefined clinical indicators, no immediately life-threatening condition was documented in more than 95% of missions. Cardiopulmonary resuscitation occurred in 0.03% of cases, and emergency physician involvement was documented in approximately 3% of cases. Conclusions: A substantial proportion of EMS missions represented a population with predominantly lower expected prehospital treatment complexity within a qualification-based dispatch framework. Structured emergency call interrogation combined with dispatch classification and linked clinical data enabled retrospective evaluation of this approach. Further validation against independent clinical reference standards and linkage with downstream outcomes are required to determine broader applicability.}, }
@article {pmid42652933, year = {2026}, author = {Ilias, I and Keskinidou, C and Poupouzas, G and Issaris, V and Lotsios, NS and Botoula, E and Tzanela, M and Vassiliadi, DA and Kokkoris, S and Vrettou, CS and Vassiliou, AG and Dimopoulou, I}, title = {Growth Hormone-Insulin-like Growth Factor Axis and GDF-15 in Critical Illness: Implications for Survival Stratification.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {42652933}, issn = {2075-1729}, abstract = {Background: The growth hormone (GH)-insulin-like growth factor (IGF) axis is profoundly dysregulated in critical illness. GDF-15 and individual IGF-binding proteins (IGFBPs) have separately been proposed as prognostic biomarkers, but to our knowledge, no prior study has simultaneously characterized all major GH-IGF axis components and GDF-15 in the same critically ill cohort, precluding assessment of their joint intercorrelation structure. Aim: To provide the first simultaneous characterization of the intercorrelation structure among ten GH-IGF axis components and GDF-15 in a single ICU cohort, testing whether this structure is robust to adjustment for illness severity; and, secondarily, to describe admission discriminatory performance relative to APACHE II and SOFA. Methods: This was a prospective observational pilot study of 43 critically ill adults with admission (T01) measurement of ten GH-IGF axis biomarkers and longitudinal follow-up to day 15. Spearman correlations and hierarchical clustering characterized the admission intercorrelation structure; partial correlations adjusting for APACHE II and SOFA, and bootstrap confidence intervals, assessed robustness. Secondary analyses included the examination of admission discrimination (ROC/AUC), a leave-one-out cross-validated combined model, and longitudinal trajectories. All analyses were exploratory, hypothesis-generating, and unadjusted for multiple comparisons unless stated. Results: Hierarchical clustering identified a coherent cluster comprising GDF-15, IGFBP-1, IGFBP-2, and growth hormone-binding protein (GHBP), distinct from classical GH-resistance markers (GHR vs. healthy controls, GHR vs. admission) and from GH, IGF-1, acid-labile subunit (ALS), and IGFBP-3. Within this cluster, GDF-15 correlated with IGFBP-1 (ρ = 0.65, 95% bootstrap CI 0.44-0.78), IGFBP-2 (ρ = 0.50, CI 0.19-0.71), and GHBP (ρ = 0.47, CI 0.20-0.68); GDF-15 showed no correlation with classical GH-resistance markers. These correlations were essentially unchanged after adjusting for APACHE II or SOFA (partial ρ within 0.03-0.16 of unadjusted values), indicating the structure is not attributable to shared confounding by illness severity. This robustness extended to further adjustment for IL-6, age, BMI, and mechanical-ventilation duration, and results from all 45 pairwise T01 correlations were re-examined with Benjamini-Hochberg false-discovery-rate correction (9 of 11 nominally significant pairs retained q < 0.05). However, the GDF-15-GHBP correlation, unlike the GDF-15-IGFBP-1/IGFBP-2 correlations, attenuated substantially after adjustment for IL-6 and was not consistent across a brain-injury/non-brain-injury subgroup sensitivity analysis, indicating this specific link is less specific than the others. In secondary exploratory analyses, GDF-15 had the highest individual admission AUC (0.74) among biomarkers but was substantially outperformed by APACHE II (AUC 0.90) and SOFA (AUC 0.81); a combined GDF-15 + IGFBP-2 model did not improve on GDF-15 alone. Conclusions: This study identifies a severity-independent intercorrelation structure linking GDF-15 to inhibitory IGFBPs, distinct from classical GH-resistance signaling, in critically ill patients. Although the findings do not support any clinical application at this stage, further study in adequately powered, multicenter cohorts can be contemplated.}, }
@article {pmid42653169, year = {2026}, author = {Terribile, G and Pedrinazzi, M and Frigerio, I and Sancini, G and Combi, R}, title = {Theranostic Innovative Strategies for Brain Diseases: New Insights on Neurovascular Unit-Associated Pathological Changes in Neurodegenerative Disorders and Aging.}, journal = {International journal of molecular sciences}, volume = {27}, number = {16}, pages = {}, pmid = {42653169}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/diagnosis ; *Aging/pathology ; Animals ; Blood-Brain Barrier/metabolism/pathology ; *Theranostic Nanomedicine/methods ; *Brain Diseases/therapy/diagnosis/pathology ; Nanoparticles ; MicroRNAs/genetics ; Nanotechnology ; }, abstract = {Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood-brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics-integrated diagnostic and therapeutic platforms-focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic "one-pill-for-one-disease" model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies.}, }
@article {pmid42653407, year = {2026}, author = {Rosenfeld, J and Salomon-Zimri, S and Tracik, F}, title = {Combination Pharmacology for ALS: A Mechanistic Rationale.}, journal = {International journal of molecular sciences}, volume = {27}, number = {16}, pages = {}, pmid = {42653407}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Drug Therapy, Combination ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves multiple converging pathogenic mechanisms, including glutamate excitotoxicity, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, neuroinflammation, iron dysregulation, and altered microRNA processing. Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.}, }
@article {pmid42656624, year = {2026}, author = {Soberano, JI and Montayre, J}, title = {Social frailty and related social vulnerabilities among older adults in the Philippines: A narrative review.}, journal = {International journal of nursing studies advances}, volume = {11}, number = {}, pages = {100655}, pmid = {42656624}, issn = {2666-142X}, abstract = {OBJECTIVES: To synthesize the evidence on social frailty among older adults in the Philippines, with attention to sociocultural and structural determinants, assessment approaches, and policy and program responses, and to derive implications for nursing practice and research.<br><br>METHODS: A narrative review with scoping elements was informed by the Scale for the Assessment of Narrative Review Articles (SANRA), with selected PRISMA-ScR items used to enhance reporting transparency. Electronic searches of PubMed, CINAHL, Web of Science, PsycINFO, and Google Scholar identified peer-reviewed and relevant verifiable discussion papers written in English from January 2015 to December 2025 (final search: 5 January 2026). The search, title, and abstract screening, full-text review, and data extraction were performed independently by two reviewers, with disagreements resolved through consensus. Eligible studies focused on community-dwelling Filipinos aged &#x2265;60 years and examined social frailty or closely related constructs, including social networks, participation, support, isolation, loneliness, and social determinants of health and functioning. Data were synthesized thematically using Bunt et al.'s four domains of social frailty.<br><br>RESULTS: Thirty-five studies were included, most using qualitative or cross-sectional designs. Evidence clustered in the domains of general resources and social behavior activities, particularly access, participation, mobility, disaster related disruption, and emerging digital engagement. Fewer studies addressed social resources and self-management abilities. Family, kinship, and faith-based networks, and community organization were important protective systems, but were increasingly strained by migration, economic insecurity, service limitations, and environmental disruption.<br><br>CONCLUSIONS: Social frailty among older Filipinos emerges at the intersection of structural disadvantage, changing informal support systems, community participation, digital access, and self-management capacities. Addressing social frailty requires multidimensional assessment, culturally grounded measurement, and coordinated nursing, community and policy responses.}, }
@article {pmid42656814, year = {2026}, author = {Fent, M and Farkas, A and Pataki, H and Nagy, ZK and Csontos, I}, title = {Spectroscopic Monitoring and Chemometric-Based Feedback Control of the Diazotization Reaction.}, journal = {Organic process research &amp; development}, volume = {30}, number = {8}, pages = {2149-2158}, pmid = {42656814}, issn = {1083-6160}, abstract = {Inline Raman spectroscopy-based monitoring enables the development of control systems that allow the implementation of Process Analytical Technology (PAT) principles even in chemical reactions, thereby improving quality, efficiency, and safety. There are only a few articles in the literature that discuss such control systems. This may be due to the numerous challenges involved, including the need for robust measurement setups and the development of chemometric algorithms capable of delivering accurate and stable real-time evaluations. Thus, this study presents the Raman spectroscopic monitoring and chemometric-based feedback control of a highly exothermic and potentially hazardous diazotization reaction, namely, the synthesis of phenyldiazonium chloride from aniline, hydrochloric acid, and sodium nitrite. Raman spectra were analyzed offline using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and in real-time using Classical Least Squares (CLS) chemometric methods to monitor and control key reaction components. The developed feedback system successfully controlled concentration levels during both acid-base and diazotization phases. The reduction of the Raman signal-to-noise ratio, induced by the decomposition of the diazonium salt, was also observed. This factor significantly affected the monitoring of the diazotization experiment. Furthermore, a calibration was established to quantify the molar concentrations of key components based on Raman spectra. The calibration experiment successfully demonstrated well-fitted linear molar-spectral relationships for both aniline (R [2] homogeneous = 0.997; R [2] heterogeneous = 0.9947) and aniline hydrochloride (R [2] = 0.9987). For aniline, the molar-spectral relationship exhibited a distinct change in tendency that precisely correlated with its solubility limit in water, marking the transition from homogeneous solution to emulsion.}, }
@article {pmid42656917, year = {2026}, author = {Zhang, J and Tang, P and Huang, L and Lv, J and Chen, Y and Wang, Y and Luo, Y}, title = {Multifaceted roles of S100A6 in neurological disorders: expression, interaction networks, and clinical implications.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1890559}, pmid = {42656917}, issn = {1663-9812}, abstract = {S100A6 (calcyclin) is a multifunctional Ca[2+]/Zn[2+]-binding protein of the S100 family, widely expressed in neurons and glia with a developmentally regulated and cell-type-specific pattern. This review synthesizes current knowledge on its roles in the nervous system. We detail its complex interactome, which includes cytoskeletal regulators, molecular chaperones, nuclear transport proteins, and cell surface receptors, positioning S100A6 as a central signaling hub. Furthermore, we examine its dynamic and context-dependent involvement in major neurological disorders. In Alzheimer's disease and amyotrophic lateral sclerosis, it functions as a glial-derived factor linking protein aggregation, metal dyshomeostasis, and neuroinflammation. In neuro-oncology, S100A6 exhibits dual roles, acting as a promoter of malignancy and immunosuppression in glioblastoma, an epigenetically silenced marker in medulloblastoma, and a diagnostic aid for peripheral nerve sheath tumors. Its expression is also altered in epilepsy, traumatic brain injury, and autoimmune encephalitis. Understanding the nuanced functions of S100A6 offers significant potential for developing novel diagnostic biomarkers and targeted therapeutic strategies for a range of challenging neurological conditions.}, }
@article {pmid42657306, year = {2026}, author = {Xie, J and Shao, J and Wang, C and Shi, X and Miao, Q and Yip, CC and Ye, J}, title = {Visual cueing and adaptive learning for teaching thyroid eye disease diagnostic assessment to ophthalmology residents.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1934529}, pmid = {42657306}, issn = {2296-858X}, abstract = {BACKGROUND: Thyroid eye disease (TED) diagnosis requires residents to interpret subtle clinical and imaging findings for activity and severity assessment. Guided by Cognitive Load Theory, visual cueing may support attention to diagnostically relevant features, whereas adaptive learning may tailor practice to learner performance. This pilot study compared visual cueing, adaptive learning, and traditional static case review for TED diagnostic training.<br><br>METHODS: Forty-five ophthalmology residents were randomised equally to static case review (SCR), an adaptive learning system (ALS), or a visual cueing atlas (VCA). Following a 45-minute intervention, residents completed immediate and two-week delayed tests. The primary outcome was immediate overall diagnostic accuracy. Secondary outcomes were Clinical Activity Score (CAS) accuracy, severity-grading accuracy, delayed-test performance (2 weeks post-intervention), and performance decline from immediate to delayed testing. Educational materials were validated by ten expert ophthalmologists. Item-level content validity indices and the scale-level content validity index were calculated from expert ratings.<br><br>RESULTS: All residents completed the study. Expert validation showed excellent content validity for the educational materials, with the Item-level Content Validity Index for all components and the overall Scale-level Content Validity Index both reaching 1.00. At the immediate post-test, VCA achieved higher CAS accuracy than SCR (84.7% vs. 64.7%, p&#x2009;<&#x2009;0.001). ALS and VCA achieved higher severity-grading accuracy than SCR (83.3% and 78.7% vs. 66.7%; p&#x2009;=&#x2009;0.004 and p&#x2009;=&#x2009;0.025, respectively), and both achieved higher overall diagnostic accuracy than SCR (66.0% each vs. 51.3%; p&#x2009;=&#x2009;0.014 and p&#x2009;=&#x2009;0.008, respectively). At two weeks, ALS showed higher severity-grading accuracy than SCR (74.0% vs. 56.0%, p&#x2009;<&#x2009;0.001), while both ALS and VCA maintained higher overall diagnostic accuracy than SCR (54.0% and 52.7% vs. 41.3%; p&#x2009;=&#x2009;0.014 and p&#x2009;=&#x2009;0.008, respectively).<br><br>CONCLUSION: In this pilot study, visual cueing was associated with higher immediate CAS accuracy, whereas adaptive learning was associated with higher severity-grading accuracy on the two-week delayed test, relative to static case review. These approaches may have complementary roles in TED diagnostic education. Larger studies using equivalent instructional exposure, matched assessment forms, and longer follow-up are needed before a staged hybrid approach is recommended.}, }
@article {pmid42651103, year = {2026}, author = {Costa, IM and Kanashiro, A and Barros, GSF and Monteiro, AJ and Bonilha, CS and Galdino, G and Veras, FP}, title = {Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651103}, issn = {2076-3425}, abstract = {Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.}, }
@article {pmid42651138, year = {2026}, author = {Lu, S and Chen, Z and Wang, Y and Bian, H and Yu, S and Huang, L}, title = {Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651138}, issn = {2076-3425}, support = {LH2019H106//Natural Science Foundation of Heilongjiang Province/ ; YQJH2023152//Excellent Young Teachers Basic Research Support Program" for Provincial Undergraduate Colleges in Heilongjiang Province/ ; ZHY2025-009//Heilongjiang&#xa0;Province&#xa0;Traditional&#xa0;Chinese&#xa0;Medicine&#xa0;Research&#xa0;Project/ ; }, abstract = {O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.}, }
@article {pmid42651198, year = {2026}, author = {Harris, KE and Lascaratos, G and Chau, KY}, title = {Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651198}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.<br><br>METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.<br><br>RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.<br><br>CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.}, }
@article {pmid42651202, year = {2026}, author = {Alshehri, S and Atabek, B and Heiman-Patterson, T and Ayaz, H}, title = {Task-Evoked Prefrontal Hemodynamics During Cognitive Assessment in Amyotrophic Lateral Sclerosis Using fNIRS.}, journal = {Brain sciences}, volume = {16}, number = {8}, pages = {}, pmid = {42651202}, issn = {2076-3425}, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease increasingly recognized for extra-motor manifestations, including cognitive dysfunction involving frontal cortical systems. Conventional clinical assessments are primarily behavioral and may not capture subtle alterations in the neural systems that support cognitive performance. This pilot study examined whether wearable functional near-infrared spectroscopy (fNIRS) could detect task-evoked prefrontal hemodynamic differences during the King-Devick Task (KDT), a rapid oculomotor number-naming task that engages visual scanning, attention, processing speed, and verbal response production. Methods: Sixteen participants, including seven individuals with ALS and nine age-matched healthy controls (HC), completed four progressively difficult KDT conditions while prefrontal cortical activity was recorded. Results: As task difficulty increased, response times became slower across participants, while accuracy remained preserved and behavioral performance did not differ significantly between groups. Prefrontal oxygenated hemoglobin (HbO) responses increased with task difficulty across all prefrontal optodes, supporting task-evoked cortical engagement. In contrast, deoxygenated hemoglobin (HbR) responses showed a group-specific pattern in the left dorsolateral prefrontal cortex: individuals with ALS demonstrated progressively increasing HbR responses across difficulty conditions, whereas HC showed relatively stable responses, with group differences emerging at higher difficulty levels. Conclusions: These findings suggest a dissociation between preserved behavioral performance and altered prefrontal hemodynamic regulation in ALS. The observed HbR pattern may reflect differences in cortical recruitment, neurovascular coupling, oxygen extraction, vascular responsiveness, or the efficiency of cortical resource allocation during increasing cognitive-motor demands. Wearable fNIRS may therefore complement behavioral assessments by revealing task-evoked neural alterations that are not evident from performance measures alone.}, }
@article {pmid42651367, year = {2026}, author = {Alshaibany, FF and Almutairy, BM and Alghamdi, A and Alshehri, WM and Aljabri, MM and Alharbi, A and Alharbi, BS and Alodhailah, AM}, title = {A Resilience-Based Nursing Intervention Framework for Internet Gaming Disorder in Saudi University Health Settings.}, journal = {Healthcare (Basel, Switzerland)}, volume = {14}, number = {16}, pages = {}, pmid = {42651367}, issn = {2227-9032}, support = {ORF-2026-1712//Ongoing Research Funding Program/ ; }, abstract = {Background/Objectives: Internet Gaming Disorder (IGD) is included in ICD-11 and poses a substantial risk to Saudi university students, yet no structured nursing intervention framework exists within Saudi higher education health services. This paper presents the Resilience-Based Nursing Intervention Framework (RBNIF), a three-tiered, theory-driven nursing architecture translating evidence on impulsivity, resilience, and IGD into practice specifications for this setting. Methods: Using secondary analysis of a dataset of 207 gaming students from four King Saud University colleges, framework development followed a four-phase Medical Research Council (MRC) process: theoretical identification (I-PACE, Dual Process Theory, COM-B), evidence synthesis, Behavior Change Wheel/Intervention Mapping, and cultural adaptation via Bernal et al.'s Ecological Validity Framework. Results: The sample (58.9% male; 20-25 years, 61.4%; bachelor's level, 73.9%) yielded three tiers differentiated by a dual-domain screening rule (elevated impulsivity and/or low resilience, rather than a single combined score): Tier 1 (universal psychoeducation); Tier 2 (six-session group program, S-UPPS-P ≥ 52 and/or CD-RISC-10 ≤ 20; 63 of 207 participants [30.4%]); and Tier 3 (10-session RIRDH clinical program, IGDS9-SF ≥ 36, met by 38 of 207 participants [18.4%]). Fifty-two participants (25.1%) met the elevated-impulsivity criterion, and 51 (24.6%) met the low-resilience criterion. Each tier specifies nursing competencies and behavior change techniques, with cultural adaptation integrating Islamic values concepts (sabr, mizan, tawakkul), family protocols, and single-sex delivery. Conclusions: To our knowledge, the RBNIF is the first theory-driven, culturally adapted nursing intervention architecture for IGD in Saudi university health services; a focused, non-systematic search of PubMed, Scopus, and CINAHL identified no directly comparable published framework. It is pre-implementation and requires feasibility testing, pilot evaluation, and a cluster-randomized controlled trial (c-RCT).}, }
@article {pmid42651639, year = {2026}, author = {Ciuro, M and Rovetto, C and Sirna, AA and Giunta, S and Leanza, G and Gulino, R}, title = {Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Biology}, volume = {15}, number = {16}, pages = {}, pmid = {42651639}, issn = {2079-7737}, support = {PG_6/2022//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1[G93A] mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS.}, }
@article {pmid42651822, year = {2026}, author = {Satoh, K and Shimamura, MI and Fujimoto, T and Kitayama, M and Akagi, A and Iwasaki, Y and Satoh, Y and Ichinose, K and Satoh, A and Iwata, IT and Yabe, I}, title = {Detection of TDP-43 Proteinopathies in Brain and Cerebrospinal Fluid Using Seed Amplification Assay.}, journal = {Current issues in molecular biology}, volume = {48}, number = {8}, pages = {}, pmid = {42651822}, issn = {1467-3045}, support = {JP 21K07417 and JP 25K02582//Japan Society for the Promotion of Science/ ; //TaNeDS Funding for Daiichi Sankyo Co/ ; 2023088970//Takeda Science Foundation/ ; 25dk0207077h0001//Japan Agency for Medical Research and Development/ ; }, abstract = {Misfolded TAR DNA-binding protein 43 (TDP-43) is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), have shown promise in detecting misfolded TDP-43 in cerebrospinal fluid (CSF) and olfactory mucosa, technically accessible methodologies are urgently required for widespread clinical application. We developed a streamlined, non-immunoprecipitation-based TDP-43 RT-QuIC assay to assess seeding activity in brain tissue and CSF. We evaluated its diagnostic performance using CSF from patients with TDP-43 proteinopathies and control subjects, and further examined its association with neurofilament light chain (NfL) and tau-related biomarkers. In CSF analysis, the assay demonstrated positive seeding activity in 70% (21/30) of patients with ALS and dementia, 50% (5/10) of patients with FTLD, and 40% (8/20) of patients with ALS alone. The assay exhibited excellent specificity, yielding negative results in >99% (199/200) of control samples, including those with autoimmune or electrophysiological abnormalities. Furthermore, CSF analysis demonstrated significantly higher NfL levels in TDP-43 SAA-positive cases compared to SAA-negative cases (p < 0.0008). The highest NfL concentrations were observed in the SAA-positive ALS with dementia and ALS cohorts, contrasting with lower levels in FTLD. Tau-related biomarkers exhibited no significant differences between the groups. Our streamlined, non-immunoprecipitation TDP-43 RT-QuIC assay provides highly specific detection of pathological TDP-43 seeding activity. While the assay detects the underlying TDP-43 proteinopathy rather than distinguishing between ALS and FTLD clinical phenotypes, its technical simplicity and combined utility with NfL measurements offer a robust, scalable framework for biomarker development. This approach provides a practical foundation for future multi-center validation and international standardization efforts.}, }
@article {pmid42652164, year = {2026}, author = {Karbownik, M and Fidura, M and Perlikowska, R}, title = {Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?.}, journal = {Biomedicines}, volume = {14}, number = {8}, pages = {}, pmid = {42652164}, issn = {2227-9059}, support = {564-20-100//Medical University of Lodz/ ; }, abstract = {Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity.}, }
@article {pmid42652219, year = {2026}, author = {Sousa-Catita, D and Mascarenhas, P and Oliveira, C and Grunho, M and Gonçalves, F and Fonseca, J}, title = {Clinical, Social, and Healthcare Factors Associated with Nutritional Status in Amyotrophic Lateral Sclerosis: A Multidimensional Approach.}, journal = {Biomedicines}, volume = {14}, number = {8}, pages = {}, pmid = {42652219}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where malnutrition significantly worsens clinical outcomes. We performed a multidimensional analysis to identify clinical, social, and healthcare factors associated with nutritional vulnerability in a real-world setting. Methods: This cross-sectional study included 97 adults with ALS recruited through a national association (APELA) and a hospital-based outpatient consultation (ANOC). Nutritional status was assessed using the Mini Nutritional Assessment (MNA[®]), Body Mass Index (BMI), and Global Leadership Initiative on Malnutrition (GLIM) criteria. Associations with total MNA[®] scores were evaluated using a prespecified multivariable linear model with HC3 robust standard errors and bootstrap validation to assess inferential stability. Results: Malnutrition prevalence was high, with 42.3% of participants classified as moderately malnourished and 43.3% as severely malnourished under GLIM criteria. Mean MNA[®] score was 19.69 (SD 4.53). In the adjusted model, ANOC recruitment was associated, after adjustment, with a 4.477-point lower MNA[®] score compared with APELA (HC3 95% CI -7.071 to -1.884; p<0.001). Other sociodemographic and clinical factors yielded imprecise estimates. Although explanatory power was modest (Adjusted R2=0.067; optimism-corrected R2=-0.005), the recruitment setting remained a robust correlate across sensitivity analyses. Conclusions: Recruitment setting emerged as the most consistent adjusted correlate of MNA[®] scores, likely reflecting differences in clinical case mix and referral pathways in the Portuguese healthcare context. These findings highlight nutritional vulnerability in ALS as a multifaceted construct that should be interpreted in relation to both clinical and healthcare-contextual factors. This study supports considering systemic factors and the need for longitudinal research that incorporates comprehensive functional and social metrics to optimize multidisciplinary nutritional interventions.}, }
@article {pmid42652396, year = {2026}, author = {Bhardwaj, S and Chakraborty, A and Mead, J and Stilos, K}, title = {Palliative Care Involvement in Hospitalized Amyotrophic Lateral Sclerosis Patients.}, journal = {International journal of environmental research and public health}, volume = {23}, number = {8}, pages = {}, pmid = {42652396}, issn = {1660-4601}, mesh = {Humans ; *Palliative Care/statistics &amp; numerical data ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; Female ; Male ; *Hospitalization ; Retrospective Studies ; Aged ; Middle Aged ; Referral and Consultation ; Aged, 80 and over ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with significant physical, psychological, and social distress. Given its terminal nature and high symptom burden, early integration of palliative care is essential. The inpatient Palliative Care Consult Team (PCCT) provides specialist palliative care to hospitalized patients with ALS. Hospitalizations are common throughout the ALS disease trajectory, particularly as patients experience progressive functional decline, respiratory compromise, and increasing care needs, making inpatient encounters important opportunities for specialist palliative care involvement. To extend palliative care beyond the inpatient setting and facilitate earlier involvement, an ALS ambulatory clinic was established in 2018. Despite the importance of palliative care, limited data describes its involvement among hospitalized ALS patients. This retrospective review examines the relationship between the PCCT and ALS patients admitted to a tertiary care facility between 2006-2019. Data collected included patient demographics, referral indications, clinical course, and disposition. Most patients referred to the PCCT had poor functional status and a guarded prognosis at initial consultation. Symptom management and support for complex decision-making were leading reasons for referral. Approximately half of patients died in the hospital within three months of referral. Most deaths occurred within one week, underscoring the importance of timely palliative care.}, }
@article {pmid42638891, year = {2026}, author = {Wollmann, L and Wolf, A and Cooke, L and Santana, M}, title = {The patient as teacher: a four-phase blueprint for institutional change.}, journal = {Frontiers in health services}, volume = {6}, number = {}, pages = {1920768}, pmid = {42638891}, issn = {2813-0146}, abstract = {INTRODUCTION: Over recent decades, patient involvement in medical education has shifted from passive case demonstrations toward active partnerships in teaching, assessment, and curriculum design, a transition that must recognize patients and relatives as persons with experiential knowledge, not merely as educational instruments. This perspective article argues that accumulated evidence now justifies a deliberate shift from scattered, champion-driven initiatives to embedded institutional strategy.<br><br>EVIDENCE AND GAPS: The evidence supports meaningful benefits across stakeholders: learners develop stronger clinical reasoning, communication skills, and empathy; patient educators report empowerment and enhanced self-esteem; and institutions advance their social accountability mission. However, the field continues to struggle with inconsistent terminology, fragmented implementation, short-term satisfaction-based outcomes, underexplored ethical considerations, and weak institutional commitment.<br><br>PROPOSED ROADMAP: To address these gaps, we propose a four-phase implementation roadmap. Phase 1 (Institutional Diagnosis) maps current practices against Towle et al.'s six-level taxonomy and establishes an institutional position statement. Phase 2 (Role Definition and Phased Goal-Setting) advocates stepwise progression, typically starting at Levels 3-4, where patients share experiences or act as trained teachers, advancing toward full curriculum governance partnership. Phase 3 (Implementation Planning and Capacity Building) addresses curriculum integration, resource allocation, faculty development, and community partnerships. Phase 4 (Outcomes Monitoring and Evaluation) calls for multilevel, longitudinal evaluation frameworks, including systematic assessment of patient educators' experiences.<br><br>DISCUSSION: We present this roadmap as an evidence-informed conceptual synthesis whose implementation depends on continued institutional commitment. Cross-cutting principles include incrementalism, sustained institutional commitment, patient co-production, representative recruitment, and rigorous longitudinal research.}, }
@article {pmid42639115, year = {2026}, author = {Harbert, DH}, title = {EIF2S1-PELO co-expression architecture in human brain: pairing-family decomposition reveals constitutive transcriptional coupling and functional layer separation.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1817096}, pmid = {42639115}, issn = {1662-5099}, abstract = {EIF2S1 (eIF2α, translation initiation surveillance) and PELO (Pelota, ribosome rescue) operate within established ribosome-associated quality control and translation-initiation surveillance pathways. Direct cross-talk between these systems is mediated through ZAK/GCN-mediated eIF2α phosphorylation under ribosome-stall stress. At the transcriptional layer, however, EIF2S1-PELO co-regulation has not been quantitatively characterized. Using pairing-family architectural decomposition on multi-region GTEx co-expression and BA9 prefrontal cortex RNA-seq from Parkinson's disease and control donors (GSE68719, n = 44 controls, n = 29 PD), we find: (1) EIF2S1 and PELO share near-identical genome-wide co-expression architecture (continuous Weighted Jaccard = 0.914) with substantial top-partner overlap (binary Jaccard at top 5% = 0.490), producing a Type 1 dissociation gap of 0.424, significantly smaller than 200 random gene-pair gaps (mean 0.644, z = -2.57, permutation p = 0.015), and the lowest gap in a 21-pair quality-control gene panel; (2) the relationship is approximately linear-monotonic (Type 6 Pearson-Spearman gap ≈ 0.004); (3) cellular functional co-dependency in DepMap CRISPR screens is essentially zero (Jaccard = 0.006, gene-effect Pearson r = -0.07), consistent with layer separation between regulatory architecture and cellular phenotype; (4) in an exploratory single-cohort comparison of PD versus control prefrontal cortex, the dissociation gap was larger in PD (0.536 versus 0.424 in control), but this between-group difference did not reach statistical significance under a group-label permutation test (p = 0.40; bootstrap 95% CI on the difference [-0.14, 0.29]), so we present it as a hypothesis for replication rather than an established effect. These findings characterize EIF2S1-PELO transcriptional co-regulation as a constitutive architectural feature distinct from the ZAK/GCN-mediated direct mechanism. The constitutive coupling replicated in independent Alzheimer's disease and ALS frontal-cortex cohorts and across microarray and RNA-seq platforms; a disease-associated weakening of the coupling was directionally consistent across all three diseases but did not reach statistical significance. We note that co-expression patterns are consistent with shared upstream regulatory programs but do not by themselves establish direct co-regulation; the architectural findings reported here are correlational at the transcriptional layer.}, }
@article {pmid42639443, year = {2026}, author = {Potla, KM and Justin Nathaniel, CM and Parameshwar Adimule, S and Vincent Raj Shanthi, JR and Bilal, H and Tawfeek, AM and Islam, MS}, title = {Electron-withdrawing group effects on the structural, electronic, reactivity, and binding characteristics of triazolopyrimidine herbicides: a comparative study of diclosulam, cloransulam-methyl, and cloransulam.}, journal = {RSC advances}, volume = {}, number = {}, pages = {}, pmid = {42639443}, issn = {2046-2069}, abstract = {Diclosulam (DS, I), cloransulam-methyl (CSM, II), and cloransulam (CS, III) are widely used herbicidal inhibitors of the AHAS/ALS enzyme for selective weed control. In the present work, a comparative experimental and theoretical study has been conducted on the impact of substituents on their structural, electronic, and reactive properties. Structural differences have been established using single-crystal X-ray diffraction. The crystal packing and interaction energy have been investigated using the Hirshfeld surface approach, while density functional theory confirmed the experimental geometry. The analysis of the electronic structure, reactivity descriptors, localization of electrons, and non-covalent interactions was carried out by the methods of frontier molecular orbitals, MEP, ELF/LOL, and RDG calculations. The binding interactions of compounds with AHAS/ALS protein targets were determined using molecular docking. The combined results reveal clear interdependencies between the structure, electronic properties, non-covalent interactions, and the behavior of molecules upon the interaction with enzymes.}, }
@article {pmid42640367, year = {2026}, author = {Iacono, D and Feltis, GC}, title = {Beyond the Ribosome: The Expanding Role of the Nucleolus in Neurodegenerative Pathways.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42640367}, issn = {1559-1182}, mesh = {*Cell Nucleolus/metabolism/pathology ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Ribosomes/metabolism ; Signal Transduction ; Aging/metabolism/pathology ; }, abstract = {The nucleolus, long defined by its canonical role in ribosome biogenesis, has emerged as a critical nexus for cellular homeostasis, stress sensing, and disease pathogenesis. This article synthesizes a broad range of evidence to construct a comprehensive model of the nucleolus in the context of aging and neurodegeneration. We begin by detailing its fundamental architecture and the intricate process of ribosome production, before exploring the paradigm-shifting discovery of its vast, non-canonical proteome, which implicates it in DNA repair, cell cycle control, and genome stability. A central theme is the nucleolus's function as a primary cellular stress sensor, which, upon disruption by genetic, metabolic, or proteotoxic insults, initiates the nucleolar stress response. We provide a detailed examination of the downstream signaling cascades, focusing on the canonical p53-MDM2 axis and the interconnected mTOR pathway, which together translate nucleolar status into decisions of cell fate, including apoptosis and cell cycle arrest. We then focus on the brain, presenting the neuropathological and morphological alterations of the nucleolus-such as atrophy, fragmentation, and changes in volume-that serve as hallmarks of normal aging and neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and C9orf72-linked ALS/FTD. We explore the deep regulatory layers of epigenetics, where DNA methylation and histone modifications of ribosomal DNA genes are dysregulated in disease, and discuss how multi-omics approaches are unraveling the complex molecular landscape of nucleolar function. Finally, we introduce the emerging concept of a gut-brain-nucleolus axis, proposing how systemic factors like the gut microbiome may influence neuronal health by triggering nucleolar stress through inflammatory and metabolic mediators. Overall, by highlighting the nucleolus as a convergence point for diverse pathogenic pathways, we frame it as a promising and druggable target for novel therapeutic strategies aimed at promoting neuronal resilience and combating neurodegenerative diseases.}, }
@article {pmid42640452, year = {2026}, author = {Copenhaver, AE and Puglisi, C and Eslami, MA}, title = {Comparison of classic statistical methods and machine learning approaches to classify readiness.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btag585}, pmid = {42640452}, issn = {1367-4811}, abstract = {MOTIVATION: Predicting physical and cognitive readiness in warfighters is critical for mission success. These predictions can be improved by identifying key biomarkers using multiple omics modalities. The MASTR-E study conducted by McKetney and colleagues is one of the most comprehensive multi-omics studies of saliva samples collected from warfighters, which also applied classic linear statistical (CLS) techniques to discover key biomarkers of readiness. Aligning with McKetney et al.'s assumptions, we operationalize readiness as a binary proxy, where pre-mission samples are labeled as 'ready' to reflect a rested, unstressed physiological baseline, while post-mission samples are labeled 'not ready' to reflect cumulative physical and cognitive load from the mission. As such, readiness here is not a direct biological or physiological construct, but an inferred state likely dominated by stress-related physiological changes. This assumption and definition is discussed further in the Introduction and Limitations sections. Here, we apply machine learning (ML) analyses to better assess generalizability, consider hidden interactions, and identify nonlinear patterns in the data. We investigated whether ML approaches could predict readiness and identify relevant biomarkers. ML models were trained on proteomics-only or metabolomics-only datasets to classify participants as ready or not ready and important model features were considered as putative biomarkers. Training and testing datasets were curated for two objectives: 1) recognize biomolecular signatures indicative of readiness within the same donor and 2) assess generalizability across warfighters by withholding donors for testing.<br><br>RESULTS: Proteomics-based models achieved AUCs of 0.907&#xb1;0.034 and 0.860&#xb1;0.063 for Objectives 1 and 2, respectively. Metabolomics-based models achieved Objective 1 AUC of 0.994&#xb1;0.007 and Objective 2 AUC of 0.993&#xb1;0.010. Comparative analysis with existing literature validates the model's feature importances, but the identified putative biomarkers significantly differ from those discovered through CLS analyses, as only one ML-identified biomarker overlapping with those identified through CLS methods. We show that these ML models and identified features are more robust to noise and generalizable across participants than those identified using CLS methods.<br><br>AVAILABILITY: The analysis pipelines are provided as Jupyter notebooks, including all code and documentation, and are available publicly on GitHub at {{https://github.com/netrias/ReadinessClassification}}.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid42641169, year = {2026}, author = {Kodama, K and Ando, M and Higuchi, Y and Yuan, JH and Yoshimura, A and Samukawa, M and Suzuki, M and Ogaya, S and Kawata, Y and Gamo, N and Hisahara, S and Yano, C and Nagatomo, R and Hobara, T and Kojima, F and Hiramatsu, Y and Nozuma, S and Sakiyama, Y and Mitsui, J and Tsuji, S and Takashima, H}, title = {Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602261477464}, pmid = {42641169}, issn = {2214-3602}, abstract = {BackgroundDistal hereditary motor neuropathy (dHMN) is characterized by slowly progressive distal muscle weakness and amyotrophy, and it exhibits clinical overlap with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Biallelic variants in SIGMAR1, encoding sigma nonopioid intracellular receptor 1, have been linked to autosomal recessive dHMN with pyramidal features. This study investigated the clinical and genetic features of patients with dHMN associated with SIGMAR1 variants in Japan.MethodsWe conducted genetic screening of Japanese patients with clinically suspected inherited peripheral neuropathies using targeted gene panels and whole-exome sequencing. SIGMAR1 variants were evaluated via segregation analysis using Sanger sequencing. Detailed clinical and electrophysiological data were systematically reviewed.ResultsBiallelic SIGMAR1 variants, including three novel variants and one previously reported variant, were identified in six patients from five unrelated families. The genotypes comprised compound heterozygous variants in four patients and homozygous variants in two patients. All patients presented with early-onset distal muscle weakness and atrophy. Enhanced tendon reflexes and pyramidal tract signs were frequently observed, whereas bulbar or respiratory involvement was absent. Nerve conduction studies consistently revealed motor-predominant axonal neuropathy with minimal sensory involvement. Disease progression was slow, and all patients remained ambulatory for years to decades after onset.ConclusionOur findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS. SIGMAR1 variants should be considered in the genetic evaluation of early-onset motor neuropathies, particularly in patients with dHMN accompanied by pyramidal features.}, }
@article {pmid42641283, year = {2026}, author = {Yoo, HE and Issenberg, SB and Roh, YS}, title = {Psychometric evaluation and responsiveness of the resuscitation self-efficacy scale among ward nurses: A pretest-posttest study.}, journal = {Nurse education in practice}, volume = {96}, number = {}, pages = {104954}, doi = {10.1016/j.nepr.2026.104954}, pmid = {42641283}, issn = {1873-5223}, abstract = {AIM: To evaluate the psychometric properties and responsiveness of the Resuscitation Self-Efficacy Scale (RSES) among ward nurses before and after simulation-based advanced life support (ALS) training.<br><br>BACKGROUND: Although the RSES was developed to measure nurses' perceived capability in resuscitation, evidence regarding its psychometric evaluation among ward nurses participating in ALS training remains limited.<br><br>DESIGN: Secondary psychometric analysis of data obtained from a simulation-based ALS training study.<br><br>METHODS: Ward nurses (N&#x202f;=&#x202f;191) from general hospitals completed the RSES before and immediately after participation in a simulation-based ALS training program. Psychometric evaluation included item analysis, internal consistency reliability, evidence based on internal structure, construct validity through convergent and discriminant validity, relations with an external performance measure and responsiveness.<br><br>RESULTS: The RSES demonstrated good internal consistency, with a Cronbach's &#x3b1; of.80 for the total scale and.88-.91 across the four factors. Factor analysis supported the original four-factor structure, with satisfactory model fit (CFI =.958, TLI =.949, RMSEA =.052 and SRMR =.072). Evidence of convergent and discriminant validity met recommended criteria. Individual resuscitation self-efficacy showed modest positive associations with team-level ALS performance and the RSES demonstrated moderate responsiveness to change (standardized response mean =.77).<br><br>CONCLUSIONS: The findings provide psychometric evidence supporting the use of the RSES for assessing resuscitation self-efficacy among ward nurses participating in simulation-based ALS training. The RSES may be useful for evaluating educational outcomes and monitoring changes in learners' self-efficacy following educational interventions.}, }
@article {pmid42642835, year = {2026}, author = {Aldaghi, FS and Siahpoosh, Z and Salehi, Z and Mashayekhi, F and Sohrabnezhad, S}, title = {Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative Disorders.}, journal = {Brain and behavior}, volume = {16}, number = {8}, pages = {e71615}, pmid = {42642835}, issn = {2162-3279}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy ; Oxidative Stress/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; Mitochondria/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Alzheimer Disease/metabolism ; Multiple Sclerosis/metabolism ; Parkinson Disease/metabolism ; Huntington Disease/metabolism ; Inflammasomes/metabolism ; }, abstract = {PURPOSE: Although Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD) present with markedly different clinical phenotypes, these neurodegenerative diseases (NDDs) appear to converge on a shared set of underlying molecular disturbances. This review sought to integrate disease-specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi-target, disease-modifying therapeutic strategies.<br><br>METHOD: Relevant classical and contemporary literature, encompassing original research and review articles on the molecular basis of AD, PD, ALS, MS, and HD, was reviewed and synthesized narratively, with attention to how neuroinflammatory and oxidative stress pathways intersect, reinforce one another through mitochondrial and inflammasome-driven feedback, and recur across the five conditions.<br><br>FINDING: In each disorder, persistently activated microglia and astrocytes secreted inflammatory mediators and reactive oxygen species, engaged the NLRP3 inflammasome, and progressively destabilized cellular homeostasis through a self-perpetuating cycle linking neuroinflammation and oxidative stress. Disease-specific lesions nonetheless persisted: amyloid-&#x3b2; and tau pathology in AD; &#x3b1;-synuclein aggregation with iron-driven mitochondrial damage in PD; RNA-binding protein dysfunction, proteostatic collapse, and excitotoxicity in ALS; inflammatory demyelination and axonal bioenergetic failure in MS; and mutant huntingtin-driven transcriptional and mitochondrial disruption in HD. These distinct triggers ultimately converged on shared downstream cascades.<br><br>CONCLUSION: Recognizing this shared pathogenic foundation supports multi-target therapies-such as Nrf2 activation, NLRP3 inhibition, mitochondria-targeted antioxidants, and gene-based interventions-that extend across diagnostic boundaries, though challenges in intervention timing, patient stratification, and clinical translation remain unresolved.}, }
@article {pmid42642938, year = {2026}, author = {Zou, L and Song, L and Yin, P and Cui, H and Lian, L and Peng, X and Jin, T and Wang, H and Liu, W}, title = {Glutathione S-transferase genes PfGSTU6 and PfGSTL1 involved in mesosulfuron-methyl resistance in Polypogon fugax.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71227}, pmid = {42642938}, issn = {1526-4998}, support = {//National Natural Science Foundation of China (32372570, 32572857)/ ; //Shandong Provincial Natural Science Foundation (ZR2025MS289)/ ; }, abstract = {BACKGROUND: Polypogon fugax is a major weed in wheat and winter canola fields in China. Two populations, SD-4 and JS-13, showing resistance to the ALS inhibitor mesosulfuron-methyl, were collected from winter wheat fields. This study aimed to characterize their resistance level and cross-resistance profile, investigate the resistance mechanism and identify its functional genes.<br><br>RESULTS: Dose-response assays showed that SD-4 and JS-13 have high-level resistance to mesosulfuron-methyl (15.9-and 16.4-fold, respectively) and cross-resistance to the ACCase inhibitors clodinafop-propargyl, fenoxaprop-P-ethyl, quizalofop-p-ethyl, and the PDS inhibitor diflufenican. Sequencing of the ALS gene revealed no known target-site mutations within the eight conserved resistance-associated regions. Pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor NBD-Cl increased herbicide sensitivity in resistant plants. The resistant plants showed higher inducible GST activity. Herbicide residues analysis observed that resistant plants exhibiting increased mesosulfuron-methyl metabolism, and the enhanced metabolism could be reduced by both inhibitors. Integrated transcriptomic and qRT-PCR analysis identified 17 stably upregulated genes, including PfGSTU6 and PfGSTL1. Escherichia coli and rice callus overexpressing PfGSTU6 and PfGSTL1 exhibit significantly enhanced herbicide tolerance to mesosulfuron-methyl, and molecular docking analysis confirmed the strong binding affinity of GST proteins to the target herbicide.<br><br>CONCLUSIONS: The P450s and GSTs mediated herbicide metabolism confer mesosulfuron-methyl resistance in P. fugax. This study elucidates the resistance mechanism and provides genetic resources for resistance monitoring and crop breeding. In addition, we characterized the cross-resistance profile of the resistant P. fugax population, which provides guidance for developing targeted field weed resistance management strategies. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid42643027, year = {2026}, author = {Christen, AL and Sobanski, E and Bitto, H and Abt-Mörstedt, B and Stieglitz, RD and Corbisiero, S}, title = {Emotional Dysregulation, Emotional Lability, Emotional Impulsiveness and Emotion in Adults with ADHD: Do All Scales Define the Same Concept?.}, journal = {Journal of attention disorders}, volume = {}, number = {}, pages = {10870547261475724}, doi = {10.1177/10870547261475724}, pmid = {42643027}, issn = {1557-1246}, abstract = {BACKGROUND: Various studies highlight emotional symptoms as a crucial component of ADHD in adulthood, suggesting independent diagnostic approaches that incorporate patients' emotional experiences into the assessment. However, the emotional symptomatology appears to be defined differently within the disorder's different constructs: Emotional Dysregulation (ED), Emotional Lability (EL), Emotional Impulsiveness (EI) and Emotion (E). Hence, the question arises: Do these symptom domains represent the same psychopathological spectrum?<br><br>METHOD: A total of 1240 adults seeking diagnostic evaluation at the ADHD specialist consultation in two different clinics (University Psychiatric Clinics (UPK) in Basel and Central Institute of Mental Health in Mannheim) were examined, whereas 611 participants were diagnosed with ADHD. They were further assessed in regard of their emotional symptoms using the following scales: ED, EL, EI and E. Additionally, affective lability was measured as a control using the Affective Lability Scale (ALS-18).<br><br>RESULTS AND DISCUSSION: The convergent and construct validity using correlations and principal component analysis (PCA) revealed that individuals with ADHD experience distinct emotional symptoms divergent from a general concept of affective lability as assessed by the ALS-18. The PCA shows that the ADHD-specific emotional symptoms may be classified into (1) difficulties with temper control and anger, (2) emotional distress and (3) emotional overreactivity and mood changes.}, }
@article {pmid42643197, year = {2026}, author = {Sigala, N and Cobandag, M and Leppard, L and Medford, N}, title = {Insight and executive functions in acquired brain injury: empirical evidence and theoretical frameworks.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1884495}, pmid = {42643197}, issn = {1664-2295}, mesh = {Humans ; *Brain Injuries/physiopathology/psychology/complications ; *Executive Function/physiology ; *Awareness/physiology ; *Prefrontal Cortex/physiopathology ; Cognitive Flexibility ; }, abstract = {Impaired self-awareness affects 30-50% of patients with moderate to severe acquired brain injury (ABI) and represents one of the most clinically consequential obstacles to effective rehabilitation. Despite substantial evidence that self-awareness and executive functions share neural substrates in prefrontal cortex, the mechanisms linking these two functions remain incompletely specified. This paper reviews the empirical evidence for the relationship between executive functions and insight in ABI, and evaluates four theoretical frameworks: the Cognitive Awareness Model, the Dynamic Comprehensive Model of Awareness, Mograbi et al.'s predictive coding framework, and Duncan's adaptive coding model. It then proposes a novel integration of the latter two as a mechanistically grounded account of why executive dysfunction and impaired self-awareness co-occur following prefrontal damage. We argue that adaptive coding describes the representational flexibility of prefrontal neurons in coding self-relevant information, whilst predictive coding provides the computational logic, driven by precision-weighted prediction errors, through which this adaptive selection is updated. We conclude by discussing assessment and rehabilitation implications in ABI.}, }
@article {pmid42645064, year = {2026}, author = {Sonkar, KS and Levi D'Ancona, V and Cramp, J and Shilling, H and Giles, E and Howell-Bray, T and Fillingham, B and Cudkowicz, ME and Nath, A and Rothstein, JD and Bowser, R and Borroni, B and Berry, JD and Sadri-Vakili, G and Buratti, E and Thrippleton, IP}, title = {Functional Activity of TDP-43: A Direct Biomarker for ALS.}, journal = {Biosensors}, volume = {16}, number = {8}, pages = {}, pmid = {42645064}, issn = {2079-6374}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis ; Humans ; *DNA-Binding Proteins/blood/metabolism ; Biomarkers/blood ; Fluorescence Resonance Energy Transfer ; *Biosensing Techniques ; C9orf72 Protein/genetics ; }, abstract = {TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (302 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular release of probe-competent TDP-43 species during cell death and exosomal shedding, rather than restored intracellular nuclear splicing function. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies.}, }
@article {pmid42645160, year = {2026}, author = {Leggett, S and Sanghai, N and Ru, C and Marcogliese, PC and Tranmer, GK}, title = {Drosophila: An Emerging New Approach Method (NAM) for Studying Amyotrophic Lateral Sclerosis (ALS).}, journal = {Cells}, volume = {15}, number = {16}, pages = {}, pmid = {42645160}, issn = {2073-4409}, support = {202210PJT-495295/CAPMC/CIHR/Canada ; RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/drug therapy/metabolism ; *Drosophila melanogaster/genetics/metabolism ; Humans ; Disease Models, Animal ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; Drug Evaluation, Preclinical ; }, abstract = {Drosophila melanogaster (D. melanogaster), or fruit flies, are a commonly used model organism in the study of neurodegenerative diseases (NDs). Their short lifespan, low cost, genetic tractability, and conserved signaling and developmental pathways make them ideal for studying NDs and associated biochemical pathways. Further, flies offer the advantage of high-throughput exploratory drug and genetic screening without stringent ethical constraints. Therefore, D. melanogaster serves as an ideal organism for preliminary drug screening before transitioning to toxicity and efficacy studies in vertebrate models. Following the recent plan by the United States FDA (US FDA) and the National Institutes of Health (NIH) to progressively phase out preclinical drug testing in vertebrate animals and introduce New Approach Methodologies (NAMs), D. melanogaster has the potential to become part of the conventional drug testing pipeline in the future. This literature review focuses on the use of D. melanogaster models as a powerful, low-cost model organism to study superoxide dismutase 1 (SOD1)- and TAR DNA-binding protein 43 (TDP-43)-linked Amyotrophic Lateral Sclerosis (ALS), as well as previous efforts to screen drugs in SOD1- and TDP-43-expressing Drosophila models.}, }
@article {pmid42646366, year = {2026}, author = {Anwar, AI and Hegazi, AA and Bhuchakra, HP and Nelson, JR and Birdsong, TL and Fontenot, CJ and Zeibo, M and Fazal-Ur-Rehman, MM and Bieber, HP and Spring, CJ and Smith, JL and Hachem, IA and Singh, T and Sawaya, MF and Murnane, KS and Kaye, AD}, title = {Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases.}, journal = {Neurology international}, volume = {18}, number = {8}, pages = {}, pmid = {42646366}, issn = {2035-8385}, abstract = {Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington's disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood-brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington's disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy.}, }
@article {pmid42646494, year = {2026}, author = {Shevchuk, D and Kuzmenko, Y and Zakharova, M and Karpov, V and Starodubova, E and Latanova, A}, title = {NLRP3 Inflammasome and Inflammation-Related Proteins Expression Characterized in Non-Cultivated Versus Cultivated Peripheral Blood Cells of Patients with Amyotrophic Lateral Sclerosis.}, journal = {NeuroSci}, volume = {7}, number = {4}, pages = {}, pmid = {42646494}, issn = {2673-4087}, support = {25-74-10090//Russian Science Foundation/ ; }, abstract = {BACKGROUND: Cell and mouse models studies demonstrate NLRP3 inflammasome involvement in amyotrophic lateral sclerosis (ALS) neuroinflammation. Peripheral blood mononuclear cells (PBMCs) are a promising, yet understudied, source of in vivo inflammasome activation biomarkers. Our study reviewed the literature on PBMC-based inflammasome studies of ALS and other neurodegenerative diseases and tested different conditions for PBMC handling to evaluate inflammasome and inflammation-related protein expression in these cells.<br><br>METHODS: Expression of NLRP3 inflammasome components and inflammation-related proteins was analyzed by Real-time qPCR and Western blot in non-cultivated/cultivated PBMCs of 23 ALS patients and 20 Healthy controls. IL-1&#x3b2; and IL-18 levels were measured in plasma and cultivated PBMC supernatants by ELISA.<br><br>RESULTS: Cultivation of PBMCs decreased expression of inflammasome components and inflammation-related cytokines on the mRNA but not protein level. NLRP3 mRNA expression was significantly higher in ALS-cultivated PBMCs. In both ALS and Healthy controls, IL-18 was detected in plasma, and IL-1&#x3b2; in supernatants of cultivated PBMCs.<br><br>CONCLUSIONS: Our findings suggest that PBMC handling conditions, i.e., cell cultivation, may determine particular parameters associated with NLRP3 inflammasome expression and activation pathway, so they should be carefully selected for PBMC-based studies of inflammasome in neurodegenerative and non-neurological disorders and taken into account when interpreting the study results.}, }
@article {pmid42646579, year = {2026}, author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A}, title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {42646579}, issn = {2076-3271}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; }, abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.<br><br>RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.<br><br>CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.}, }
@article {pmid42647236, year = {2026}, author = {Sanchis-Sanchis, E and de la Rubia Ortí, JE and Sancho-Cantus, D and Cunha-Pérez, C and Casaña-Mohedo, J}, title = {The Microbiota-Gut-Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations-Scoping Review.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {33}, number = {3}, pages = {}, pmid = {42647236}, issn = {1873-149X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota-gut-brain axis represents a critical bidirectional pathway in which intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries and maps the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in patients with ALS, characterized by severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage to the intestinal mucosa, alteration of Paneth cells, and downregulation of tight junction proteins (zonulin), triggering a "leaky gut" phenomenon. Subsequent systemic translocation of lipopolysaccharides (LPS) induces TLR4-mediated endotoxemia, microglial hyperactivation, and accelerated motor neuron apoptosis. Conversely, therapeutic modulation via Fecal Microbiota Transplantation (FMT), psychobiotics, and metabolic interventions (ketogenic or Mediterranean diets) has demonstrated significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Incorporating microbiome-targeted biomarkers into clinical protocols is crucial for implementing a stratified, multi-systemic therapeutic strategy aimed at enhancing patient prognosis and psychological well-being.}, }
@article {pmid42647657, year = {2026}, author = {Denčevski, A and Bataveljić, D and Bogdanović Pristov, J and Krmpot, AJ and Rabasović, MD and Nikolić, L}, title = {Characterizing Single-Cell Differences in Aquaporin-4 and Glutamate Transporter-1 Between Control and hSOD1G93A Astrocytes Using Integrated Epifluorescence and Structured Illumination Microscopy.}, journal = {Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada}, volume = {32}, number = {4}, pages = {}, doi = {10.1093/mam/ozag095}, pmid = {42647657}, issn = {1435-8115}, support = {451-03-33/2026-03/200053//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; 451-03-33/2026-03/200178//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; 451-03-33/2026-03/200007//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; //Institute of Physics Belgrade/ ; //Science Fund of the Republic of Serbia/ ; }, mesh = {*Astrocytes/chemistry/metabolism ; *Aquaporin 4/analysis/metabolism ; Animals ; *Excitatory Amino Acid Transporter 2/analysis ; Microscopy, Fluorescence/methods ; *Single-Cell Analysis/methods ; Cells, Cultured ; Humans ; }, abstract = {Astrocytes, the abundant glial cells of the central nervous system (CNS), maintain water and glutamate homeostasis through aquaporin-4 (AQP4) and glutamate transporter-1 (EAAT2). In the hSODG93A animal model of amyotrophic lateral sclerosis, astrocytes exhibit alterations in these homeostatic proteins. AQP4 and EAAT2 changes are observed in both hSODG93A-expressing astrocytes in the CNS and in cell cultures. Here, we provide a detailed analysis of differences between cultured control and hSOD1G93A astrocytes in AQP4 and EAAT2 fluorescence patterns, subcellular localization, and spatial overlap, using side-by-side epifluorescence and structured illumination microscopy modes of a custom imaging system [two-dimensional structured illumination microscopy (2D SIM)]. 2D SIM system characterization and fluorescence signal analysis demonstrated uniform epifluorescence illumination and high-contrast SIM patterns, enabling whole-cell imaging of AQP4 and EAAT2 and resolving their signals into distinct puncta in both control and hSOD1G93A astrocytes with SIM. Compared with control astrocytes, AQP4 expression increased and EAAT2 expression decreased in the plasma membrane and cytoplasm of hSOD1G93A astrocytes at both diffraction-limited and superresolution scales. Subdiffraction-scale analysis revealed differences in the spatial distributions of AQP4 and EAAT2, showing increased colocalization between these proteins in hSOD1G93A astrocytes. These findings demonstrate the utility of integrated imaging approaches for quantitative, single-cell-resolution analysis of disease-associated protein alterations in astrocytes.}, }
@article {pmid42648119, year = {2026}, author = {Wu, D and Kojic, A and Ross, JP and Li, D and Walther, P and Goyal, N and Sampson, J and Wu, JC}, title = {Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.}, journal = {Stem cell research}, volume = {95}, number = {}, pages = {104085}, doi = {10.1016/j.scr.2026.104085}, pmid = {42648119}, issn = {1876-7753}, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene constitutes the leading genetic driver of amyotrophic lateral sclerosis (ALS). This fatal neurodegenerative disorder is characterized by the systematic loss of both the upper and lower motor neurons across both the central and peripheral nervous systems. This work describes the successful reprogramming of two human induced pluripotent stem cell (iPSC) lines originating from two independent ALS patients, both of whom carry a C9orf72 HRE mutation. Validation of the two established iPSC lines confirmed the expression of pluripotency markers, normal karyotypes, and successful trilineage differentiation. Consequently, these lines provide a robust in vitro platform to model ALS and study C9orf72-mediated disease mechanisms.}, }
@article {pmid42648633, year = {2026}, author = {Akamatsu, H and Kodama, Y and Terai, A and Imamura, M and Oda, K and Jono, H and Ohyama, K}, title = {Development and validation of machine learning model for selecting the optimal population pharmacokinetic model for vancomycin.}, journal = {Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy}, volume = {}, number = {}, pages = {103058}, doi = {10.1016/j.jiac.2026.103058}, pmid = {42648633}, issn = {1437-7780}, abstract = {INTRODUCTION: Therapeutic drug monitoring (TDM) of vancomycin is recommended based on the area under the concentration-time curve (AUC). The Practical Antimicrobial TDM (PAT) software incorporates two population pharmacokinetic (popPK) models developed by Oda et al. and Yasuhara et al.; however, no objective criteria for model selection have been established. This study aimed to develop and validate a machine learning (ML) model to optimize popPK model selection for initial vancomycin dosing.<br><br>METHODS: The primary outcome was comparison of the two models to identify which yielded a lower absolute relative prediction error for AUC in each patient. Thirty-three clinical variables were screened using Lasso regression to select predictors. Six ML algorithms were compared using nested cross-validation. Performance was evaluated using the area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, calibration plots, and decision curve analysis (DCA).<br><br>RESULTS: Among 531 patients, Oda et al.'s model was more accurate in 60.1% of cases. Lasso selected 22 predictors. Among the algorithms, logistic regression showed the highest mean AUROC (0.720&#xb1;0.084), whereas the support vector machine demonstrated favorable calibration performance (intercept=0.01, slope=0.97). The multi-layer perceptron achieved the lowest Brier score (0.307). Longer hospitalization, lower C-reactive protein (CRP), and female sex were associated with a high predictive probability of accuracy for Oda et al.'s model. DCA suggested the clinical utility of ML-based model selection.<br><br>CONCLUSION: We developed an ML model for selecting between two popPK models for planning vancomycin dosing regimens in PAT. Considering length of hospital stay, CRP levels, and sex may aid accurate popPK model selection.}, }
@article {pmid42649099, year = {2026}, author = {,  and Kassardjian, CD and Desai, U and Živković, SA and Simmons, Z and Narayanaswami, P}, title = {It's Virtually Here: Telemedicine, Virtual Care, and Neuromuscular Disease.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70382}, pmid = {42649099}, issn = {1097-4598}, abstract = {The COVID-19 pandemic forced a partial shift in neuromuscular clinical practice away from in-person care to remote means. However, this shift was unexpected, abrupt, reactive to the emergency of a pandemic, and disruptive to the usual manner of care, without adequate time to adapt or study the optimal manner to provide care remotely. While traditionally associated with hub-and-spoke telemedicine models, the pandemic popularized direct-to-home virtual care, mostly unsupported by on-site examiners or standardized platforms. In chronic neuromuscular disorders such as amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG), virtual care has demonstrated feasibility, patient satisfaction, and potential cost savings, particularly for geographically or functionally disadvantaged populations. Disease-specific adaptations such as the Myasthenia Gravis Core Exam and wearable-based assessments (e.g., home spirometry, grip strength monitoring, and digital outcome measures) have enabled more structured remote evaluations. However, diagnostic accuracy may be compromised by the inability to perform detailed neurological examinations or electrodiagnostic studies. Equity concerns persist due to variability in digital literacy, internet and digital device access, and socioeconomic status. Post-pandemic, patients with disabilities may continue to benefit in a combined virtual/in-person paradigm of care. More evidence is required to evaluate the impact of virtual care on neuromuscular practice quality of care and outcomes. We outline some of the questions that require further study, hoping to spur research and quality improvement investigations of these new care models.}, }
@article {pmid42649384, year = {2026}, author = {Guo, H and Savard, A and Manser, C and Dutta, K and Taylor, JA and Rousseaux, MWC and Pozzi, S and Julien, JP and Baird, S and Gibbings, D}, title = {Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.}, journal = {Nature biomedical engineering}, volume = {}, number = {}, pages = {}, pmid = {42649384}, issn = {2157-846X}, support = {183767//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Sant&#xe9; du Canada)/ ; TR180076//Weston Brain Institute/ ; }, abstract = {In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43[G298S] iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43[ΔNLS] mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.}, }
@article {pmid42650212, year = {2026}, author = {Varrassi, G and Tran, YV and Farì, G and Narvaez Encinas, M and Corriero, A and Puntillo, F and Pham, PV and Leoni, MLG}, title = {The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {8}, pages = {}, doi = {10.3390/antiox15080948}, pmid = {42650212}, issn = {2076-3921}, support = {//Tam Anh General Hospital, Ha Noi/ ; }, abstract = {Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.}, }
@article {pmid42650794, year = {2026}, author = {Mitsumoto, H and Blasco, H and Corcia, P and Silani, V}, title = {ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?.}, journal = {Biomolecules}, volume = {16}, number = {8}, pages = {}, doi = {10.3390/biom16081126}, pmid = {42650794}, issn = {2218-273X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Mitochondria/metabolism/pathology ; *Energy Metabolism ; Animals ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.}, }
@article {pmid42650874, year = {2026}, author = {Wang, Z and Fu, Y and Li, S and Zhang, Y and Sun, T and Miao, N}, title = {The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.}, journal = {Biomolecules}, volume = {16}, number = {8}, pages = {}, doi = {10.3390/biom16081208}, pmid = {42650874}, issn = {2218-273X}, mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; RNA, Competitive Endogenous ; Animals ; *Gene Regulatory Networks ; *Motor Neuron Disease/genetics/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Muscular Atrophy, Spinal/genetics/pathology/metabolism ; }, abstract = {Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in motor dysfunction. Emerging evidence underscores the significant roles of long non-coding RNAs (lncRNAs) in motor neuron development and disease. However, only a few have been experimentally confirmed as true ceRNA regulators, highlighting the need to differentiate validated mechanisms from mere associations or predictions. This review summarizes the regulatory roles of lncRNA-associated ceRNA networks in motor neuron development, evaluates the evidence for their involvement in MNDs, and explores their potential impact on disease progression. It also addresses current challenges, knowledge gaps, and future research directions for understanding ceRNA-mediated mechanisms and developing therapeutic strategies for MNDs.}, }
@article {pmid41387577, year = {2026}, author = {Major, AJ and Abdaltawab, A and Phillips, JM and Wang, T and Lee, EK and Lichtenfeld, MJ and Chandrasekaran, C and Saalmann, YB and Maier, A and Desimone, R and Miller, EK and Bastos, AM and Mendoza-Halliday, D}, title = {A. J. Major et al. reply.}, journal = {Nature neuroscience}, volume = {29}, number = {2}, pages = {284-286}, pmid = {41387577}, issn = {1546-1726}, support = {R01 MH110311/MH/NIMH NIH HHS/United States ; R01MH110311//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; NS135361//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 1R01MH131715//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R21 NS135361/NS/NINDS NIH HHS/United States ; R01 EY029666/EY/NEI NIH HHS/United States ; NS121409//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R00 NS092972/NS/NINDS NIH HHS/United States ; CAREER 2339210//National Science Foundation (NSF)/ ; P51 OD011106/OD/NIH HHS/United States ; R01 MH131715/MH/NIMH NIH HHS/United States ; R01 NS121409/NS/NINDS NIH HHS/United States ; R00 MH116100/MH/NIMH NIH HHS/United States ; R00NS092972//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; Young Investigator Award//Brain and Behavior Research Foundation (Brain &amp; Behavior Research Foundation)/ ; NS122969//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R00MH116100//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01 NS122969/NS/NINDS NIH HHS/United States ; }, abstract = {Our study made two contributions: (1) discovery of a ubiquitous cortical motif and (2) a tool derived from it—the Frequency-based Layer Identification Procedure (FLIP and vFLIP). Mackey et al. critique the tool, questioning its advantage over classic current source density (CSD) analysis, and reason backwards to challenge the motif’s ubiquity. In our rebuttal, we confirm the spectrolaminar motif in diverse cortical areas using data from multiple research groups (who joined us in this rebuttal) as well as Mackey et al.’s own dataset. Additionally, we introduce vFLIP2, an improved version of our tool that addresses their comments. It reliably identified and localized the motif in our data and Mackey et al.’s data. Our findings reaffirm the motif’s ubiquity. We value Mackey et al.’s comments, which helped refine our tool.}, }
@article {pmid42634270, year = {2026}, author = {Shen, D and Ding, J and Zhai, F and Shi, J and Liu, M and Liu, Q and Cui, L}, title = {A de novo FUS frameshift variant (p.Gly501Valfs*30) presenting with tremor and prominent extrapyramidal features in young-onset motor neuron disease: a case report.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2721279}, pmid = {42634270}, issn = {2167-9223}, abstract = {Fused in sarcoma (FUS) mutations are a recognized cause of juvenile-onset amyotrophic lateral sclerosis (ALS), typically associated with early age at onset and rapid disease progression. Here we report a 32-year-old Chinese man who presented with bilateral hand tremor as the initial symptom, followed by progressive dysarthria, bradykinesia, and multi-segment upper and lower motor neuron involvement. Whole-exome sequencing identified a de novo heterozygous FUS frameshift (p.Gly501Valfs*30), confirmed absent in both parents. Electromyography revealed predominantly chronic neurogenic changes. At approximately 2.5 years from symptom onset, the patient remains ambulatory with a walking frame, with a notably milder course than the previously reported frameshift at the same Gly501 codon. This case expands the phenotypic spectrum of FUS-associated motor neuron disease and highlights tremor and extrapyramidal features as potential early manifestations in adult patients.}, }
@article {pmid42634335, year = {2026}, author = {Langmead, AP and Keane, BA and Jacob, JA and Ramana, KV}, title = {Metformin in Neurodegenerative Diseases: Mechanisms and Therapeutic Implications.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X476604260704180015}, pmid = {42634335}, issn = {1875-6190}, abstract = {As the global burden of neurodegenerative disorders continues to rise with aging populations, there is growing interest in identifying widely available drugs that can be repurposed to target shared metabolic and inflammatory mechanisms underlying these conditions. Increasing evidence suggests that metabolic dysfunction, mitochondrial impairment, and chronic neuroinflammation play central roles in the pathogenesis of neurodegeneration, demonstrating the need for therapeutics that can modulate these interconnected pathways. Metformin has served as the gold standard for the management of type 2 diabetes for 7 decades. It offers a superior safety profile, established metabolic advantages, and affordability. Recent studies suggest that, in addition to its antihyperglycemic actions, it could also be repurposed to treat several inflammatory complications and infectious diseases. Further, recent preclinical and clinical studies suggest that, by regulating AMPK, mTOR, and mitochondrial function, metformin could also control the initiation and progression of neurodegenerative diseases. Several studies also indicate that metformin suppresses neuroinflammation by inhibiting the NF-κB signaling pathway and the NLRP3 inflammasome, thereby improving insulin signaling and metabolic homeostasis. This review integrates metabolic, inflammatory, and mitochondrial mechanisms to present a unified mechanistic framework to explain how metformin may modulate the onset and progression of neurodegeneration. Specifically, we discuss recent studies showing the therapeutic significance of metformin in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, this review highlights metformin as a potential therapeutic candidate for future development in neurodegenerative diseases.}, }
@article {pmid42635322, year = {2026}, author = {Palumbo, F and Iazzolino, B and Canosa, A and Manera, U and Vasta, R and Grassano, M and Matteoni, E and Cabras, S and Maccabeo, A and Pellegrino, G and Giai Merlera, F and Dei Giudici, A and Callegaro, S and Balz, L and Moglia, C and Chiò, A and Calvo, A and Lulé, D}, title = {Theory of mind impairment related to C9orf72 repeat expansion in amyotrophic lateral sclerosis: a case-control study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2694499}, pmid = {42635322}, issn = {2167-9223}, abstract = {Objective: To investigate cognitive and affective theory of mind (ToM) in amyotrophic lateral sclerosis (ALS) patients carrying the C9orf72 repeat expansion (C9orf72+), compared with matched non-mutated (C9orf72-) ALS patients and healthy controls (HCs). Methods: We assessed 34 C9orf72+ ALS patients, 34 C9orf72- ALS patients matched for sex, age, education, and cognitive category, and 34 HC matched for sex, age, and education. Participants underwent neuropsychological evaluation, including the Story-Based Empathy Task (SET), assessing cognitive ToM (Intention Attribution, IA), affective ToM (Emotion Attribution, EA), and Causal Inference (CI). Results: C9orf72+ patients showed lower SET-global score than C9orf72- patients (p = 0.028). Compared with HC, C9orf72+ showed lower score in SET-global score and all SET subtests (all p < 0.05). C9orf72+ cognitively normal differed from HC in SET-global score, IA, and EA (all p < 0.038), whereas C9orf72- cognitively normal did not differ from HC. Multiple linear regression analyses indicated that ALS-specific cognitive domains only explained ∼25% of ToM variance, with no association with demographic, clinical, or behavioral variables. Cluster analysis identified three cognitive profiles based on SET performance, with the most impaired cluster showing the highest proportion of C9orf72+ patients (68%). Conclusion: C9orf72-mutated ALS patients showed more pronounced impairment in cognitive and affective ToM than non-mutated ALS patients, independent of demographic, clinical, and cognitive features. These findings, although requiring confirmation on larger samples, suggest that ToM dysfunction may represent a sensitive marker of cognitive involvement in ALS-C9orf72-associated disease, particularly in its affective component.}, }
@article {pmid42635866, year = {2026}, author = {Chakraborty, S and Manickam, V}, title = {Decoding the Neuroinflammatory Potential of Non-Nutritive Sweeteners Through An Integrative Computational Approach.}, journal = {Neurotoxicity research}, volume = {44}, number = {5}, pages = {}, pmid = {42635866}, issn = {1476-3524}, support = {F.N. 5/9/1328/2020-Nut//Indian Council of Medical Research/ ; SG20250066//VIT University/ ; }, mesh = {Humans ; *Non-Nutritive Sweeteners/adverse effects/metabolism/chemistry ; *Neuroinflammatory Diseases/chemically induced/metabolism/genetics ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Animals ; }, abstract = {Non-nutritive sweeteners (NNS) are commonly used in the beverage, food, and pharmaceutical industries, however, their possible link to neuroinflammation remains a contentious issue. Hence, to investigate this potential association and identify the molecular pathways involved, targets of the most frequently consumed NNSs, namely sucralose, aspartame, acesulfame, cyclamate, and saccharin, were extracted from the STITCH, Super-PRED, STP, SEA and CTD databases, while neuroinflammatory targets were extracted from GeneCards, OMIM, and NCBI databases. A total of 124 targets were obtained by overlapping NNS and neuroinflammatory targets, of which 20 key targets, including CASP3, PPARγ, MTOR, and MMP9, were identified for further analysis. KEGG enrichment analysis suggested a significant association of these targets with pathways related to Alzheimer's disease and neuroactive ligand-receptor interaction. Gene Ontology analysis revealed enrichment in biological processes associated with inflammatory response and reactive oxygen species. The associated cellular components were primarily localised in the axon, dendrite, and synaptic membrane. Molecular docking followed by molecular dynamics simulations was performed to evaluate the stability of the NNS-key target complexes, revealing favourable binding affinities and stable interaction profiles. Gene expression analysis of these key targets predicted their differential regulation across four majorly recognised neuroinflammatory disorders, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, with a significant up or downregulation of these key targets. Results of this study suggest that NNS may be associated with neuroinflammatory processes through these key targets and identified pathways, highlighting the need for improving the standards in food safety.}, }
@article {pmid42636000, year = {2026}, author = {Benatar, M and Barmada, S and Jicha, GA and Lagier-Tourenne, C and Gregory, J and Al-Chalabi, A and Boeve, BF and Jack, CR and Seeley, WW and Maragakis, NJ and Wuu, J and Zeier, Z and Onyike, C and Lewcock, J and Hovinga, C and Jafar-Nejad, P and Uspenskaya, O and Simmons, A and Browne, SE and Rohrer, J and Petrucelli, L and Shapiro, J and Scharper, D and Boxer, A and Ostrow, LW and Staffaroni, AM and Dacks, P and Turner, MR and Dave, KD and de Majo, M and Mitic, L and Fradette, S and Budd Haeberlein, S and Simuni, T and Dunn, B and McMillan, CT and Lee, EB}, title = {TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2026.2812}, pmid = {42636000}, issn = {2168-6157}, abstract = {IMPORTANCE: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.<br><br>OBSERVATIONS: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.<br><br>CONCLUSIONS AND RELEVANCE: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.}, }
@article {pmid42636496, year = {2026}, author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H}, title = {End-of-Life Care in an Acute Neurological Ward: A Retrospective Analysis of Clinical Practices During the Last Week of Life.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {}, number = {}, pages = {}, doi = {10.1097/JNN.0000000000000906}, pmid = {42636496}, issn = {1945-2810}, support = {//Icelandic Nurses Association, University of Iceland Research Fund of Ingibjorg R. Magnusdottir, Landspitali, National University Hospital of Iceland/ ; }, abstract = {BACKGROUND: The care of patients with neurological diseases near the end of life (EOL) is challenging and often complicated by prognostic uncertainty. Difficulty recognizing the terminal phase may delay transitions to EOL care, leading to continued use of diagnostic procedures and medical interventions with a limited focus on comfort.<br><br>METHODS: This retrospective observational study included medical records of 209 deceased patients with neurological diseases who died in an acute hospital ward. Diagnostic procedures and medical and supportive interventions delivered during the final 7 days of life were extracted. Patients were categorized into 2 groups: acute neurological diseases (ischemic stroke and hemorrhagic stroke) and progressive neurological diseases (Parkinson disease or extrapyramidal and movement disorders, and amyotrophic lateral sclerosis). Frequencies of interventions were compared between diagnostic groups and according to documented EOL decision status.<br><br>RESULTS: In both groups, documented EOL decisions were associated with reduced use of diagnostic procedures and increased use of support measures. Medication administration and supportive care patterns differed between the acute and progressive disease groups and were related to documented EOL decisions. The most frequently administered interventions were oral suctioning (97%), intravenous fluids (70%), antibiotics (45%), pain relief medications (98%), and benzodiazepines (93%). Patients with progressive neurological diseases received more respiratory support interventions than those with acute neurological diseases.<br><br>CONCLUSIONS: Our findings suggest that documenting EOL decisions was related to comfort-focused care, although the frequency varied by disease group. Neurological disease-specific EOL guidelines should be implemented to identify the terminal phase in alignment with the goals of comfort-focused care in a timely manner.}, }
@article {pmid42636890, year = {2026}, author = {Guha, L and Malik, JA and Bose, B}, title = {Living drug carriers: Microbial and bioengineered platforms redefining precision therapeutic and immunomodulatory delivery.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {}, number = {}, pages = {115274}, doi = {10.1016/j.jconrel.2026.115274}, pmid = {42636890}, issn = {1873-4995}, abstract = {Microbial living therapeutics are a new class of drug-delivery materials that combine synthetic biology, immunomodulation, and advanced formulations to achieve controllable therapeutic effects in space and time. In the broad field of living drug-delivery systems, therapeutic platforms include engineered microorganisms, mammalian immune cells, stem cells, viral vectors, extracellular-vesicle-producing cells, and hybrid bioengineered living materials. This review focuses on engineered microbial living drug carriers, including genetically modified bacteria and probiotic platforms, because these systems uniquely integrate programmable biosensing, in situ therapeutic synthesis, adaptive immunomodulation, and controllable drug delivery within a single living chassis. Designed microbes and consortia possess other unique functions, such as microenvironment sensing, programmed control of gene expression, and long-lasting in situ manufacturing of therapeutic payloads not available with small-molecule or biologic drugs. Recent progress in microbial chassis engineering, genetic circuit design, and biocontainment has enabled fine-tuning of immune responses, metabolic pathways, and tissue-specific signaling in a wide range of diseases from cancer to autoimmune and inflammatory diseases, to metabolic and endocrine disorders, neuro-immunological conditions (e.g., amyotrophic lateral sclerosis), infectious diseases including infectious threats without existing approved vaccines (Zika virus) as well as rare genetic disorders. Advances in formulation science, including encapsulation technologies, biomaterial-microbe hybrids, and stimuli-responsive release platforms, have enabled overcoming key translation challenges concerning microbial viability, biodistribution, safety, and controlled activation in complex physiological milieus like the gut (for enteric pathogens), tumor microenvironment (for oncolytic organisms), or injured tissues (for tissue-targeting organisms). Increasing numbers of clinical-stage LBP studies are now conducted under good manufacturing practice, standardized QC, and clinical conditions, ranging from emerging PK, biodistribution, and biomarker-driven studies to those adapted to living entities. The addition of host microbiome profiling, multi-omics analysis, and computational modeling is anticipated to increase therapeutic predictability and patient stratification. Taken together, these advances position live microbial therapeutics as programmable biological medicines with the potential for adaptive, context-specific administration and warrant further clinical development and increased integration within precision medicine-informed therapeutic approaches.}, }
@article {pmid42637046, year = {2026}, author = {Lauck, KC and Ahmed, A and Tolkachjov, SN}, title = {Response to Jean et al's "Alopecia after glucagon-like peptide-1 agonist therapy: A TriNetX Database active comparator retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.074}, pmid = {42637046}, issn = {1097-6787}, }
@article {pmid42637106, year = {2026}, author = {Heinsinger, N and Wang, Y and Grauer, S and Zhang, Z and Wong, J and Simov, V and Bukhtiyarova, M and Ai, X and Parish, C and Klein, RM and Uslaner, J and Smith, S and Tian, Y}, title = {Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107582}, doi = {10.1016/j.nbd.2026.107582}, pmid = {42637106}, issn = {1095-953X}, abstract = {ATXN2 is associated with an increased risk of Amyotrophic Lateral Sclerosis (ALS), while down-regulation of ATXN2 has been shown to mitigate TDP-43 proteinopathy in ALS models. In this study, we demonstrated that Ataxin-2 protein levels were upregulated in rNLS8 mice following doxycycline withdrawal, which coincided with TDP-43 overexpression, phosphorylation, and aggregation. To reduce Ataxin-2 protein levels, we explored the approach of splicing modulation at the RNA level. Through bioinformatical analysis, we identified an alternative 5' splicing site of ATXN2 in intron 8. This alternative splicing results in an additional 47 base pairs at the 3' end after Exon 8. The insertion of the extra nucleotides causes a frameshift that leads to reduced mRNA production and, consequently, protein levels. Following the discovery of this alternative splicing site, we conducted an antisense oligonucleotide (ASO) micro-walk to screen ASOs targeting this region. We identified ASOs that specifically modulate this splicing, including those that either enhance or inhibit alternative splicing. We validated that the ASOs that promote alternative splicing and reduce constitutive splicing can lower Ataxin-2 protein levels, which in turn decreases TDP-43 aggregation and stress granule formation in a cell-based model of TDP-43 toxicity. Furthermore, we confirmed that reducing Ataxin-2 levels via previously validated ASO delivery ameliorated TDP-43 pathology in rNLS8 mice. The discovery of ATXN2 alternative splicing, along with the confirmation of splicing modulation using ASOs in human cell-based assays, provides evidence for a proof-of-principle strategy to modulate Ataxin-2 protein levels for the treatment of ALS.}, }
@article {pmid42637886, year = {2026}, author = {Rashed, AM and El-Sayed, IET and Lu, X and Abdel-Bary, HM and Fouad, MK and Tony, MA}, title = {Re-engineering alum sludge using choline-glycine ionic liquid for enhanced dewatering and dye adsorption in wastewater treatment.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42637886}, issn = {2045-2322}, abstract = {Large quantities of by-product alum sludge (Al-S) generated from drinking water treatment plants pose significant environmental and disposal challenges due to their high water content and large volume. This study aims to develop a sustainable conditioning and valorization strategy for Al-S using a choline-glycine ionic liquid ([Ch]-[AA]). The ionic liquid was synthesized and applied as a sludge conditioner to enhance dewatering performance. Under optimized conditions, the dewatering efficiency reached 47%, accompanied by a notable zeta potential shift, indicating partial charge neutralization and improved floc structure. To enable sludge valorization, the conditioned sludge was reused as an adsorbent, either directly or after thermal treatment. The modified materials exhibited high adsorption capacities toward Synozol KHL dyes, reaching 43.6 and 90.1 mg g[-][1] for Red and Blue dyes, respectively. Adsorption behavior was well described by the Langmuir isotherm and pseudo-second-order kinetic model. Thermodynamic analysis indicated an exothermic adsorption process, with spontaneity dependent on operating conditions. Overall, the results demonstrate an effective waste-to-resource approach in which enhanced dewatering facilitates the conversion of alum sludge into a functional adsorbent for wastewater treatment, supporting sustainable sludge management.}, }
@article {pmid42638006, year = {2026}, author = {Sreekanth, D and Singh, C and Pawar, DV and Yadav, MK and Sahadeo, IK and Basavaraj, PS and Kumar, R and Mahesh, S}, title = {CRISPR/Cas-Mediated Genome Editing for Developing Herbicide Tolerant Rice: A Step-by-Step Protocol.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {3017}, number = {}, pages = {47-57}, pmid = {42638006}, issn = {1940-6029}, mesh = {*Oryza/genetics/drug effects/growth &amp; development ; *CRISPR-Cas Systems ; *Gene Editing/methods ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Acetolactate Synthase/genetics ; Plants, Genetically Modified/genetics ; Benzoates ; Pyrimidines ; }, abstract = {Weed management in rice cultivation has predominantly relied on acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides, particularly against Echinochloa spp. (watergrass). However, these herbicides carry a high risk of resistance evolution, as evidenced by the numerous resistant biotypes reported worldwide. The emergence of herbicide resistance necessitates innovative and sustainable weed control strategies. Genome editing, particularly through the CRISPR/Cas system, provides a precise and efficient platform for introducing targeted genetic modifications to develop herbicide-tolerant (HT) rice cultivars. In this protocol, we present a step-by-step approach for generating bispyribac sodium-tolerant rice using the CRISPR/Cas-mediated editing of the ALS gene. The method encompasses guide RNA design, vector construction, transformation, selection of edited plants, and molecular confirmation of targeted mutations. This approach offers a robust framework for producing HT rice lines, potentially reducing reliance on conventional herbicide regimes and mitigating the risk of resistance development in weed populations.}, }
@article {pmid42638120, year = {2026}, author = {Tang, L and Fan, D}, title = {Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42638120}, issn = {2047-9158}, support = {CX25YZ13//the Chinese Institutes for Medical Research, Beijing/ ; 2022YFA1303003//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/therapy ; *Precision Medicine/methods/trends ; *Neuroinflammatory Diseases/immunology/therapy ; Animals ; Immunotherapy/methods ; }, abstract = {Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.}, }
@article {pmid42638122, year = {2026}, author = {Zhang, Y and Liu, Y and Shi, S and Li, Q and Huo, Y and You, P and Shu, M and Cheng, X and Zhang, J and Liang, D and Zhang, A and Lu, C and Shen, B and Zhou, J and Niu, Q}, title = {JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42638122}, issn = {1741-7015}, support = {82071434//the National Natural Science Foundation of China/ ; DL202410//the clinical Research Disease Project of Jiangsu Provincial People's Hospital/ ; LC202404//Jiangsu Provincial People's Hospital-Zero magnetic Medicine Special Project/ ; JSPH-MA-2023-5//Jiangsu Province Hospital Clinical Capacity Enhancement Project/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Autophagy/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Antioxidant Response Elements ; Signal Transduction/drug effects ; *Oligopeptides/pharmacology ; Male ; Humans ; Spinal Cord/metabolism ; }, abstract = {BACKGROUND: The simultaneous modulation of oxidative stress and autophagy represents a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS), yet agents capable of coordinately regulating both processes remain scarce. The Keap1‑Nrf2‑ARE pathway serves as a critical hub linking redox homeostasis and autophagic regulation, making it an attractive target for ALS intervention. JWA is a stress‑responsive protein involved in cellular protection against oxidative injury, and its neuroprotective effects have been shown to depend on activation of the MEK/ERK‑Nrf2 axis. JP1 is a functional oligopeptide derived from the JWA protein that has been engineered to cross the blood-brain barrier and specifically target integrin αVβ3. Based on the link between JWA and Nrf2 signaling, we hypothesized that JP1 activates the Keap1‑Nrf2‑ARE pathway to coordinate antioxidant defense and autophagic clearance. Here, we evaluated this hypothesis in the SOD1‑G93A mouse model, a well‑established transgenic model of familial ALS, and elucidated the underlying mechanisms.<br><br>METHODS: We evaluated the efficacy of JP1 in the SOD1-G93A mice model using behavioral phenotyping and survival analysis. The coordinated mechanism was investigated in spinal cord tissues by profiling the Keap1-Nrf2-ARE pathway and oxidative stress, quantifying autophagic flux (by Western blotting and transmission electron microscopy) and neuronal apoptosis, and evaluating histology (by Nissl staining and immunofluorescence). Integrated transcriptomic and proteomic analyses further elucidated the global molecular landscape underlying the therapeutic effects of JP1.<br><br>RESULTS: JP1 treatment ameliorated motor deficits and extended survival in SOD1-G93A mice without adversely affecting liver or kidney function. JP1 crossed the blood-brain barrier, targeted motor neurons expressing integrin &#x3b1;V&#x3b2;3, and activated the ERK pathway. This promoted Keap1/Cul3 degradation and Nrf2 nuclear translocation, thereby activating the Keap1-Nrf2-ARE pathway to alleviate oxidative stress. Concurrently, JP1 restored autophagic flux, increased autophagic activity, attenuated motor neuron injury, suppressed neuronal apoptosis, and preserved neuronal structural integrity. The Nrf2 inhibitor ML385 reversed the protective effects of JP1 on survival, motor function, autophagy, oxidative stress, and neuronal apoptosis, which confirms that JP1 acts via the Nrf2 pathway.<br><br>CONCLUSIONS: JP1 acts as a promising coordinator of antioxidant and autophagic processes by targeting the Keap1-Nrf2-ARE pathway, thus highlighting its therapeutic potential for ALS.}, }
@article {pmid42626598, year = {2026}, author = {Pinky, PP and Wang, ZM and Khare, P and Jhaveri, JR and Sullivan, A and Basudkar, V and Rao, KS and Lawrence, A and Pingali, A and Dave, KM and Stolz, DB and Sun, M and Zheng, SY and Shiva, SS and Milligan, C and Delbono, O and Manickam, DS}, title = {Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.}, journal = {Extracellular vesicle}, volume = {7}, number = {}, pages = {}, pmid = {42626598}, issn = {2773-0417}, support = {R25 NS100118/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1[G93A] transgenic mouse model of ALS.}, }
@article {pmid42626968, year = {2026}, author = {Lautrup, S and Cao, SQ and Long, X and Liu, BHM and Escobar-Doncel, B and Ferrante, A and Frank, J and Schmauck-Medina, T and Leung, GHD and Liang, KX and Lu, N and Veverova, K and Vyhnalek, M and Pun, FW and Zhavoronkov, A and Fang, EF}, title = {A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD[+]-mitophagy axis on aging and neurodegeneration.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71680}, pmid = {42626968}, issn = {1552-5279}, support = {#119986//NordForsk Foundation/ ; PTC-Gene-25-1439553/ALZ/Alzheimer's Association/United States ; #334361//Research Council of Norway/ ; #101073251//HORIZON-TMA-MSCA-DN/ ; #269901//Akershus University Hospital/ ; #2020001//The South-Eastern Norway Regional Health Authority (Helse S&#xf8;r-&#xf8;st RHF)/ ; #282952//Cure Alzheimer's Fund/ ; #2021021//The South-Eastern Norway Regional Health Authority (Helse S&#xf8;r-&#xf8;st RHF)/ ; #281956//Norwegian Health Association/ ; /WT_/Wellcome Trust/United Kingdom ; #104617//Ellcome Leap's Dynamic Resilience Program (jointly funded by Temasek Trust)/ ; #TO01000215//Czech Republic-Norway KAPPA programme/ ; #262960//Akershus University Hospital/ ; #43622//Norwegian Health Association/ ; #262175//Research Council of Norway/ ; #NW26-04-00501//Czech Ministry of Health project/ ; #81971327//National Natural Science Foundation of China/ ; #284930//Cure Alzheimer's Fund/ ; #261973//Akershus University Hospital/ ; #2023093//The South-Eastern Norway Regional Health Authority (Helse S&#xf8;r-&#xf8;st RHF)/ ; #207819//the Rosa sl&#xf8;yfe/Norwegian Cancer Society and Norwegian Breast Cancer Society/ ; #281931//Civitan Norges Forskningsfond/ ; }, mesh = {Humans ; Animals ; *Aging/metabolism ; Caenorhabditis elegans ; *NAD/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitophagy/physiology ; *Brain/metabolism/pathology ; *Artificial Intelligence ; Neurons/metabolism ; Alzheimer Disease/metabolism/genetics ; Induced Pluripotent Stem Cells ; }, abstract = {INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD[+]) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD[+]-mitophagy axis contributes to brain aging and neurodegeneration.<br><br>METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD[+]-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.<br><br>RESULTS: The NAD[+]-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.<br><br>DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD[+]-mitophagy axis as a central player in brain aging and AD.}, }
@article {pmid42627134, year = {2026}, author = {Mahjoubin-Tehran, M and Sahebkar, A}, title = {RNA interference (RNA)-based therapeutics for treating neurodegenerative diseases.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/17582024.2026.2722300}, pmid = {42627134}, issn = {1758-2032}, }
@article {pmid42628519, year = {2026}, author = {Mohassel, P}, title = {Rethinking ALS through the spatiotemporal vulnerability of the entire motor unit.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2026.08.011}, pmid = {42628519}, issn = {1525-0024}, support = {R01 NS138167/NS/NINDS NIH HHS/United States ; }, }
@article {pmid42628773, year = {2026}, author = {Tani, H}, title = {A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1891}, number = {}, pages = {150513}, doi = {10.1016/j.brainres.2026.150513}, pmid = {42628773}, issn = {1872-6240}, abstract = {Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.}, }
@article {pmid42629129, year = {2026}, author = {Sha, L and Jha, S}, title = {Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.}, journal = {Advances in immunology}, volume = {171}, number = {}, pages = {307-341}, doi = {10.1016/bs.ai.2026.04.008}, pmid = {42629129}, issn = {1557-8445}, mesh = {Humans ; *Extracellular Traps/immunology/metabolism ; *Microglia/immunology/metabolism ; Animals ; *Neurodegenerative Diseases/immunology/therapy/metabolism/pathology ; Histones/metabolism ; Signal Transduction ; Neuroinflammatory Diseases/immunology ; }, abstract = {Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.}, }
@article {pmid42630952, year = {2026}, author = {Tang, C and De Vocht, J and Van Damme, P and Van Laere, K and Koole, M}, title = {Metabolic connectivity alterations in amyotrophic lateral sclerosis: Individual network analysis based on Wasserstein distances.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {4}, number = {}, pages = {}, pmid = {42630952}, issn = {2837-6056}, abstract = {Molecular connectivity analysis with positron emission tomography (PET) imaging offers a promising approach for characterising brain network alterations in neurodegenerative disorders. In this study, we introduce Wasserstein distance (WD) as an alternative to Kullback-Leibler divergence similarity estimation (KLSE) for constructing single-subject metabolic connectivity networks. Using [18]F-FDG PET data from 167 individuals with amyotrophic lateral sclerosis (ALS), 36 healthy volunteers (HV), and 25 ALS mimics, we generated WD- and KLSE-based connectivity matrices across 77 atlas-defined brain regions and evaluated corresponding graph theory-based nodal metrics. WD- and KLSE-derived nodal measures were strongly correlated, indicating methodological consistency. Compared with HVs, age-matched subjects in the ALS group (ALSamHV) showed significant alterations in frontal, temporal, cerebellar, and occipital network nodes, with WD-based metrics revealing differences across more brain regions than the KLSE-based approach. Support vector machine classification of ALSamHV vs. HV demonstrated that both connectivity approaches matched voxel-wise PET performance with accuracy higher than 0.80 (yet significantly lower than voxel-wise data, p < 0.05), while significantly outperforming image-based classification for ALS vs. ALS mimics (p < 0.01), with WD achieving the highest accuracy of 0.65 (p < 0.001). These findings support WD-based metabolic connectivity as a sensitive, data-efficient framework for detecting disease-related network alterations and motivate its application to a broader range of PET tracers and cohorts.}, }
@article {pmid42631129, year = {2026}, author = {Nuñez, E and Muguruza-Montero, A and Arrizabalaga-Iriondo, A and Zayas-Arrabal, J and M-Alicante, S and Urrutia, J and Revuelta, M}, title = {KV3.1 channel modulation: a systematic review of pharmacological intervention strategies.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1821275}, pmid = {42631129}, issn = {1663-9812}, abstract = {INTRODUCTION: Voltage-gated potassium channels of the KV3 subfamily, particularly KV3.1 (encoded by KCNC1), are essential regulators of fast-spiking inhibitory interneuron activity and high-frequency neuronal firing, enabling precise control of neuronal excitability and network synchrony. Growing evidence links KV3.1 dysfunction to epilepsy, schizophrenia, tinnitus, fragile X syndrome, amyotrophic lateral sclerosis, and KCNC1 related developmental and epileptic encephalopathies, positioning this channel as a promising therapeutic target.<br><br>METHODS: This systematic review, conducted in accordance with PRISMA guidelines, evaluates original studies published between 2016 and January 2026 that investigated pharmacological modulation of KV3.1 using in vitro, in vivo, structural, and translational approaches.<br><br>RESULTS: A total of thirty-two studies met the predefined PICOS criteria. The literature reveals two pharmacological strategies: positive allosteric modulation aimed at enhancing fast-spiking inhibitory interneuron function and restoring excitation inhibition balance, and state-dependent channel inhibition, particularly relevant for pathogenic gain of function KCNC1 variants.<br><br>DISCUSSION: While early positive allosteric modulators demonstrated proof of mechanism with limited clinical success, second-generation compounds exhibit improved translational potential, including evidence that they modulate functional brain networks in humans. In parallel, clinically approved antidepressants have been identified as open-channel blockers of KV3.1, enabling mutation-specific therapeutic repurposing.<br><br>CONCLUSIONS: Collectively, these findings highlight KV3.1 modulation as a context-dependent and increasingly precise pharmacological strategy for neurological and neurodevelopmental disorders.}, }
@article {pmid42632702, year = {2026}, author = {Wu, L and Zhu, X and Wang, X and Wu, Y and Bu, Q and Dai, T and Wen, X and Zhong, K and Guo, H and Gao, H}, title = {Fermentation with aspergillus costiformis enhances the anti-migratory activity of Aquilaria sinensis leaves with possible involvement of MAPK-related pathways.}, journal = {Food research international (Ottawa, Ont.)}, volume = {242}, number = {Pt 2}, pages = {119955}, doi = {10.1016/j.foodres.2026.119955}, pmid = {42632702}, issn = {1873-7145}, mesh = {Humans ; *Aspergillus/metabolism ; *Plant Leaves/chemistry ; *Fermentation ; *Thymelaeaceae/chemistry/metabolism ; HeLa Cells ; *Plant Extracts/pharmacology ; *Cell Movement/drug effects ; *MAP Kinase Signaling System/drug effects ; Flavonoids ; Cell Proliferation/drug effects ; }, abstract = {Aquilaria sinensis leaves (ALs) are an underutilized plant resource rich in polyphenols and flavonoids. Microbial fermentation has been proposed as an effective strategy to enhance the functional value of plant materials. However, its impact on the bioactivity and mechanisms of ALs remains unclear. This study aimed to evaluate the effects of fermentation with Aspergillus costiformis AHHC on the chemical composition and biological activities of ALs, and to elucidate the molecular mechanisms underlying the fermentation-induced functional changes. Non-targeted metabolomic analysis was performed to assess fermentation-induced metabolic alterations. The biological activities of fermented ALs (ALDT) and non-fermented ALs (ALT) extracts were evaluated using HeLa S3 cell-based assays. Network pharmacology and transcriptomic analyses were integrated to identify potential pathways and molecular targets, which were further validated by molecular analyses. The results revealed that fermentation significantly reshaped the metabolite profile of ALDT, particularly in flavonoid-related pathways. Compared with ALT, ALDT showed a stronger inhibitory effect on HeLa S3 cell migration while maintaining comparable anti-proliferative activities at higher concentrations. The integrated analyses indicated that fermentation-enriched metabolites were mainly associated with pathways related to cell migration and stress response, with prominent involvement of MAPK signaling. Molecular assays confirmed enhanced phosphorylation of MAPK components and increased expression of regulatory genes such as GADD45B and NR4A1 in response to ALDT treatment. Overall, fermentation with A. costiformis enhanced the anti-migratory activity of ALDT in HeLa S3 cells, with possible involvement of MAPK-related signaling pathways. These findings provide molecular-level evidence supporting microbial fermentation as a strategy to improve the functional value of this plant resource.}, }
@article {pmid42632821, year = {2026}, author = {Tragesser, C and Joy, AG and Sodhi, CP}, title = {Early-onset inflammatory bowel disease: progress and persistent inequities.}, journal = {Pediatric research}, volume = {}, number = {}, pages = {}, pmid = {42632821}, issn = {1530-0447}, abstract = {This commentary discusses Yue et al.'s population-based study, "The Shifting Burden of Early-Onset Inflammatory Bowel Disease: A Global Analysis", and highlights how declining mortality, increasing prevalence, and widening socioeconomic disparities are reshaping the global landscape of early-onset inflammatory bowel disease.[1] The findings emphasize the importance of combining scientific advances with equitable healthcare delivery to improve outcomes for children worldwide.}, }
@article {pmid42632975, year = {2026}, author = {Saeed, Y and Fatima, M and Rehman, MU and Aslam, MH}, title = {Diagnostic Delay in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis Comparing Time From Symptom Onset to Diagnosis in Bulbar-Onset Versus Limb-Onset Disease.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e113188}, pmid = {42632975}, issn = {2168-8184}, abstract = {Diagnostic delay is a recognized challenge in amyotrophic lateral sclerosis (ALS), depriving patients of timely access to disease-modifying therapy and multidisciplinary care. Although several individual cohorts have reported diagnostic delay separately for bulbar-onset and limb-onset ALS, few studies have directly compared the two, and their estimates have not been pooled. We aimed to compare time from symptom onset to diagnosis in bulbar-onset versus limb-onset ALS. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception through April 2026 for studies reporting diagnostic delay separately for the two onset types. Where upper- and lower-limb onset were reported separately, these were combined into a single limb-onset group using standard formulae; medians with interquartile ranges were converted to means and standard deviations using the method of Wan et al. A random-effects meta-analysis (DerSimonian-Laird) pooled studies reporting a usable measure of dispersion by onset group, with the remaining studies summarized narratively. The outcome was the mean difference (MD) in diagnostic delay in months, where a negative value indicates faster diagnosis in bulbar onset; heterogeneity was quantified with I[2] and risk of bias with the Newcastle-Ottawa Scale. In total, 13 studies (898 bulbar-onset and 2,438 limb-onset patients from eight countries) met the inclusion criteria; nine contributed to the meta-analysis, as four reported no usable measure of dispersion and were summarized narratively. Bulbar-onset patients were diagnosed significantly faster than limb-onset patients (MD = -4.42 months; 95% confidence interval -5.73 to -3.11; p < 0.001), with moderate heterogeneity (I[2] = 56%). The direction of effect was consistent across all studies, and the pooled estimate was stable on leave-one-out analysis. The four non-pooled studies were each directionally consistent. Bulbar-onset ALS is diagnosed approximately 4 months faster than limb-onset ALS, likely because distinctive bulbar symptoms prompt earlier specialist referral whereas limb weakness is attributed to more common musculoskeletal or orthopedic conditions. Strategies raising awareness of limb-onset ALS among primary care and orthopedic physicians are warranted.}, }
@article {pmid42622006, year = {2026}, author = {de la Rubia Ortí, JE and Bargues-Navarro, G and Sancho-Castillo, S and Privado, J and Benlloch García, M and Sanchis Sanchis, CE and Garcia Martinez, L and Cuerda-Ballester, M and Bolós, PM and Roig, FJ}, title = {Cross sectional analysis of gut microbiota of ALS patients with and without percutaneous endoscopic gastrostomy.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1842792}, pmid = {42622006}, issn = {1664-302X}, abstract = {INTRODUCTION: This cross-sectional study investigated the differences in gut microbiota in patients with Amyotrophic Lateral Sclerosis (ALS) with and without percutaneous endoscopic gastrostomy (PEG), exploring their cross-sectional associations with nutritional intake.<br><br>METHODS: Use of shotgun metagenomics and dietary assessments.<br><br>RESULTS: We identified significant taxonomic shifts and changes in diversity across groups. PEG patients exhibited reduced abundance of short-chain fatty acids (SCFAs)- producing genera, such as Faecalibacterium and Lachnospira, suggesting a dysbiotic profile; the Firmicutes/Bacteroidetes ratio was also lower in PEG patients but is reported as a descriptive indicator only. Correlations between specific bacterial taxa and nutrient intake, highlight the potential role of the gut microbiota in ALS pathophysiology. These findings describe cross-sectional differences in microbial composition associated with nutritional status and feeding route.<br><br>DISCUSSION: Our results provide a foundation for microbiome-targeted interventions in the management of ALS, although findings related to PEG should be interpreted as exploratory given the limited sample size. Furthermore, all comparisons involving the external control group (BioProject PRJNA961076) must be interpreted with caution due to potential batch effects from differences in sample collection, DNA extraction kits, and sequencing platforms.}, }
@article {pmid42622454, year = {2026}, author = {Boccanegra, B and Tulimiero, L and Quarta, R and Conte, E and Licandro, SA and Decio, A and Lenti, R and Ladisa, A and Dinoi, G and Carbone, G and Claudione, L and Camerino, GM and Pierno, S and Mantuano, P and Cappellari, O and Fossati, G and Steinkühler, C and De Luca, A}, title = {LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors.}, journal = {Annals of the New York Academy of Sciences}, volume = {1562}, number = {1}, pages = {e70364}, pmid = {42622454}, issn = {1749-6632}, support = {22.004//Duchenne Parent Project/ ; GJC25P084//Fondazione Telethon/ ; PRIN MUR 2020ELYA32//Ministero dell'Universit&#xe0; e della Ricerca/ ; 2023-UNBACLE-0245439//Universit&#xe0; degli Studi di Bari "Aldo Moro"/ ; }, mesh = {Animals ; *Histone Deacetylase Inhibitors/pharmacology ; *Muscular Dystrophy, Duchenne/genetics/metabolism/drug therapy ; Mice ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Humans ; *Epigenesis, Genetic/drug effects ; Disease Models, Animal ; AMP-Activated Protein Kinase Kinases ; MicroRNAs/genetics/metabolism ; Mice, Inbred mdx ; Vorinostat ; AMP-Activated Protein Kinases/metabolism ; Muscle, Skeletal/metabolism/drug effects ; }, abstract = {Efficient skeletal muscle contraction requires tight mechano-metabolic coupling, a process regulated by AMP-activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1-STRADα-MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx) and patient-derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad-spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR-451, miR-195, and miR-17, which function as post-transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin-A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1-STRADα-MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.}, }
@article {pmid42623241, year = {2026}, author = {Yi, T and Guan, H and Li, J and Li, W and Li, B and Zhu, C}, title = {Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits.}, journal = {Cell reports}, volume = {45}, number = {9}, pages = {117885}, doi = {10.1016/j.celrep.2026.117885}, pmid = {42623241}, issn = {2211-1247}, abstract = {TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.}, }
@article {pmid42624563, year = {2026}, author = {Mehta, B and Nambiar, S and Shirke, O and Pandita, S and Markandeya, YS}, title = {Histone deacetylases in neurodegeneration and neuronal plasticity.}, journal = {Methods in enzymology}, volume = {733}, number = {}, pages = {321-366}, doi = {10.1016/bs.mie.2026.06.025}, pmid = {42624563}, issn = {1557-7988}, mesh = {Humans ; *Histone Deacetylases/metabolism/genetics ; Animals ; *Neuronal Plasticity ; *Neurodegenerative Diseases/enzymology/metabolism/pathology/drug therapy/genetics ; Cell Nucleus/metabolism ; Neurons/metabolism/pathology ; Histone Deacetylase 6/metabolism ; Brain/metabolism/pathology ; Protein Transport ; }, abstract = {This chapter pulls together current research on how HDAC shuttling between the nucleus and cytoplasm affects neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and epilepsy. It takes a close look at why these shifts in HDAC localization matter so much in brain disease and its implications for new treatments. Histone deacetylases (HDACs) are a big deal when it comes to gene regulation in the brain. They play key roles in both neurodegeneration and the brain's ability to adapt, working inside the nucleus and out in the cytoplasm. This chapter unpacks the molecular mechanisms behind HDAC trafficking-how they move around-highlights the different roles of HDAC isoforms, and compares localization-specific effects. It digs into how HDACs impact protein aggregation and synaptopathies. Some findings stand out: HDAC4 and HDAC1 are tightly controlled by phosphorylation signals, which change their cellular localization and influence neuronal mortality. For example, HDAC6 is majorly involved in cellular trafficking and clearing protein aggregates, whereas HDAC4 aggregation in the nucleus is responsible for driving neuronal toxicity. If HDAC1 undergoes nuclear export, it interacts with motor proteins to impact mitochondrial transport. Drugs that block HDAC6 look promising in preclinical models-they help restore neuronal transport systems and clear protein aggregation. Moving HDAC4 out of the nucleus seems to support better synaptic function and motor skills. As a general rule, HDAC accumulation in the nucleus shuts down genes that keep neurons alive, but keeping them in the cytoplasm helps preserve connections between neurons. You'll also find thorough, practical advice on how to study HDACs in brain research-covering everything from enzyme assays and cell experiments to live animal models, plasticity tracking, drug testing, and data analysis. A major innovation featured here is using CRISPR-based tricks to control exactly where HDACs go inside cells: forced targeting using dCas9 fusions, editing natural localization signals, and even using optogenetics for precise on-demand control. In short, the chapter is a hands-on guide for anyone trying to unravel HDAC mechanisms in diseases like Alzheimer's, Parkinson's, Huntington's, or in studies of brain plasticity. Some standout methods include tracking HDAC localization in the cells, measuring how phosphorylation affects their shuttling, and using HDAC2 inhibitors for cognitive boosts. It also covers isoform-specific approaches in Huntington's models, manipulating HDAC location with CRISPR for deeper insights, and combining live-cell imaging with biochemical and chromatin studies for robust validation. This chapter sheds light on the latest advances, with a strong focus on precision, quantitative results, and translating these findings into real-world applications.}, }
@article {pmid42624937, year = {2026}, author = {Aboukhalil, FM and Khamis, EF and El-Sayed, MA and Youssef, RM and El-Yazbi, AF}, title = {Green analytical methods for quantification of a new combination therapy for amyotrophic lateral sclerosis: assessment by EPPI framework.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42624937}, issn = {2045-2322}, mesh = {*Celecoxib/therapeutic use/analysis ; *Ciprofloxacin/therapeutic use/analysis ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Chromatography, High Pressure Liquid/methods ; *Green Chemistry Technology/methods ; Spectrophotometry, Ultraviolet/methods ; Tablets ; Drug Therapy, Combination ; Reproducibility of Results ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to progressive muscle weakness, paralysis, and respiratory failure. The recently proposed combination therapy consisting of celecoxib and ciprofloxacin hydrochloride has emerged as a potential treatment for amyotrophic lateral sclerosis and other neurodegenerative disorders. The present study aimed to develop and validate simple, sensitive, environmentally friendly, and cost-effective analytical methods for the simultaneous determination of celecoxib and ciprofloxacin hydrochloride in bulk powders, laboratory-prepared tablets and plasma. Two ultraviolet spectrophotometric methods were established. The first method relies on direct absorbance measurements of ciprofloxacin hydrochloride at 318 nm and celecoxib at the isosbestic point at 266 nm, while the second one employs first-derivative ratio spectrophotometry for the selective determination of ciprofloxacin hydrochloride and celecoxib at 280 nm and 254 nm, respectively. Moreover, a reversed-phase high-performance liquid chromatographic method was developed using a C18 stationary phase, an optimized mobile phase composition and both diode array and fluorescence detectors, achieving efficient separation and accurate quantification of both analytes. The developed procedures were successfully applied to laboratory-prepared tablets and plasma following optimization of the sample preparation protocol to minimize matrix interference and to improve analytes recovery. Validation results showed excellent linearity over the investigated concentration ranges together with satisfactory accuracy, precision, selectivity, and sensitivity, confirming the reliability of the proposed methods for routine quality control and bioanalytical applications. The overall analytical performance and environmental sustainability of the developed methods were further assessed using the environmental performance and practicality Index framework, demonstrating their suitability as reliable and sustainable analytical approaches for the determination of celecoxib and ciprofloxacin hydrochloride.}, }
@article {pmid42625715, year = {2026}, author = {Chen, D and Shen, T and Ren, H and Qiu, P}, title = {Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1901811}, pmid = {42625715}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/diagnostic imaging ; Diagnosis, Differential ; Phenotype ; Magnetic Resonance Imaging ; *Spinal Cord Diseases/diagnosis/physiopathology ; *Spinal Cord Compression/diagnosis/physiopathology ; }, abstract = {Differentiating amyotrophic lateral sclerosis (ALS) from degenerative cervical myelopathy (DCM) remains difficult because the two disorders can converge clinically while diverging biologically. ALS is a progressive motor neuron disease, whereas DCM is a potentially treatable compressive myelopathy; however, both may present with upper-limb weakness, hand wasting, hyperreflexia, gait disturbance, and cervical MRI abnormalities. This narrative review examines ALS-DCM overlap through the concept of explanatory sufficiency: whether the available clinical, imaging, and electrophysiological evidence adequately explains the whole syndrome rather than a single visible abnormality. We synthesize evidence on phenotype-specific overlap, MRI-clinical mismatch, EMG/NCS distribution, somatosensory and motor evoked potentials, Gold Coast diagnostic criteria, primary lateral sclerosis, and coexistence of motor neuron disease with structural cervical pathology. The review emphasizes that MRI is indispensable but not self-interpreting, EMG/NCS is most useful when interpreted by distribution rather than positivity alone, and SEPs/MEPs can add a functional cord-conduction layer when MRI and examination are discordant. We also provide action-oriented clinical warning signs for common overlap scenarios. Rather than offering a rigid algorithm, this review proposes a clinically driven reasoning framework that helps distinguish ALS, DCM, radiculopathy, and coexistence while reducing premature diagnostic closure in neuro-spine practice.}, }
@article {pmid42625845, year = {2026}, author = {Wu, IH and Schwarze, JE and Helwig, C and D'Hooghe, T and Schellschmidt, I}, title = {Clinical Appraisal of "Micronized Vaginal Progesterone Dose and Serum Progesterone Thresholds Determine Reproductive Outcomes in Frozen-Thawed Embryo Transfer With Hormone Replacement Therapy".}, journal = {Reproductive medicine and biology}, volume = {25}, number = {1}, pages = {e70088}, pmid = {42625845}, issn = {1445-5781}, abstract = {This paper critically evaluates Sekiguchi et al.'s study of vaginal progesterone dose, serum progesterone thresholds, and reproductive outcomes in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The study conflates descriptive, predictive, and causal aims without a clearly prespecified primary question, limiting interpretability. Major concerns include non-random treatment allocation, potential residual confounding, absence of a causal framework for covariate selection, unaddressed temporal confounding related to Japan's 2022 insurance reform, and exclusion of an available progesterone formulation. Additionally, formulation specific pharmacokinetics, single-time-point progesterone measurement, and internally derived thresholding limit comparability, predictive validity, and clinical applicability.}, }
@article {pmid42625892, year = {2026}, author = {Dimitrov, M and Grosskreutz, J and Ilse, B and Rakers, F and Steinbach, R}, title = {Short-term ambient temperature increases are associated with higher mortality in amyotrophic lateral sclerosis: a case-crossover study of weather conditions.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1868482}, pmid = {42625892}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with vastly differing survival times. The influence of environmental exposures such as weather conditions on mortality among people living with ALS remain poorly defined. The aim of this study was to evaluate the association between short-term meteorological phenomena and the odds of death among patients with ALS.<br><br>METHODS: We conducted a retrospective case-crossover study of 298 deaths among clinically verified ALS patients that occurred within a weather-station catchment area. Daily mean data for temperature, atmospheric pressure, and relative humidity were analyzed. Associations were analyzed by comparing hazard intervals (1-3&#x202f;days before death) with bidirectional control intervals in generalized linear mixed models. Results are expressed as odds ratios (OR) and 95% confidence intervals (CI).<br><br>RESULTS: Absolute meteorological conditions (temperature, pressure, humidity) showed no significant association with mortality, which was independently supported by seasonal/monthly death count analyses. Short-term temperature rises of 3 &#xb0;C in the 24&#x202f;h preceding the day before death were associated with 25% higher odds of death (OR 1.25; 95% CI 1.05-1.49). Exploratory subgroup analyses suggested that this association was most pronounced in female, ventilated, and older patients (&#x2265;65&#x202f;years). Changes in relative humidity and atmospheric pressure were not significantly associated with the odds of death.<br><br>CONCLUSION: Short-term temperature increases are associated with higher odds of death among people living with ALS, independent of absolute weather conditions or seasonal patterns. These findings support attention of stable ambient temperatures in end-stage care, while further studies of weather-related hazards in ALS are needed.}, }
@article {pmid42626456, year = {2026}, author = {Pollard, C and Miller, R and Stirland, I and Keni, M and Jenkins, A and Saito, E and Hill, JT and Jenkins, T}, title = {Circulating neuron-derived cfDNA for blood-based detection of Alzheimer's and other neurodegenerative conditions.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1822479}, pmid = {42626456}, issn = {1664-2295}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; DNA Methylation ; *Neurons/metabolism ; *Cell-Free Nucleic Acids/blood ; Biomarkers/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Female ; Male ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; }, abstract = {Blood-based biomarkers for neurodegenerative diseases are improving early detection and staging, but current assays primarily reflect aggregate neuropathology or generalized neuronal injury and do not resolve the specific neuronal populations affected. Circulating cell-free DNA (cfDNA) retains stable DNA methylation patterns reflective of tissue and cellular origin, making it a promising substrate for cell-of-origin analysis. However, conventional methylation approaches are limited by bisulfite-associated DNA damage and amplification-related bias, hindering the detection of neuron-derived cfDNA, a small fraction of total circulating cfDNA. Here, we present proof-of-concept evidence that native nanopore sequencing can support both brain methylation atlas generation and downstream cfDNA cell-of-origin classifier development in neurodegenerative disease. By directly profiling endogenous DNA methylation without bisulfite conversion or PCR amplification, nanopore sequencing preserves native molecules, reduces processing-related bias, and enables flexible, genome-wide methylation profiling that can be iteratively expanded as additional reference cell types are incorporated. Using whole-genome native nanopore sequencing, we generated a methylation reference atlas from six primary human neural cell populations-cortical neurons, dopaminergic neurons, spinal motor neurons, astrocytes, Schwann cells, and microglia-and developed cell-type-informed cfDNA classifiers. Classifier performance was assessed in silico using dilution series designed to model physiologic admixture. The framework was then applied to 137 blood plasma samples from individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and healthy controls. Elevated circulating cfDNA fragments exhibited methylation patterns similar to reference profiles from selectively vulnerable neuronal populations, including cortical neuron-like signatures in AD and progressive MCI, dopaminergic neuron-like signatures in PD, and spinal motor neuron-like signatures in ALS. Multivariate integration of neuronal signatures improved the separation of diagnostic groups within this cohort (AUC > 0.85). Although the reported atlas is limited and additional validation in larger and independent cohorts will be required, these results support the feasibility of native cfDNA nanopore methylation sequencing as a flexible platform for brain-derived cfDNA analysis and more cell-type-informed investigation of neurodegeneration from peripheral blood.}, }
@article {pmid42621473, year = {2026}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as TREM2 Agonists for Treating Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Nasu-Hakola Disease, and Stroke.}, journal = {ACS medicinal chemistry letters}, volume = {17}, number = {8}, pages = {1723-1724}, pmid = {42621473}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Nasu-Hakola disease, and stroke, and processes for preparing such compounds.}, }
@article {pmid42621714, year = {2026}, author = {Wang, SL and He, L and Yang, J and Zhang, N and Sun, YZ and Liu, GP}, title = {["Jiaji" (EX-B2) electroacupuncture modulates NLRP3 inflammasome activation to improve limb dysfunction in amyotrophic lateral sclerosis mice].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {51}, number = {8}, pages = {1044-1052}, doi = {10.13702/j.1000-0607.20251237}, pmid = {42621714}, issn = {1000-0607}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics/immunology/physiopathology/metabolism ; *Electroacupuncture ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/immunology ; Mice ; Humans ; *Inflammasomes/genetics/metabolism/immunology ; Male ; Acupuncture Points ; Disease Models, Animal ; Interleukin-1beta/genetics/immunology ; *Extremities/physiopathology ; Female ; Spinal Cord/metabolism ; Mice, Inbred C57BL ; }, abstract = {OBJECTIVES: To investigate the regulatory effect of "Jiaji" (EX-B2) electroacupuncture (EA) on the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in the lumbar spinal cord and to explore its mechanism in improving limb dysfunction in amyotrophic lateral sclerosis (ALS) mice.<br><br>METHODS: Fifty-four mice carrying the human superoxide dismutase 1 G93A (hSOD1[G93A]) gene were randomly divided into model, Jiaji EA, and inhibitor groups, with 18 mice per group. Eighteen mice not carrying the hSOD1[G93A] gene served as wild group. At 60 d of age, the Jiaji EA group was given EA at L1-L2 and L5-L6 EX-B2 points with continuous wave, 1 mA, 2 Hz. The needles retained for 20 min, twice every week. The inhibitor group received intraperitoneal injection of the NLRP3 inhibitor (10 mg/kg, twice every week). All treatments were administered for 4 consecutive weeks. The survival period of mice in each group was observed to assess disease progression&#xff1b;the rotarod test was conducted to evaluate motor coordination and limb motor function&#xff1b;HE staining was used to observe pathological changes in the gastrocnemius, and muscle atrophy was assessed by measuring the cross-sectional area of the gastrocnemius fiber&#xff1b;Nissl staining was performed to evaluate the number of motor neurons in the lumbar spinal cord anterior horns&#xff1b;the protein expressions of NLRP3, Caspase-1, apoptosis-associated speck-like protein (ASC), interleukin-1&#x3b2; (IL-1&#x3b2;), interleukin-18 (IL-18), and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) in the lumbar spinal cord were detected by Western blot&#xff1b;the mRNA expressions of NLRP3, Caspase-1, ASC, IL-1&#x3b2;, IL-18, and TNF-&#x3b1; were detected by real-time quantitative PCR.<br><br>RESULTS: Compared with the wild group, mice in the model group exhibited shortened survival time (P<0.01)&#xff1b;reduced time spent on the rotating rod starting from the 13[th] week of age (P<0.05)&#xff1b;significantly shorter and rounded gastrocnemius fibers with enlarged inter-fiber spaces, nuclear translocation and leakage. The cross-sectional area of the gastrocnemius fibers was reduced (P<0.01)&#xff1b;the number of motor neurons in the spinal anterior horns was decreased (P<0.01)&#xff1b;protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1&#x3b2;, IL-18, and TNF-&#x3b1; were increased in the lumbar spinal cord (P<0.01). Compared with the model group, survival time was prolonged in the Jiaji EA and inhibitor groups (P<0.01)&#xff1b;rotarod time was prolonged starting from the 13[th] week of age (P<0.05)&#xff1b;gastrocnemius fibers exhibited more regular margins and larger morphology, with reduced inter-fiber spaces, and reduced number of rounded fibers and improvement in nuclear translocation and leakage&#xff1b;cross-sectional areas of gastrocnemius fiber were increased (P<0.01)&#xff1b;the numbers of motor neurons in the spinal anterior horns were increased (P<0.01)&#xff1b;protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1&#x3b2;, IL-18, and TNF-&#x3b1; decreased in the lumbar spinal cord (P<0.05, P<0.01). Compared with the inhibitor group, mice in the Jiaji EA group exhibited prolonged rotarod time from the 17[th] week of age (P<0.05)&#xff1b;the cross-sectional area of the gastrocnemius fiber increased (P<0.05)&#xff1b;protein and mRNA expressions of NLRP3, Caspase-1 and IL-18 in the lumbar spinal cord were higher (P<0.05, P<0.01), while protein and mRNA expressions of TNF-&#x3b1; were lower (P<0.05, P<0.01).<br><br>CONCLUSIONS: EX-B2 EA improves limb function and prolongs survival in ALS mice, with its underlying mechanism potentially involving the alleviation of neuroinflammation through inhibition of NLRP3 inflammasome activation.}, }
@article {pmid42620667, year = {2026}, author = {Hawley, ZCE and Guise, AJ and Pardo, ID and Chowdhury, T and Hana, S and Zavodszky, MI and Engle, L and Wiltberger, K and Bartlett, D and Raitcheva, D and Bommegowda, S and Lee, WH and Chen, SK and Sheehy, A and Driscoll, R and Peterson, M and Sebalusky, J and Hamann, S and Marsh, G and Doherty, J and Chicoine, KE and Cundiff, P and Dwyer, S and Clarner, P and Zeng, W and Ferretti, D and Tuczkewycz, T and Isaza, I and Patrovanie, M and Mcgladrigan, C and Chu, J and Morrison, JP and Arnold, HM and Shen, S and Hurt, JA and Trapa, P and Graham, DL and Plowey, ED and Lo, SC}, title = {Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201818}, pmid = {42620667}, issn = {3117-387X}, abstract = {Adeno-associated virus (AAV) artificial microRNAs (amiRNAs) targeting superoxide dismutase 1 (SOD1) have been proposed as a therapeutic strategy for people living with amyotrophic lateral sclerosis (ALS) who harbor toxic gain-of-function variants in the SOD1 gene. Clinical efforts have primarily focused on AAV delivery via the cerebrospinal fluid (CSF), as blood-brain-barrier-crossing capsids are still being developed preclinically. However, intra-CSF delivery has been shown to be highly variable and increases the risk for AAV-related adverse events such as dorsal root ganglion (DRG) toxicity. Here, we show that immunosuppressants (IMS) following intra-CSF delivery of AAV9-amiR-SOD1 in non-human primates (NHPs) prevented AAV-related DRG toxicity, and this benefit was maintained for over 300 days even after immunotherapy stopped at 90 days post-AAV treatment. In line with prior literature, we found intra-CSF delivery of AAV9-amiR-SOD1 to be highly variable in adult mice and NHPs, requiring higher doses of virus to achieve efficacious endpoints. To address this concern, we developed a proof-of-principle study showing that AAV9-amiR-SOD1, in combination with a SOD1-targeting antisense oligonucleotide, provided an additive therapeutic benefit in SOD1-G93A mice compared with AAV9-amiR-SOD1 alone. This combinatorial approach lowered the viral load needed to reach efficacious endpoints, which could mitigate AAV-related adverse events alongside IMS.}, }
@article {pmid42621206, year = {2026}, author = {Couto, CM and de Melo Queiroz, E and da Cunha, MC and Santos, SCL and Ferreira, AR and Nascimento, OJM}, title = {Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1883977}, pmid = {42621206}, issn = {1664-2295}, mesh = {Humans ; Brazil/epidemiology ; Female ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Retrospective Studies ; Middle Aged ; Genetic Testing ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Aged ; *Genetic Profile ; C9orf72 Protein/genetics ; Cohort Studies ; Adult ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Genetic testing in amyotrophic lateral sclerosis (ALS) is increasingly recommended for all patients, but real-world implementation in middle-income countries remains heterogeneous. Brazilian motor neuron disease genetics has largely been characterized through protocol-based cohorts focused on the founder VAPB p.Pro56Ser variant (amyotrophic lateral sclerosis type 8, ALS8). The broader genetic landscape beyond ALS8 in Brazilian clinical populations has not been described in a large multiregional cohort. We aimed to characterize this profile.<br><br>METHODS: We retrospectively analyzed 1,911 patients with motor neuron disease followed at six SARAH Network rehabilitation hospitals across Brazil between 2007 and 2024. Genetic testing was clinically directed; ALS8 cases (n&#x202f;=&#x202f;78) were characterized separately. We assessed characteristics of genetically tested versus untested patients, the temporal evolution of testing modalities, and the diagnostic yield by gene and by Byrne family history classification.<br><br>RESULTS: Of 1,833 patients without ALS8, 318 (17.3%) underwent genetic testing, with selection bias toward younger age, higher educational attainment, and positive family history of ALS or frontotemporal dementia (all p&#x202f;<&#x202f;0.001). Testing expanded markedly after 2020, particularly C9orf72 screening and next-generation sequencing panels. Panel/exome sequencing identified pathogenic or likely pathogenic variants in 13 of 66 patients (19.7%), consistent with international literature for mixed familial-sporadic cohorts. Across all modalities, 30 patients without ALS8 carried pathogenic or likely pathogenic variants in six genes: SOD1 (n&#x202f;=&#x202f;15), C9orf72 (n&#x202f;=&#x202f;11; 7.0% of 157 tested), and VCP, FUS, TBK1, and SETX (n&#x202f;=&#x202f;1 each). ATXN2 intermediate-length CAG repeats were identified in 15 of 230 patients tested (6.5%), replicating the 6.3% previously reported in a Brazilian multicenter sample. Yield by Byrne classification followed a marked gradient (Definite: 89.7%, Probable: 24.0%, Possible: 15.4%, Sporadic: 4.9%; p&#x202f;<&#x202f;0.001). The SOD1 spectrum included recurrent variants of likely Iberian/European origin.<br><br>CONCLUSION: This 18-year cohort defines a real-world genetic profile of motor neuron disease beyond ALS8, with diagnostic yield comparable to the literature and a Byrne gradient supporting universal testing. Beyond family history, socioeconomic factors appeared to shape access to testing, reinforcing the importance of equitable genetic testing for diagnostic precision, family counseling, and access to gene-targeted therapy.}, }
@article {pmid42621238, year = {2026}, author = {Palakkot, S and Banik, A}, title = {Auditory Biomarkers in Neurodegenerative Disorders: A Literature Review.}, journal = {Journal of otology}, volume = {21}, number = {3}, pages = {160-166}, pmid = {42621238}, issn = {2524-1753}, abstract = {The prevalence of neurodegenerative diseases is escalating globally. However, the conventional diagnostic framework fails to identify the pathology until substantial neuronal damage occurs. The evidence from the recent literature indicates that auditory dysfunction commonly precedes motor and cognitive symptoms across multiple neurodegenerative diseases. The pathophysiology involves both the peripheral and cortical auditory structures, which produce distinctive patterns reflects systemic neurodegeneration. Hence, this suggests auditory assessment as a valuable tool for early identification of neural degeneration. This review synthesises the contemporary literature on auditory dysfunctions and underlying pathophysiology in Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, Amyotrophic lateral sclerosis, etc. The analysis included the temporal trajectories of auditory impairment, subjective-objective measurements, and evaluated the importance of early identification and longitudinal tracking. Objective measures of central auditory processing, including Auditory Brainstem Responses, P300, Mismatch Negativity, and speech-in-noise testing, provide objective, non-invasive diagnostic tools and its sensitivity comparable to established biomarkers. Integration of standardised auditory assessment batteries into clinical protocols could enable the early identification of pathology, differential diagnosis and the development of novel therapeutic strategies for both auditory and cognitive deficits. Current review suggests that future longitudinal studies with neurodegenerative conditions should focus on the clinical utility of auditory, cognitive, and neuroimaging biomarkers and facilitate clinical translation of these findings.}, }
@article {pmid42615765, year = {2026}, author = {Khazaal, M and Stretavská, P and Kuźma-Kozakiewicz, M and Nieporęcki, K and Betík, A and Vlčková, E and Koprušáková, MT and Petrovic, R and Cetin, H and Keritam, O and Löscher, W and Eggers, C and Iglseder, S and Orenčák, R and Molnár, MJ and Grosz, Z and Szlepák, T and Koritnik, B and Koszewicz, MA and Baumgartner, D and Slachtova, L}, title = {SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70717}, pmid = {42615765}, issn = {1468-1331}, support = {PRIMUS UK 21/MED/012//Univerzita Karlova v Praze/ ; OP JAK MSCA GOALS//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; 65269705//Fakultni nemocnice Brno/ ; MUNI/A/1728/2025//Masarykova Univerzita/ ; TKP2021 NVA-15//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; OTKA139010//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/therapy/drug therapy ; *Superoxide Dismutase-1/genetics ; Female ; Middle Aged ; Male ; Genetic Testing ; Adult ; Europe, Eastern/epidemiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce.<br><br>METHODS: Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region.<br><br>RESULTS: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy.<br><br>CONCLUSION: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.}, }
@article {pmid42615866, year = {2026}, author = {Horton, DK and Raymond, J and Larson, T and Goutman, SA and Mehta, P}, title = {Multidisciplinary clinic attendance and patterns of care in the U.S. National ALS Registry, 2013-2023.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2717968}, pmid = {42615866}, issn = {2167-9223}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) multidisciplinary clinics (MDCs) are the standard model of care, but national-level data on utilization and outcomes in the United States are lacking.<br><br>OBJECTIVE: To compare baseline characteristics and symptoms, clinical interventions and specialized care processes, and healthcare utilization among U.S. National ALS Registry (Registry) participants by MDC attendance.<br><br>METHODS: Registry data from 2013 to 2023 were analyzed for participants completing demographic and clinical surveys, stratified by MDC attendance (attendance vs. no attendance by survey completion).<br><br>RESULTS: Among 4764 participants, 77.0% reported attending an MDC. Baseline characteristics were similar between groups, including sex, age at diagnosis, and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. MDC attendees reported lower prevalence of dysphagia (23.6% vs. 27.5%, p&#xa0;=&#xa0;0.007) and bowel/bladder issues (10.7% vs. 14.3%, p&#xa0;=&#xa0;0.001). Attendees were more likely to use evidence-based interventions, including wheelchairs/scooters, noninvasive ventilation, percutaneous endoscopic gastrostomy (PEG), communication devices, and ALS disease-modifying therapies, specifically riluzole (72.7% vs. 48.1%) and edaravone (10.5% vs. 2.6%) (all p&#xa0;<&#xa0;0.001). MDC attendees also demonstrated higher rates of specialized care processes, including advance directive completion, genetic testing, and prior research participation (all p&#xa0;<&#xa0;0.001). For healthcare utilization, MDC attendance was associated with fewer emergency department visits among those with any use (RR 0.90, 95% confidence interval (CI) 0.82-0.99) and shorter hospital stays (&#x3b2;&#xa0;=&#xa0;-2.67&#xa0;days, 95% CI -4.56 to -0.78).<br><br>CONCLUSION: MDC attendance was associated with greater uptake of evidence-based interventions, higher rates of specialized care processes, and reduced healthcare utilization intensity, consistent with previously reported multidisciplinary ALS care outcomes.}, }
@article {pmid42616178, year = {2026}, author = {Nolen, A and Zweig, N and Selby, D and Bonares, MJ}, title = {Factors associated with requests for Medical Assistance in Dying (MAiD) referral among patients with amyotrophic lateral sclerosis receiving specialist palliative care.}, journal = {Journal of neurology}, volume = {273}, number = {9}, pages = {}, pmid = {42616178}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; *Palliative Care/statistics &amp; numerical data ; *Referral and Consultation/statistics &amp; numerical data ; Retrospective Studies ; Aged ; Middle Aged ; *Suicide, Assisted/statistics &amp; numerical data ; Noninvasive Ventilation/statistics &amp; numerical data ; Cohort Studies ; Canada ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) have among the highest rates of medical assistance in dying (MAiD), yet factors associated with requesting MAiD remain poorly understood. We examined sociodemographic and clinical characteristics associated with MAiD referral and receipt among patients with ALS receiving specialist palliative care.<br><br>METHODS: We conducted a retrospective sequentially matched cohort study of patients attending a multidisciplinary ALS clinic at a Canadian tertiary care center. Patients who requested a MAiD referral were matched with the next consecutive patient without a MAiD request. Multivariable logistic regression identified factors associated with MAiD referral and, among referred patients, receipt of MAiD.<br><br>RESULTS: The cohort included 272 patients (130 MAiD referrals; 142 no referral). Rural residence was independently associated with higher odds of requesting a MAiD referral (adjusted odds ratio [aOR] 2.38, 95% confidence interval [CI] 1.02-5.58), whereas non-invasive ventilation (NIV) was associated with lower odds (aOR 0.56, 95% CI 0.32-0.90). Gastrostomy tube use demonstrated a non-significant trend toward lower odds of MAiD referral (aOR 0.59, 95%CI 0.33-1.07). Age, sex, and limb and bulbar symptom severity were not associated with MAiD referral. Among patients referred for MAiD, no factors were independently associated with receipt of MAiD.<br><br>CONCLUSION: In patients with ALS receiving specialist palliative care, use of NIV was associated with a lower likelihood of requesting a MAiD referral, while rural residence was associated with higher odds of referral. These findings suggest that decisions regarding MAiD may be influenced less by disease severity than by preferences regarding life-prolonging interventions and warrant further investigation.}, }
@article {pmid42617572, year = {2026}, author = {Tang, WX and Yang, C and Zhang, M and Kushida, CA and de Lecea, L and Li, SB}, title = {Sleep-wake control with age and neurodegenerative diseases.}, journal = {Sleep medicine reviews}, volume = {90}, number = {}, pages = {102352}, doi = {10.1016/j.smrv.2026.102352}, pmid = {42617572}, issn = {1532-2955}, abstract = {Aging causes dramatic alterations in bodily functions. Among them, sleep quality declines with age, particularly in individuals with neurodegenerative diseases. In this review, we first describe alterations in sleep-wake architecture and discuss potential mechanisms underlying sleep disorders that arise with age. We discuss evidence linking sleep disorders with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) syndrome. Even though the causes of AD, PD, PSP, and HD are diverse, several shared symptoms including difficulty falling asleep, fragmented sleep, and disrupted circadian rhythm collectively suggest their pathologies disrupt sleep-wake control. Hyperexcitability of implicated neurons is commonly observed prior to neurodegeneration. Upregulated neuronal excitability in the early phase of these diseases appears as a potential shared mechanism among neurodegenerative diseases. Abnormal protein accumulation and aggregation in these diseases exacerbate neuronal circuit hyperactivity by increasing neurons' intrinsic excitability or dampening inhibitory inputs to neurons controlling sleep-wake cycles. A better understanding of the mechanisms underlying sleep disorders that emerge with age may greatly benefit the development of novel preventative and therapeutic strategies for neurodegenerative diseases, and therefore improve the life quality of older adults.}, }
@article {pmid42618027, year = {2026}, author = {Wolter, A and Ritz, L and Wolter, JS and Kurkevych, A and Thul, J and Bedei, I and Schenk, J and Königbauer, JT and Weichert, A and Axt-Fliedner, R}, title = {Prenatally diagnosed Ebstein's anomaly and tricuspid valve dysplasia: associated anomalies and predictors of outcome in a multicenter cohort study.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2932-8445}, pmid = {42618027}, issn = {1438-8782}, abstract = {PURPOSE: To describe associated anomalies and outcomes of prenatally diagnosed Ebstein's anomaly (EA)/tricuspid valve dysplasia (TVD) in a multicenter cohort and to identify predictors of adverse outcome (intrauterine or postnatal death).<br><br>MATERIALS AND METHODS: In this retrospective study, cardiothoracic ratio, aortic valve diameter (AVD), pulmonary and atrioventricular valve measurements, ventricular dimensions, vena contracta, chamber areas, Celemajer index, peak tricuspid regurgitation velocity (TR_max), and pulmonary flow direction between survivors and non-survivors were compared across three gestational intervals.<br><br>RESULTS: Among 87 fetuses, 7 (8.0%) intrauterine deaths and 7 (8.0%) terminations occurred; 14 (16.1%) were lost to follow-up. Fifty-nine (67.8%) live births with follow-up were documented; 52 (88.1%) underwent active postnatal management, with a survival rate of 69.2% (36/52). Non-survivors more frequently had hydrops, earlier delivery, and lower birth weight. z-score AVD (zAVD) was lower and pulmonary flow more often retrograde in non-survivors before 32 weeks. TR_max was lower in interval 1 (<24 weeks), and right atrial area and vena contracta were larger in interval 2 (24-32 weeks). No significant differences were observed after 32 weeks.<br><br>CONCLUSION: This is one of the largest prenatal multicenter cohorts employing a longitudinal design, with echocardiographic data evaluation across three gestational intervals. Established predictors (pulmonary flow, TR_max) were confirmed and zAVD was identified as a simple, clinically applicable parameter, highlighting the relevance of left ventricular involvement in EA/TVD. Zusammenfassung: Ziel: Ziel dieser retrospektiven, multizentrischen Studie war es, assoziierte Anomalien und das Outcome bei pr&#xe4;natal diagnostizierter Ebstein-Anomalie /Trikuspidalklappendysplasie (EA/TVD) zu analysieren sowie Pr&#xe4;diktoren f&#xfc;r ein ung&#xfc;nstiges Outcome (intrauteriner Fruchttod (IUFT), postnataler Tod) zu identifizieren.<br><br>MATERIAL UND METHODEN: Retrospektiv wurden kardiothorakale Ratio, Aortenklappendurchmesser (AVD), pulmonale und atrioventrikul&#xe4;re Klappen, Ventrikeldimensionen, Vena contracta, Vorhof-/Ventrikelfl&#xe4;chen, Celemajer-Index, maximale Trikuspidalinsuffizienzgeschwindigkeit (TR_max) und Pulmonalflussrichtung zwischen &#xdc;berlebenden und Nicht-&#xdc;berlebenden in drei3 Gestationsintervallen verglichen. Ergebnisse: Von 87 Feten traten 7 (8,0%) IUFT auf, 7 (8,0%) Schwangerschaftsabbr&#xfc;che erfolgten, 14 (16,1%) waren lost to follow-up. Insgesamt wurden 59/87 (67,8%) Lebendgeburten dokumentiert; 52 (88,1%) erhielten ein aktives postnatales Management mit einer &#xdc;berlebensrate von 69,2% (36/52). Nicht-&#xdc;berlebende zeigten h&#xe4;ufiger Hydrops, fr&#xfc;here Entbindung und geringeres Geburtsgewicht. Der Z-Score des AVD (zAVD) war <32 Wochen niedriger, der Pulmonalfluss h&#xe4;ufiger retrograd. TR_max war <24 Wochen niedriger, rechte Vorhoffl&#xe4;che und Vena contracta zwischen 24-32 Wochen gr&#xf6;&#xdf;er. Nach 32 Wochen bestanden keine signifikanten Unterschiede. Schlussfolgerung: : Dies ist eine der gr&#xf6;&#xdf;ten pr&#xe4;natalen, multizentrischen Kohorten mit longitudinaler Auswertung &#xfc;ber drei3 Gestationsintervalle. Etablierte Pr&#xe4;diktoren (Pulmonalfluss, TR_max) wurden best&#xe4;tigt, und zAVD als einfacher, klinisch anwendbarer Parameter identifiziert, der die Relevanz der linksventrikul&#xe4;ren Beteiligung bei EA/TVD unterstreicht.}, }
@article {pmid42618698, year = {2026}, author = {Shrestha, N and Munn, Z and Calma, A and Pavey, N and Tsuji, Y and Menon, P and Padovani, A and Risi, B and Ferullo, L and Filosto, M and Jewett, G and Shibuya, K and Otani, R and Shimizu, T and Kuwabara, S and Noto, YI and Kitaoji, T and Johnsen, B and Shen, D and Cui, L and van den Berg, LH and van Eijk, RPA and van Damme, P and Kiernan, MC and Giles, L and Vucic, S}, title = {Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.}, journal = {Journal of neurology}, volume = {273}, number = {9}, pages = {}, pmid = {42618698}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: To evaluate the diagnostic accuracy of the Gold Coast criteria (GCC) and compare their performance with the revised El Escorial (rEEC) and Awaji criteria in patients with suspected amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Embase, MEDLINE, and Scopus were searched for English-language studies published between January 1, 2020, and August 11, 2025. Eligible studies assessed the diagnostic accuracy of GCC compared with rEEC and Awaji criteria in suspected ALS. Authors were invited to contribute individual participant data. Data were checked, harmonised, and recoded. A one-stage individual-participant data meta-analysis, adjusted for age and sex, was performed. Diagnostic performance was assessed using pooled sensitivity, specificity, and area under the receiver operating characteristic curve. Risk of bias was assessed using QUADAS-2 and QUADAS-C, and certainty of evidence using GRADE for diagnostic test accuracy. The study was registered with PROSPERO, CRD420251123597.<br><br>RESULTS: Individual participant data were available for 3007 participants from five international studies. GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95% confidence interval [CI] 0.93-0.98) versus 0.87 (95% CI 0.78-0.92) and 0.87 (95% CI 0.78-0.93), respectively. Certainty of evidence for sensitivity was moderate at pre-test probabilities of 50% and 75%, and low at 25%. Specificity was numerically lower for GCC at 0.68 (95% CI 0.53-0.81) compared with rEEC at 0.73 (95% CI 0.59-0.83) and the Awaji criteria at 0.72 (95% CI 0.57-0.83). The certainty of evidence for specificity was rated as very low across all assessed pre-test probabilities (25%, 50%, and 75%).<br><br>CONCLUSIONS: GCC provide a sensitive framework for suspected ALS and may support earlier diagnosis in specialist settings. Specificity was imprecise and heterogeneous, supporting use with mimic exclusion and longitudinal reassessment.}, }
@article {pmid42618940, year = {2026}, author = {Saka, AK and Godhwani, K and Ramasamy, V and Soh, BL and Lingam, M and Lofters, A and Gerstle, D and Selby, P and LeBlanc, A and Pritlove, C and Sayani, A}, title = {The use of deliberative dialogue in health services research: a scoping review.}, journal = {Research involvement and engagement}, volume = {12}, number = {1}, pages = {}, pmid = {42618940}, issn = {2056-7529}, support = {TLP - 185094/CAPMC/CIHR/Canada ; }, abstract = {INTRODUCTION: Deliberative Dialogue (DD) is a structured participatory approach that brings together research evidence, professional expertise, and lived/living experience to support informed discussion and decision-making in health research. DD is increasingly used in the co-design, co-implementation, and co-evaluation of health-promoting interventions, where decisions must be both evidence-informed and responsive to local contexts, priorities, and needs. However, published studies vary considerably in how DD is described and reported, particularly in relation to facilitation, evidence use, participant preparation, power dynamics, and follow-up. This scoping review examined the application of DD in health services research, focusing on its methodological processes, reported outcomes and challenges, engagement of different interest-holders, and the rationales underlying its use.<br><br>METHODS: A scoping review was conducted following Arksey and O'Malley's framework and reported in accordance with PRISMA-ScR guidelines. Searches of OVID Medline, PsycINFO, PubMed, CINAHL, and Scopus identified 1,793 records. After screening and consolidating duplicate reports, 15 unique studies met the inclusion criteria. Data were extracted using a template informed by the Guidance for Reporting Involvement of Patients and the Public (GRIPP2), the Consolidated Standards of Reporting Trials (CONSORT), and Boyko et al.'s model of DD. The review was conducted using a critical Patient-Oriented Research (cPOR) approach, which centres lived/living experience, promotes shared decision-making between patient partners and researchers, and attends to the influence of power and structural contexts on knowledge production. The interdisciplinary team, including patient partners, researchers, clinicians, policymakers, and decision-makers, co-developed the study, contributed to data interpretation, and collaboratively refined the findings through iterative and reflexive discussion.<br><br>FINDINGS: The 15 included studies were published between 2012 and 2024 and represented diverse geographic and health-system contexts. DD was used to support intervention co-design, implementation planning, evaluation, priority-setting, guideline development, and service improvement. Studies consistently reported the involvement of multiple interest-holder groups and the development of practical outputs, including curricula, decision aids, care models, action plans, guidelines, and priority-setting frameworks. However, reporting of methodological processes was inconsistent. Only a minority of studies described facilitation protocols, participant preparation, strategies to address power dynamics, accessibility supports, or follow-up activities. While DD was associated with enhanced trust, mutual understanding, contextual relevance, and collaborative decision-making, evidence of longer-term impacts was limited. The synthesis also revealed substantial variation in how studies reported participant engagement, evidence use, consensus-building processes, and the translation of deliberative outputs into intervention-related decisions.<br><br>This review highlights DD as a valuable approach for collaborative, evidence-informed, and context-sensitive health services research. Across the included studies, DD was used to bring together diverse forms of knowledge and generate practical outputs to support intervention development and improvement. However, methodological details related to facilitation, accessibility, participant support, management of power dynamics, decision-making processes, and longer-term impacts were often underreported. These gaps point to the need for more transparent and equity-oriented reporting of DD, particularly in relation to how people with lived/living experience are engaged and how their contributions influence intervention-related decisions. Strengthening reporting in these areas may improve the transparency, reproducibility, and accountability of DD in the co-design, co-implementation, and co-evaluation of health interventions.}, }
@article {pmid42619018, year = {2026}, author = {Davias, A and Knekt, P and Rantakokko, P and Hansen, J and Weisskopf, MG}, title = {Associations between Pre-Disease Biomarkers of Persistent Organic Pollutants and Amyotrophic Lateral Sclerosis Survival in the Danish Diet, Cancer and Health Study Cohort.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78334}, pmid = {42619018}, issn = {1531-8249}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord. Most patients survive 3 to 5 years after diagnosis, although some live 10 years or more. Prognostic factors are incompletely understood, but previous case-control studies suggest that exposure to persistent organic pollutants (POPs) may be associated with ALS survival, but this has not been explored within prospective analysis of POP biomarkers. In this study, we aimed to prospectively investigate the relationship between exposure to POPs-assessed in pre-disease plasma samples-and survival with ALS in the Danish Diet, Cancer, and Health study cohort.<br><br>METHODS: We identified 166 incident ALS cases using the Danish National Patient Register via International Classification of Diseases (ICD) codes. We measured concentrations of 13 polychlorinated biphenyls (PCBs), 9 organochlorine pesticides, and 3 polybrominated diphenyl ethers in plasma samples collected at inclusion in the study (baseline). To assess the relationship between POP exposures and ALS survival, we used separate Cox models for each POP group adjusting for diagnosis age, sex, smoking status, body mass index, and marital status. We selected the most relevant POP groups for ALS survival using an elastic net penalized Cox proportional hazards regression model and then ran a model using a summary environmental risk score (ERS).<br><br>RESULTS: Single-pollutant Cox models showed that exposure to non-dioxin like PCBs, hexachlorobenzene (HCB), &#x3b2;-hexachlorocyclohexane (&#x3b2;-HCH), and chlordane compounds were associated with shorter survival. Elastic net penalized Cox proportional hazards regression selected HCB and chlordane compounds as the most relevant POPs for survival. The ERS Cox model showed a significant association with shorter survival (hazard ratio [HR]: 1.4, 95% confidence interval [CI]: 1.1-1.7). A 1 standard deviation (SD) higher ERS score was associated with an HR for death of 1.4 (95% CI: 1.1-1.7). Predicted median survival for those with an ERS score 1 SD higher than the mean was 12&#x2009;months shorter (26 vs 38&#x2009;months).<br><br>INTERPRETATION: Our study suggests that pre-disease exposure to some POPs such as HCB and chlordane compounds could negatively influence ALS survival. ANN NEUROL 2026.}, }
@article {pmid42619255, year = {2026}, author = {Gadhave, DG and Jadhav, AB and Waghamode, NB and Khot, S and Khan, R and Hole, R and Dhobale, SM and Aswar, M and Paudel, KR}, title = {Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.}, journal = {Advanced healthcare materials}, volume = {}, number = {}, pages = {e71594}, doi = {10.1002/adhm.71594}, pmid = {42619255}, issn = {2192-2659}, abstract = {Aging is a significant risk factor of neurodegenerative disorders (NDs) such as Huntington's, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Although several clinical, neuroimaging, and biomarker-based diagnostic approaches are available for NDs, their limited sensitivity for early-stage detection, disease specificity, and prediction of disease progression continue to present significant clinical challenges, often resulting in delayed diagnosis and therapeutic intervention. According to previously published works, the preliminary pathological feature of such disorders is mitochondrial dysfunction. This may lead to elevated oxidative stress, impaired mitophagy, unbalanced mitochondrial function, and bioenergetic failure. This review examines how mitochondria-targeted nanotherapeutic approaches can overcome these pathological barriers and improve therapeutic outcomes in aging-associated neurodegeneration. Targeted delivery of drug-loaded nanocarriers, such as gene-delivery, lipid-based, metallic, and polymeric nanoparticles, has emerged as a potential platform to deliver medication directly to defective mitochondria. It may increase mitochondrial biogenesis, maintain redox balance, and protect against neuronal degeneration. This work incorporates disease-specific mitochondrial pathology with current progress in targeted nanotherapeutics, age-associated delivery barriers, clinical revolution, and emerging artificial intelligence (AI)-enabled precision therapeutic approaches. Mitochondria-targeted nanotherapeutics depict a potential disease-modifying strategy for aging-related NDs. However, further advancements in targeting efficacy, scalable production, long-term safety, and clinical validation can facilitate a successful clinical revolution.}, }
@article {pmid42619804, year = {2026}, author = {Spillman, AM and Alsop, EB and Gittings, LM and Garcia-Mansfield, K and Piras, I and Bonfitto, A and Martinez, MN and Sharma, R and Preller, KR and Huentelman, M and Pirrotte, P and Van Keuren-Jensen, K and Sattler, R}, title = {Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.26.740405}, pmid = {42619804}, issn = {2692-8205}, abstract = {Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.}, }
@article {pmid42619860, year = {2026}, author = {Barretto, N and Fullerton, BT and Daly, AC and Casel, O and Kuksenko, O and Kang, K and Petrescu, J and Xia, M and Eschbach, J and Leung, M and Khiste, S and Gebremedhin, B and Smith, C and Jackson, CA and Phatnani, H}, title = {A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.24.740361}, pmid = {42619860}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper motor neurons in the motor cortex (MTC) and lower motor neurons in the spinal cord, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the site of ALS symptom onset influences the molecular alterations underlying MN and glial dysfunction and whether these alterations are shared between the MTC and lumbar spinal cord (LSC). To address these questions, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS donors clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS donors. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In contrast to the LSC, we observe layer-specific increases in synaptic signaling in the MTC of ALS donors. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.}, }
@article {pmid42611011, year = {2026}, author = {Zdrowak, KE and Mefferd, AS and Stipancic, KL}, title = {Dissociable Effects of Dysarthria Etiology and Severity on the Minimally Detectable Change of Speech Intelligibility.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-13}, doi = {10.1044/2026_JSLHR-25-00740}, pmid = {42611011}, issn = {1558-9102}, abstract = {PURPOSE: The minimally detectable change (MDC) provides a threshold for interpreting changes in outcome measures that are outside of measurement error. There is emerging evidence that dysarthria etiology and speech severity impact the MDC of speech intelligibility; however, an investigation of these factors is needed to determine the unique effects of dysarthria etiology and speech severity. The purpose of the current study was to calculate and compare MDCs of speech intelligibility across five dysarthria etiology groups and four severity levels.<br><br>METHOD: Speech Intelligibility Test recordings from 200 speakers were used as stimuli, including recordings from healthy controls (n = 40) and individuals with neurodegenerative diseases such as amyotrophic lateral sclerosis (n = 16), Huntington's disease (n = 44), multiple sclerosis (n = 60), and Parkinson's disease (n = 40). Thirty inexperienced listeners provided orthographic transcriptions of 20 speakers each. MDCs were calculated, and speech severity levels were categorized based on empirically defined speech severity levels reported in Stipancic et al. (2021). Statistical analyses, including multiple linear regression, assessed the effects of etiology and severity on MDCs.<br><br>RESULTS: Speech severity was a significant predictor of MDCs, with greater impairments to speech intelligibility resulting in higher MDCs. Dysarthria etiology was not a significant predictor of MDCs.<br><br>CONCLUSION: The impact of speech severity on MDCs of intelligibility in dysarthria underscores the need to calculate and provide MDCs across severity ranges to enhance the interpretation of patient outcomes.}, }
@article {pmid42612409, year = {2026}, author = {Iacobelli, V and Vizziello, M and Clementi, L and Anversa, P and Cazzato, D and De Grado, A and Gallone, A and Izzo, MGA and Lanteri, P and Usai, S and Lauria, G and Rossi Sebastiano, D and Dalla Bella, E}, title = {Revisiting somatosensory evoked potentials in motor neuron diseases: neurophysiological insights from a large cohort.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {191}, number = {}, pages = {2112372}, doi = {10.1016/j.clinph.2026.2112372}, pmid = {42612409}, issn = {1872-8952}, abstract = {OBJECTIVE: To systematically investigate Somatosensory Evoked Potential (SEP) abnormalities in a large cohort of patients with Motor Neuron Disease (MND), and to explore their relationship with Motor Evoked Potentials (MEPs) and clinical phenotypes.<br><br>METHODS: We retrospectively analyzed 267 patients with confirmed MND who underwent standardized SEPs and transcranial magnetic stimulation. Patients were divided into pure/predominant Upper Motor Neuron (UMN) and pure/predominant Lower Motor Neuron/Amyotrophic Lateral Sclerosis (LMN/ALS) groups. SEP abnormalities were assessed using internal normative data, including prolonged latencies, reduced amplitudes, and increased N20-P25 amplitudes. MEPs were classified semi-quantitatively as normal or abnormal by independent raters.<br><br>RESULTS: At least one SEP abnormality was detected in 75&#xa0;% of patients, with no significant differences between the UMN and LMN/ALS groups. Increased N20-P25 amplitudes were observed in both phenotypes, suggesting widespread sensory cortical hyperexcitability across the MND spectrum. In contrast, abnormal MEPs were significantly more frequent in UMN patients (p&#xa0;<&#xa0;0.001). No significant association was found between SEP abnormalities and MEP findings. Upper- and lower-limb SEP latencies were strongly correlated (all p&#xa0;<&#xa0;0.001), whereas increased SEP amplitudes did not correlate with latency abnormalities.<br><br>CONCLUSIONS: SEP abnormalities are highly prevalent in MND and appear largely independent from corticospinal dysfunction. Increased SEP amplitudes likely reflect primary cortical sensory hyperexcitability rather than impaired sensory conduction.<br><br>SIGNIFICANCE: These findings support the concept of MND as a multisystem network disorder that involves sensory cortical circuits and highlight the role of SEPs in the diagnostic workup.}, }
@article {pmid42612795, year = {2026}, author = {Li, J and Duan, H and Hao, P and Zhao, W and Gao, Y and Yang, Z and Li, X}, title = {Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.trsl.2026.08.005}, pmid = {42612795}, issn = {1878-1810}, abstract = {In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.}, }
@article {pmid42612865, year = {2026}, author = {Gerrit Noordergraaf, GJ and Przemek Jakubowski, P}, title = {SpO2 during CPR: from distraction towards a physiological goal.}, journal = {Resuscitation}, volume = {}, number = {}, pages = {111260}, doi = {10.1016/j.resuscitation.2026.111260}, pmid = {42612865}, issn = {1873-1570}, }
@article {pmid42613144, year = {2026}, author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J}, title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.}, journal = {International review of neurobiology}, volume = {189}, number = {}, pages = {205-236}, doi = {10.1016/bs.irn.2026.01.013}, pmid = {42613144}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; }, abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.}, }
@article {pmid42613225, year = {2026}, author = {Light, A and Peters, M and Ahmed, HU and Shah, TT}, title = {Reply to Marcio C. Moschovas, Ugo Falagario, Francesco Pellegrino, et al's Letter to the Editor re: Alexander Light, Max Peters, Manit Arya, et al's Salvage Focal Therapy vs Radical Prostatectomy for Localized Radiorecurrent Prostate Cancer. JAMA Oncol 2026;12:364-73.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.07.033}, pmid = {42613225}, issn = {1873-7560}, }
@article {pmid42613627, year = {2026}, author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA}, title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.}, journal = {Stem cell research &amp; therapy}, volume = {17}, number = {1}, pages = {}, pmid = {42613627}, issn = {1757-6512}, mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; }, abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.}, }
@article {pmid42613642, year = {2026}, author = {Wang, JDJ and Teo, AYT and Xiao, B and Chao, Y and Zhou, ZD and Tan, BJ and Chan, LL and Rosalie, E and Tan, EK}, title = {PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42613642}, issn = {2047-9158}, support = {LCG//National Medical Research Council/ ; STaR//National Medical Research Council/ ; }, mesh = {Humans ; *PCSK9 Inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Proprotein Convertase 9/metabolism/genetics ; Animals ; }, abstract = {Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.}, }
@article {pmid42613694, year = {2026}, author = {Shukla, S and Srivastava, V and Gaur, H and Rai, A}, title = {Myelin and Oligodendrocyte Dysfunction in Demyelinating and Neurodegenerative Disorders: Signaling Pathways and Therapeutic Targets.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273437393260729093129}, pmid = {42613694}, issn = {1996-3181}, abstract = {INTRODUCTION: Oligodendrocytes (OLs) synthesize myelin, a substance that plays a significant role in ensuring proper functioning of the Central Nervous System (CNS). Myelin abnormalities are involved in disease pathogenesis in AD, MS, and ALS. In contrast, MS involves autoimmune reactions directed against myelin. On the other hand, AD and ALS are characterized by neurodegeneration. This article seeks to give a critical discussion on myelin and OL dysfunction in these diseases, among others.<br><br>METHODS: A narrative literature search was carried out in various databases including Scopus, Google Scholar, Web of Science, and PubMed, focusing on papers relating to myelination, remyelination, and OLs, particularly those addressing signaling pathways and treatment strategies.<br><br>RESULTS: MS is an autoimmune disease characterized by inflammation that causes demyelination and OL dysfunction. Oxidative stress and mitochondrial dysfunction play roles in the pathogenesis of ALS, whereas AD is a result of disrupted neuronal supportive functions and myelin damage. Important signaling pathways involved in OL formation and myelin repair include the Wnt/&#x3b2;-catenin, AKT/mTOR, and ERK/MAPK pathways. Drugs like edaravone, ocrelizumab, and siponimod have been identified for promoting myelin repair.<br><br>DISCUSSION: The relationship between abnormal oligodendrocyte function, demyelination, and specific disease-related pathological processes demonstrates that although there is a similarity among MS, AD, and ALS, each condition possesses its own unique molecular foundation. One potential treatment approach would be targeting shared signaling pathways relevant to myelination and remyelination. Nonetheless, disease variability and specific pathogenic characteristics demand a targeted therapy approach.<br><br>CONCLUSION: Myelin integrity and oligodendrocyte function are central to the progression of demyelinating and neurodegenerative diseases. Targeting molecular pathways involved in myelination offers significant potential for improving disease outcomes and developing advanced therapeutic strategies.}, }
@article {pmid42613775, year = {2026}, author = {Nalicho, JC and Mabeyo, PE and Paluch, AS and Paul, L}, title = {Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1-Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy.}, journal = {ChemistryOpen}, volume = {15}, number = {9}, pages = {e70286}, doi = {10.1002/open.70286}, pmid = {42613775}, issn = {2191-1363}, mesh = {*NF-E2-Related Factor 2/metabolism/antagonists &amp; inhibitors/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Benzoquinones/chemistry/pharmacology/metabolism/therapeutic use ; *Kelch-Like ECH-Associated Protein 1/metabolism/antagonists &amp; inhibitors/chemistry ; Humans ; Quantitative Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Signal Transduction/drug effects ; Drug Discovery ; Oxidative Stress/drug effects ; }, abstract = {Oxidative stress drives neuronal vulnerability in amyotrophic lateral sclerosis (ALS), making the Keap1-Nrf2 pathway a vital therapeutic target. While thymoquinone (TQ) modulates this axis, its efficacy is limited by low potency and poor drug-likeness. We utilized an integrated in silico workflow-including validated QSAR modeling (R[2] = 0.68, Q[2] ext = 0.66), ADMET profiling, docking, 200 ns molecular dynamics, and MM-PBSA analysis-to identify improved TQ-derived Keap1 inhibitors. Screening 64 analogs prioritized three leads (CHEMBL3416163, CHEMBL4636830, and CHEMBL221598) with favorable safety and blood-brain barrier permeability. Docking and dynamics confirmed these analogs form stable interactions with Kelch domain hotspots. MM-PBSA calculations revealed significantly enhanced binding free energies (-75.10 to -93.79 kJ mol[-1]) compared to parent TQ (-21.05 kJ mol[-1]), driven primarily by van der Waals and hydrophobic forces. This study identifies structurally tractable TQ analogs with improved predicted potency and establishes a robust computational framework for neuroprotective discovery. The prioritized leads are compelling candidates for in vitro and in vivo validation as redox-modulating agents in ALS.}, }
@article {pmid42614000, year = {2026}, author = {Wei, LC and Lee, CH}, title = {Healthcare Resilience Should Include the Worker-Patient Safety Loop: A Taiwan Psychiatric Hospital Perspective.}, journal = {The International journal of health planning and management}, volume = {}, number = {}, pages = {}, doi = {10.1002/hpm.70130}, pmid = {42614000}, issn = {1099-1751}, abstract = {Research before and during COVID-19 has framed health-system resilience as the capacity to absorb shocks, adapt, transform and learn while sustaining essential functions. Building on this broader literature, including Meredith et al.'s account of local public-health adaptation under political and resource constraints, we propose a worker-patient safety loop from a Taiwan psychiatric hospital perspective: workforce strain can weaken safety-critical care; near misses, adverse events and continuity failures should trigger reporting, organisational learning and corrective action; and the resulting changes should protect workers, patients and care continuity. The loop can be monitored through indicators of workforce wellbeing and safety, safety-event learning, and continuity across settings, supported by digital incident, staffing and handoff systems with safeguards for privacy and data quality. Informed by professional experience and published evidence, this conceptual framework applies to acute shocks and continuing operational pressures. Its proposed domains require prospective empirical validation before they can be treated as established measures of hospital resilience.}, }
@article {pmid42614182, year = {2026}, author = {Shevchuk, DV and Nuzhnyi, EP and Fedotova, EY and Ershova, MV and Minaev, IV and Anikin, GA and Protsenko, AR and Abramycheva, NY and Zakharova, MN and Illarioshkin, SN}, title = {Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1889931}, pmid = {42614182}, issn = {1664-2295}, mesh = {Humans ; *Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications/diagnostic imaging ; *Cerebellar Ataxia/genetics/physiopathology/diagnostic imaging ; Phenotype ; Male ; Middle Aged ; Female ; Adult ; Mutation/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) associated with mutations in the superoxide dismutase 1 (SOD1) gene is recognized for phenotypic variability, yet cerebellar ataxia as a presenting feature has been reported only in isolated cases.<br><br>METHODS: We describe four unrelated patients: three men and one woman, aged 35 to 49 years at symptom onset, who carried the SOD1 D91A (p.Asp91Ala) mutation. Two patients were heterozygous and two homozygous for the D91A variant. Clinical, neuroimaging, electrophysiological and genetic data were reviewed.<br><br>RESULTS: All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS. Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years. Cerebellar signs included gait and limb ataxia, dysmetria, intention tremor, and oculomotor abnormalities; neuroimaging revealed mild cerebellar atrophy only in one case, and electrophysiological evidence of lower motor neuron involvement was often limited at initial assessment. To our knowledge, this is the largest reported case series of patients homogeneous for a single SOD1 mutation and a shared cerebellar ataxia-onset ALS phenotype.<br><br>CONCLUSION: The findings expand the clinical spectrum of SOD1-associated ALS and underscore the importance of SOD1 genetic testing in patients with progressive adult-onset ataxia of undetermined origin, particularly given the emerging availability of SOD1-targeted therapies.}, }
@article {pmid42614249, year = {2026}, author = {Sheppard, B and Durnell, L and Haufler, AJ}, title = {From emergence to amplification: an analysis of lifecycle models to address health mis-disinformation in the digital environment.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1814102}, pmid = {42614249}, issn = {2296-858X}, abstract = {Health misinformation and disinformation (mis-disinformation) on social media presents a growing threat to individual and population health, societal resilience, and national security. While social media enables the rapid dissemination of health information, it also facilitates the spread of health mis-disinformation, a challenge further compounded by foreign influence campaigns, AI-generated content, and divergent regulatory environments. Effective interventions require tailoring to local socio-cultural and geo-political contexts. This article proposes a lifecycle model for health professionals that conceptualizes how content creation, dissemination, exposure, belief formation, and behavioral outcomes interact and can be targeted through strategic interventions to improve health outcomes and mitigate adverse behavioral effects. To achieve this, the article characterizes the challenges posed by the current and emerging health information environment; identifies and evaluates mis-disinformation lifecycle models in order to strengthen the existing knowledge base; and assesses the current state of knowledge and gaps on comparing intervention strategies to elicit desired behavioral responses, with an emphasis on individual approaches (e.g., debunking, media literacy, fact checking). A review of literature (2020-2025) identified 13 cross-comparative intervention studies which focused on key findings. Four lifecycle models were identified and assessed against six criteria derived from the lifecycle literature to identify the most suitable framework for adaptation in the public health domain. Kruijver et al.'s C5 Interaction Model emerged as the framework that satisfied the greatest number of criteria and was selected for adaptation. The model was extended to account for diverse socio-political and information environments, emerging technological interventions, and the distinct challenges posed by both mis-disinformation. Adaptation involved integrating concepts from risk perception, the Social Amplification of Risk Framework, and Social Judgment Theory, alongside health-specific examples to enhance relevance and practical applicability. To help translate the insights gained to strategy, we also convey the information in an Integrated Framework for Managing Health Mis-disinformation. By linking the evolution of health mis-disinformation to targeted interventions, the model and framework provide a foundation for promoting healthier behaviors and mitigating the adverse effects of misleading health information across diverse socio-demographic and cultural settings to improve health outcomes.}, }
@article {pmid42614372, year = {2026}, author = {Watanabe, N and Kawahori, Y and Ta, V and Wang, D and Ohgi, KA and Wang, H and Kleschevnikova, N and Ishikawa, E and Head, BP}, title = {i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1[G93A] mice.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201820}, pmid = {42614372}, issn = {3117-387X}, abstract = {Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1[G93A] mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1[G93A] mice.}, }
@article {pmid42614391, year = {2026}, author = {Gomes-Duarte, A and Wong, JK and Moro, A and Pasteuning-Vuhman, S and Pos, W and Haselberg, R and Sogorb-González, M and Pascoal, S and Borst, L and Chatterjee, M and Giera, M and Tsimikas, S and Sadiq, SA and van Deventer, S}, title = {Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201822}, pmid = {42614391}, issn = {3117-387X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder defined by progressive motor neuron loss and TDP-43 proteinopathy, yet the upstream drivers of this pathology remain unclear. Oxidized phosphatidylcholines (PC-OxPL) have emerged as potent inducers of proteinopathy in the central nervous system (CNS), but their role in ALS has not been systematically explored. We identify a distinct PC-OxPL signature in the cerebrospinal fluid (CSF) of patients with sporadic ALS (sALS) and show that apolipoprotein E (apoE)-containing particles are the primary PC-OxPL carriers in this compartment. In human iPSC-derived motor neurons, PC-OxPL exposure triggered disease-relevant transcriptional alterations and TDP-43 pathology, establishing PC-OxPL as a mediator of ALS-like neurodegeneration in vitro. To counteract this toxicity, we engineered an Adeno-Associated Virus (AAV)-delivered single-chain antibody fragment (scFv), PC-OxPL-VecTab, targeting PC-OxPL neoepitopes. PC-OxPL-VecTab neutralized PC-OxPL-induced neurotoxicity, reduced TDP-43 aggregation, and prevented motor neuron death and behavioral deficits in a sALS CSF transfer mouse model. Intrathecal delivery of PC-OxPL-VecTab in minipigs achieved broad CNS biodistribution and transgene expression, supporting the feasibility of CNS delivery. These findings position PC-OxPL as a mechanistic contributor to ALS pathogenesis and establish PC-OxPL-VecTab as a therapeutic strategy for ALS with potential broader applicability to disorders associated with PC-OxPL accumulation.}, }
@article {pmid42604981, year = {2026}, author = {Falcone, C and Arckens, L and Baiula, M and Bedini, A and Bocchi, R and Broadhead, MJ and Caprini, M and Cavaliere, F and Cesca, F and Chowdhury, HH and Ciuba, K and Civiero, L and Escartin, C and Ferroni, S and Formaggio, F and Frasca, A and Gratton, R and Holt, M and Iraci, N and Kreft, M and Leggio, L and Lia, A and Malik, AR and Min, R and Müller, FE and Murat, C and Pereira, MJ and Pekowska, A and Petrelli, F and Ramos-Gonzalez, P and Sanchez-Mico, MV and Smole, Z and Sokolova, D and Solas, M and Soldano, A and Szewczyk, LM and Torazza, C and Severino, FPU and Urrestizala-Arenaza, N and Zeug, A and Zhou, J and Zonta, M and Zorec, R and Verkhratsky, A and Gunhanlar, N}, title = {Written in the Stars: Astrocyte Biology From Evolution to Disease.}, journal = {Acta physiologica (Oxford, England)}, volume = {242}, number = {9}, pages = {e70289}, pmid = {42604981}, issn = {1748-1716}, support = {CNS2025-166813//MICIU/AEI (Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/Agencia Estatal de Investigaci&#xf3;n, Spain)/ ; RYC2021-033202-I//MICIU/AEI (Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/Agencia Estatal de Investigaci&#xf3;n, Spain)/ ; PID2023-146385NA-I00//MICIU/AEI (Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/Agencia Estatal de Investigaci&#xf3;n, Spain)/ ; PID2024-160537OB-I00//MICIU/AEI (Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/Agencia Estatal de Investigaci&#xf3;n, Spain)/ ; 951923//European Commission (H2020)/ ; //European Union - NextGenerationEU/PRTR/ ; 2023.17564.ICDT//FCT (Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia, Portugal)/ ; UMO-2018/01/H/NZ4/00001//National Science Centre (NCN, Poland)/ ; UMO-2021/43/B/NZ2/02934//National Science Centre (NCN, Poland)/ ; UMO-2021/42/E/NZ2/00392//National Science Centre (NCN, Poland)/ ; UMO-2023/51/D/NZ3/02998//National Science Centre (NCN, Poland)/ ; 2024/54/E/NZ4/00134//National Science Centre (NCN, Poland)/ ; 2024/53/B/NZ4/03058//National Science Centre (NCN, Poland)/ ; A2023021F//BrightFocus Foundation/ ; 2023.00418.BD//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia (FCT) doctoral fellowship/ ; G0C9922N//KU Leuven Research Council (C14/20/071) and the Research Foundation Flanders (FWO), Belgium/ ; }, mesh = {Humans ; *Astrocytes/physiology/pathology ; Animals ; *Biological Evolution ; *Brain ; *Neurodegenerative Diseases/metabolism/pathology ; *Nervous System Diseases ; }, abstract = {In the 21st century, neuroglial research has entered a period of Renaissance, extending the views of prominent neuroanatomists and neurologists of the 19th and early 20th centuries, who assigned to glial cells numerous physiological functions and highlighted their fundamental role in the pathophysiology of nervous system diseases. Astrocytes are highly diversified in structure and function; they control brain homeostasis, support synaptic connectivity, and enable information processing in neural networks. Evolutionary diversification of astrocytes, initially emerging as supportive cells of primitive sensory organs, drove a continuous expansion of astroglial complexity and functional versatility, ultimately making them indispensable neuroprotectors and homeostatic regulators. The large, morphologically elaborate astrocytes of the human brain arguably reflect an evolutionary response to increased neuronal homeostatic demands. Astrocytes are indispensable for synaptic function, serving as the principal regulators of neurotransmitter turnover and neuronal excitability. Astrocytes also govern brain energy metabolism, mitochondrial dynamics, and calcium signaling, thereby actively shaping cortical plasticity and circuits. Astrocytes are fundamental elements of the pathophysiology of neurological, neuropsychiatric, and neurodegenerative diseases, including Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Rett syndrome, genetic astrocytopathies, and neurotrauma, where they demonstrate complex reactive changes directed at tissue preservation and regeneration, but which can also contribute to disease progression. Advances in single-cell transcriptomics, calcium imaging, chemogenetics, and iPSC-based models have transformed our understanding of astrocyte diversity and disease-specific dysfunction, opening new avenues of investigation. Given that no CNS disorder is known to occur without astrocyte involvement, multiple astrocyte-specific molecules represent compelling targets for cell-directed therapeutic strategies.}, }
@article {pmid42605296, year = {2026}, author = {Ferdoush, S and Seklani, M and Kumar, P and Abekoon Mudiyanselage, SRJ and Dsouza, A}, title = {Acute Hypercapnic Respiratory Failure as the Initial Presentation of Motor Neuron Disease: A Respiratory Diagnostic Challenge.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e112832}, pmid = {42605296}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons, with respiratory muscle involvement typically occurring in the later stages of the disease. Presentation with acute hypercapnic respiratory failure as the initial clinical manifestation is uncommon and frequently leads to diagnostic delay or misattribution to primary cardiopulmonary pathology. We present the case of a 60-year-old man with no prior respiratory history who presented with acute dyspnea and was found to have severe hypercapnic respiratory failure requiring urgent noninvasive ventilation. Clinical examination and initial investigations revealed no clear intrinsic pulmonary cause. A detailed history subsequently identified a four-month progression of neurological symptoms, including dysarthria, sialorrhea, asymmetric upper limb weakness, and significant unintentional weight loss. Neurological examination demonstrated tongue fasciculations, widespread muscle wasting, and a combination of upper and lower motor neuron signs. Following acute stabilization and discharge with domiciliary noninvasive ventilation, a specialist neurological assessment confirmed a diagnosis of ALS. This case highlights the clinical importance of considering underlying neuromuscular causes in patients presenting with unexplained hypercapnic respiratory failure, particularly when clinical findings are discordant with the severity of the gas exchange abnormalities. Early recognition of ALS in this context facilitates the timely initiation of ventilatory support and multidisciplinary care, which are essential for optimizing survival and quality of life.}, }
@article {pmid42606140, year = {2026}, author = {Flores, SV and Lillo, P and Briceño-Moya, J}, title = {Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations.}, journal = {Annals of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1111/ahg.70052}, pmid = {42606140}, issn = {1469-1809}, abstract = {BACKGROUND: The SOD1 gene encodes superoxide dismutase 1, an antioxidant enzyme in which pathogenic variants cause a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the clinical and molecular consequences of SOD1 variants are well established, its locus-wide population genetic architecture has not been systematically characterized across global populations.<br><br>OBJECTIVE: To characterize patterns of genetic diversity, population differentiation, and evolutionary constraint across the SOD1 locus in worldwide human populations.<br><br>METHODS: We analyzed genomic variation spanning the SOD1 region in the five continental populations of the 1000 Genomes Project. Nucleotide diversity (&#x3c0;), fixation index (FST), and allele frequency distributions were estimated using sliding-window analyses. Bootstrap resampling was used to compare diversity within and outside the coding region. Recent positive selection was assessed using XP-nSL, and codon-based evolutionary analyses were performed using primate SOD1 orthologs.<br><br>RESULTS: The coding region consistently exhibited a twofold to threefold reduction in nucleotide diversity relative to adjacent genomic sequences across all populations. Bootstrap analyses confirmed significantly lower diversity within the locus than in flanking regions (p < 0.05 in all populations). Population differentiation was low (mean FST &#x2248; 0.03) and showed no pronounced peaks within the coding interval, whereas allele frequency distributions were broadly similar across continental populations. XP-nSL analyses detected no evidence of population-specific recent selective sweeps. Codon-based analyses identified only 31 variable codons among 155 analyzed positions, six codons under negative selection, and no evidence of positive selection.<br><br>CONCLUSION: The SOD1 locus exhibits reduced standing genetic variation, limited continental differentiation, and strong evolutionary conservation, consistent with sustained functional constraint. These findings provide a comprehensive population genetic framework for interpreting genetic variation at this medically important locus.}, }
@article {pmid42606797, year = {2026}, author = {Raghunathan, T and Parthasarathy, B and Prabhu, P and Mahesh, P and Dhanushkodi, A}, title = {Regenerative strategies for ALS: stem cells and extracellular vesicles.}, journal = {Discover nano}, volume = {21}, number = {1}, pages = {}, pmid = {42606797}, issn = {2731-9229}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is caused by progressive degeneration of upper and lower motor neurons. The disease is late onset, and to date, no early diagnosis is possible. Patients with ALS have a 5-year survival rate since diagnosis. Though recent studies highlighted the possible mechanisms of motor neuron degeneration in ALS, the treatment options are extremely limited. This underscores the urgent need to develop effective therapeutic strategies that can prolong patient survival and ultimately slow/halt ALS progression. Extracellular vesicles released from the degenerative milieu contribute to ALS propagation and progression by shuttling misfolded proteins, proinflammatory cytokines, and neurotoxins; thus, they could serve as a biomarker for diagnosis and prognosis. The advancement of stem cell-based therapies for neurodegenerative diseases and the evolving understanding of extracellular vesicles as potential biotherapeutics provide a ray of hope for millions of patients suffering from neurological disorders/neurodegenerative diseases like ALS.}, }
@article {pmid42607915, year = {2026}, author = {Zhang, Y and Dong, X and Shai, Y and Alam, M and Han, D and Hu, Y and He, Z and Zhou, Z and Jiang, H}, title = {Annexin A1 inhibits neuronal apoptosis in amyotrophic lateral sclerosis by restraining the Hippo pathway.}, journal = {Brain research}, volume = {1891}, number = {}, pages = {150510}, doi = {10.1016/j.brainres.2026.150510}, pmid = {42607915}, issn = {1872-6240}, abstract = {Annexin A1 (ANXA1) is a multifunctional regulatory protein involved in neuroinflammation and cellular homeostasis, but its role in amyotrophic lateral sclerosis (ALS) remains unclear. In this study, we investigated the relationship between ANXA1 and Hippo pathway signaling in ALS. Bioinformatic analysis of transcriptomic data from iPSC-derived motor neurons showed that ANXA1 expression was reduced in ALS and associated with apoptosis and Hippo pathway-related changes. Decreased ANXA1 expression was confirmed in hSOD1^G93A transgenic mice and NSC34 motor neuron-like cells. Phosphorylation levels of MST1/2, LATS1/2, and YAP1 were elevated, indicates activation of the Hippo pathway. Functional experiments showed that ANXA1 overexpression reduced Hippo pathway activation, enhanced cell viability, and decreased apoptosis, as increased Bcl-2 expression and reduced Bax and cleaved caspase-9 levels. In contrast, ANXA1 knockdown further activated Hippo pathway and aggravated apoptotic changes. These findings identify ANXA1 as an upstream regulator associated with Hippo pathway activation in ALS and suggest that the ANXA1/Hippo axis may represent a potential therapeutic target.}, }
@article {pmid42607955, year = {2026}, author = {Wang, SY and Hunter, ER and Valdes Morales, KL and Perry, NJ and Feldman, E and Sobanko, JF and Etzkorn, JR and Higgins, HW and Zhang, J and Walker, JL and Miller, CJ}, title = {Response to Guan et al.'s, "Letter to the Editor 'Rethinking Routine Cartilage Grafting for Alar Defects'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.037}, pmid = {42607955}, issn = {1097-6787}, }
@article {pmid42608759, year = {2026}, author = {Talukdar, G and Cvetanovic, M}, title = {Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01950}, pmid = {42608759}, issn = {1673-5374}, abstract = {Ataxin-1 (ATXN1) was originally identified as a gene in which abnormal expansion of glutamine encoding CAG repeats causes inherited neurodegenerative disease spinocerebellar ataxia type 1. Spinocerebellar ataxia type 1 is characterized by alterations in movement, cognition, and mood, with severe pathology in the cerebellum and brain stem. Studies in spinocerebellar ataxia type 1 mouse models indicated that CAG expansion predominantly causes pathogenic ATXN1 gain-of-function in the cerebellum. Conversely, mice lacking ATXN1 are severely impaired in cognitive tests and exhibit abnormalities in cortical functions. Subsequent genetic and functional studies have associated ATXN1 with intelligence and several neurological conditions, including Alzheimer's disease, amyotrophic lateral sclerosis, schizophrenia, and multiple sclerosis. In some conditions, association is found with CAG expansions in ATXN1 and in others with the loss of ATXN1 expression. Additionally, recent studies indicate the role of ATXN1 in glial cells. Here, we review current genetic and functional evidence of how ATXN1 CAG expansion and loss of ATXN1 function contribute to brain dysfunction in spinocerebellar ataxia type 1, Alzheimer's disease, and multiple sclerosis, with an emphasis on glial cells.}, }
@article {pmid42608803, year = {2026}, author = {Xiao, Y and Yao, X and Mao, H and Xu, Y and Liu, Z and Li, Y and Yang, X and Liu, X}, title = {Annual monitoring reveals spatiotemporal dynamics of multiple herbicide resistance in Echinochloa crus-galli populations across Zhejiang Province, China.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71186}, pmid = {42608803}, issn = {1526-4998}, support = {//"Three Rural Areas-Nine Parties" Science and Technology Collaboration Program of Zhejiang Province/ ; //National Key Research and Development Program of China/ ; //National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Echinochloa crus-galli is a damaging weed in global rice production with rapidly evolving herbicide resistance. This study investigated resistance dynamics to six major herbicides across Zhejiang Province, China (2022-2024), to inform region-specific management.<br><br>RESULTS: A 3-year systematic monitoring covering 356 populations from 27 counties revealed that the annual resistance frequency of quinclorac consistently exceeded 50.00%. Cyhalofop-butyl resistance ranged from 32.18% to 61.18%. Penoxsulam resistance ranged from 24.14% to 50.59%. Resistance to bispyribac-sodium was detected in 25.00% of populations in 2023 and 81.18% in 2024. Resistance to the newly introduced florpyrauxifen-benzyl was detected in 49.41% of populations in its first monitoring year (2024). Metamifop remains largely effective due to low resistance frequency (6.90%-16.47%). In 2023, four populations resistant to all tested herbicides were detected, increasing to seven in 2024. Molecular analysis identified acetyl-CoA carboxylase (ACCase) target-site mutations I2041N and C2088R and the acetolactate synthase (ALS) mutation W574L as contributing factors, but the majority of cross-resistant populations lacked known target-site mutations, suggesting that non-target-site metabolic resistance is predominant. Under controlled conditions, propanil maintained complete control against all tested multiple-resistant populations.<br><br>CONCLUSION: Observed trends in E. crus-galli resistance include the widespread emergence of multiple resistance to ALS and ACCase inhibitors and regional variation linked to cropping intensity. Reported resistance frequencies are conditional estimates from problem fields, not unbiased provincial rates. Non-target-site resistance predominates among cross-resistant populations. Propanil is a promising alternative pending field validation. These findings support developing region-specific resistance management strategies for rice production in Zhejiang. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid42609140, year = {2026}, author = {Wedgwood, HE and Tuxworth, RI and Ahmed, Z}, title = {Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.}, journal = {The journal of gene medicine}, volume = {28}, number = {8}, pages = {e70106}, pmid = {42609140}, issn = {1521-2254}, support = {//LifeArc/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Animals ; Disease Models, Animal ; *Genetic Therapy/methods ; Humans ; Motor Neurons/pathology/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease, for which there is currently no known cure. ALS primarily affects motor neurons, with rapid deterioration, meaning symptoms develop quickly, from problems with speech and muscle weakness to breathing issues and paralysis. This systematic review aimed to explore the preclinical efficacy of various genetic therapies used to target ALS using in vivo rodent models.<br><br>METHODS: In vivo studies of genetic therapies targeting ALS and its symptoms published between January 2015 and December 2025 were included in this review. The following databases were used: Web of Science, Scopus and PubMed. The primary outcome investigated was the total number of motor neurons, with secondary outcomes of rodent survival and muscle function by observing rotarod performance also being analysed. The SYRCLE tool was used to assess risk of bias in included studies.<br><br>RESULTS: Of the 451 studies identified by searching the databases, 53 studies were found to be eligible for this systematic review. The articles were divided into subcategories depending on the gene target of each therapy. Meta-analysis of outcomes within appropriate studies showed significant improvements for the majority of selected outcomes (p&#x2009;<&#x2009;0.05), favouring genetic therapy intervention.<br><br>CONCLUSIONS: Results suggest that genetic therapies in rodent models targeting ALS are effective. However, due to a high risk of bias in preclinical studies, further high-quality studies are warranted to support this conclusion and onward translation into the clinic.}, }
@article {pmid42609516, year = {2026}, author = {Li, T and Zhang, Q and Wu, Y and Huang, R}, title = {Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.}, journal = {MedComm}, volume = {7}, number = {9}, pages = {e70915}, pmid = {42609516}, issn = {2688-2663}, abstract = {Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease-specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B-cell lymphoma 2 (BCL2) family signaling, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein activation, NOD-like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4-linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease-specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.}, }
@article {pmid42609692, year = {2026}, author = {Lazinkaitė, M and Avery, M and Olley, R and Stankūnienė, A and Czabanowska, K and Stankūnas, M}, title = {Authentic Leadership in Lithuanian Healthcare: A Qualitative Exploratory Study of Health Managers' Views and Experiences.}, journal = {Acta medica Lituanica}, volume = {33}, number = {1}, pages = {74-85}, pmid = {42609692}, issn = {1392-0138}, abstract = {Authentic Leadership (AL) is a value-based approach to leadership that focuses on self-awareness, relational transparency, balanced processing, and an internalized moral perspective. AL nurtures a supportive, high-trust work environment that boosts team cohesion, productivity, and ethical standards. In the healthcare workforce, the challenges and demands of person-centred care are significant, making AL a valuable opportunity to enhance the effectiveness of leadership and management. This study explored the key constructs and opportunities of AL within the context of the Lithuanian health system. A qualitative interpretative phenomenological approach was used to conduct semi-structured interviews with senior healthcare managers in Lithuania. The goal was to explore how these leaders understood and practiced AL. Thematic analysis was performed on the transcriptions of study participants' semi-structured interviews about perceptions of AL's four theoretical dimensions. The findings identified that Lithuanian healthcare leaders view self-awareness, moral integrity, and adaptability as central to effective leadership. Leaders emphasized self-reflection, openness to feedback, and moral consistency as crucial to their roles, enabling them to manage complex ethical responsibilities and strengthen organizational trust. AL has been shown to promote resilience in dynamic healthcare settings, thereby enabling adaptability and innovation. Leaders valued transparency and inclusive decision-making to ensure that diverse perspectives informed the team strategies. This study indicates that AL is an effective leadership approach for healthcare management in Lithuania. Our findings suggest that healthcare organizations could benefit from AL-based training programs, which may improve leaders' self-reflective practices, ethical decision-making, and collaboration skills.}, }
@article {pmid42609882, year = {2026}, author = {Bottale, I and Spinelli, EG and Basaia, S and Ghirelli, A and Gardoni, A and Russo, T and Canu, E and Castelnovo, V and Schito, P and Falzone, Y and Filippi, M and Agosta, F}, title = {Altered perivascular space diffusivity dynamics in motor neuron disease.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag307}, pmid = {42609882}, issn = {2632-1297}, abstract = {Converging evidence supports a key pathogenic role of the glymphatic system in the accumulation of pathological aggregates in several central nervous system proteinopathies, including amyotrophic lateral sclerosis and other motor neuron diseases. This study aimed to investigate potential glymphatic impairment using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) across motor neuron disease phenotypes, to examine its clinical correlates, and to assess its relationship with white matter damage. Fifty-seven patients with motor neuron disease and 32 age- and sex-matched healthy controls underwent a 3 Tesla brain MRI scan, including diffusion tensor imaging sequences. We obtained the DTI-ALPS index from each individual, evaluating its relationship with measures of motor and cognitive disability, site of symptom onset, cognitive status, genetic status and fractional anisotropy of white matter tracts. Comparisons between groups were evaluated using analysis of covariance adjusting for age, sex, local fractional anisotropy and white matter hyperintensity burden. Partial correlations with clinical and cognitive measures were also tested. Patients with motor neuron disease exhibited significantly lower DTI-ALPS index values relative to healthy controls (P = 0.05). Patients with bulbar onset had lower DTI-ALPS values than those with spinal onset (P = 0.017). Comparable DTI-ALPS values were found across patients with classical amyotrophic lateral sclerosis clinical presentation and predominant upper or lower motor neuron clinical presentations, with no effect of cognitive diagnosis or genetic status. DTI-ALPS exhibited a significant correlation with disease duration (r = -0.38, P = 0.01). Motor neuron disease patients presenting insomnia had significantly lower DTI-ALPS values compared to those without sleep disturbances (P = 0.002). Significant positive correlations were found between ALPS index and fractional anisotropy values across major white matter tracts, including the internal and external capsules, superior longitudinal fasciculi, anterior, posterior and superior corona radiata, posterior thalamic radiation, fornix and the genu and body of the corpus callosum. This study confirms the presence of altered interstitial fluid diffusivity dynamics across motor neuron disease phenotypes, with greater impairment observed in bulbar-onset cases, patients with longer disease duration, and those experiencing more pronounced sleep disturbances. These findings may support a potential pathogenic role of glymphatic failure in the accumulation of TAR DNA-binding protein 43 proteinopathy and widespread microstructural axonal damage in motor neuron diseases.}, }
@article {pmid42610023, year = {2026}, author = {Ettl, F and Eibensteiner, F and Greif, R and Mayhardt, S and Nern, S and Kurz, LM and Daniels, BA and Körmöczi, GF and Anvari-Pirsch, A and Grafeneder, J and Schriefl, C}, title = {Virtual reality, real-world rhythm: evaluating gamified training for medical students.}, journal = {Frontiers in public health}, volume = {14}, number = {}, pages = {1833908}, pmid = {42610023}, issn = {2296-2565}, mesh = {Humans ; Male ; *Students, Medical/statistics &amp; numerical data ; *Virtual Reality ; Female ; Surveys and Questionnaires ; *Education, Medical, Undergraduate/methods ; Adult ; Clinical Competence ; Young Adult ; Electrocardiography ; *Video Games ; }, abstract = {BACKGROUND: Virtual reality (VR) and gamification are increasingly recommended as adjuncts in resuscitation education, but their integration into undergraduate medical curricula and data on usability and learner acceptance remain limited. We evaluated a newly developed, gamified VR training application for medical students during their preparation for an Objective Structured Clinical Examination (OSCE).<br><br>METHODS: In this single-centre observational questionnaire study, fourth-year medical students completed VR-based advanced life support (ALS) training with randomized electrocardiogram (ECG) rhythms and gamified decision tasks. The primary outcome was usability measured with the Virtual Reality System Usability Questionnaire (VRSUQ; 0-100 points). Secondary outcomes included VR-induced symptoms (VRSQ; 0-100 points), self-rated rhythm-analysis competence before and after training (1-10), self-rated in-app performance (0-10), and trainer-reported feasibility. Continuous variables are presented as median (interquartile range [IQR]). Associations between outcomes were assessed using Spearman rank correlation coefficients.<br><br>RESULTS: Of 660 eligible students, 294 (44.5%) participated in the VR-study and completed the questionnaires. Usability was high (VRSUQ 83.3 [IQR 72.2-91.7]). VR-induced symptoms were low (VRSQ 8.3 [IQR 0.0-16.7]). Self-rated competence increased from 5.0 (IQR 4.0-7.0) before training to 8.0 (IQR 7.0-8.0) after training (p&#x202f;<&#x202f;0.001), corresponding to a competence gain of 2.0 points (IQR 1.0-3.0). Self-rated performance was 7.0 (IQR 5.0-8.0) and correlated with usability (&#x3c1;&#x202f;=&#x202f;0.44, p&#x202f;<&#x202f;0.001). Overall training quality was rated 9.0 (IQR 8.0-10.0), and 91.9% would participate again. Usability did not differ between genders but was higher among students with prior VR experience. Trainers reported short setup times, manageable supervision ratios, and occasional technical support needs.<br><br>CONCLUSION: Gamified VR-based ALS training for medical students is feasible, demonstrates high usability and low symptom burden, and improves self-assessed competence. VR appears to be a well-accepted adjunct to undergraduate resuscitation education.}, }
@article {pmid42610209, year = {2026}, author = {Lv, C and Zhu, W and Wen, X and Da, Y}, title = {Spatiotemporal Dynamics and Cellular States of Neuroinflammation in Amyotrophic Lateral Sclerosis: Implications for Stage‑Specific Therapeutics.}, journal = {ASN neuro}, volume = {18}, number = {1}, pages = {2715625}, doi = {10.1080/17590914.2026.2715625}, pmid = {42610209}, issn = {1759-0914}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/pathology/therapy ; Animals ; *Neuroinflammatory Diseases/immunology/pathology/therapy ; Disease Progression ; Blood-Brain Barrier ; Inflammation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex and heterogeneous pathogenesis. Accumulating preclinical and clinical evidence indicates that neuroinflammation is an important modulator of ALS pathophysiology, involving activation of resident central nervous system immune cells, dysfunction of glial support systems, disruption of neurovascular barriers, and altered recruitment of peripheral immune cells. ALS-associated neuroinflammation is temporally dynamic and varies across anatomical compartments and cellular contexts. Multiple animal models, human neuroimaging, and post-mortem tissue suggest that relatively regulated or compensatory immune responses during early stage may progressively shift to persistent, maladaptive, and potentially neurotoxic inflammatory circuits in later stage. Although previous studies have described stage-dependent changes in individual immune cell populations, an integrated stage-dependent systematic framework that unifies dynamic alterations in both central and peripheral immune compartments remains insufficiently established. In this review, we propose a four-phase conceptual framework for ALS neuroinflammation across the progressive ALS pathogenesis, aiming to provide theoretical guidance for staging inflammatory therapeutic interventions.}, }
@article {pmid42596047, year = {2026}, author = {Ohta, K and Fujino, Y and Sada, Y}, title = {Allelic dosage across four functional ALS loci shapes ALS-inhibitor resistance in allotetraploid Pontederia vaginalis.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71188}, pmid = {42596047}, issn = {1526-4998}, abstract = {BACKGROUND: Pontederia vaginalis, carrying four functional ALS genes, is a major weed in Asian rice paddies. Acetolactate synthase (ALS)-inhibitor resistance is caused by target-site mutations, but how resistant allelic dosage affects whole-plant susceptibility in weeds with more than three functional ALS loci remains unclear. This study quantified the effect of resistant allele number on herbicide susceptibility in P. vaginalis using progeny of a cross between two lineages carrying Pro197Ser substitutions in different ALS loci.<br><br>RESULTS: Hybridization between lineages carrying Pro197Ser in MvALS1 or MvALS3 yielded F2 progeny with varying resistant allelic dosages, and genotyping confirmed independent segregation of these loci. Dose-response assays with imazosulfuron and bensulfuron-methyl revealed that susceptibility decreased sharply as resistant alleles increased from zero to two (ED90 (effective dose to have 90% reduction of dry weights) shifts ~3000-fold for imazosulfuron), whereas additional alleles beyond two conferred only marginal further resistance (~four- to five-fold). For genotype-confirmed one-resistant-allele plants (n&#x2009;=&#x2009;25), the bootstrap 95% confidence interval (CI) for ED90 was 16.7-292.0&#x2009;g active ingredient (a.i.)&#x2009;ha[-1] (median: 92.6&#x2009;g&#x2009;a.i. ha[-1]), encompassing the registered field dose (90&#x2009;g&#x2009;a.i.&#x2009;ha[-1]) and non-overlapping with the CIs of the zero- and two-allele classes. The F2 segregation ratios matched theoretical expectations, suggesting non-target-site resistance does not substantially distort inheritance patterns.<br><br>CONCLUSION: These results demonstrate a clear allelic dosage effect on ALS-inhibitor resistance in P. vaginalis, with diminishing returns beyond two resistant alleles. The CI for one-resistant-allele plants encompasses the registered field dose, indicating genuinely uncertain control outcomes at standard application rates. These findings challenge fixed dominant/recessive classifications and highlight the need to quantify allelic dosage effects in polyploid weeds for accurate resistance risk assessment. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid42597242, year = {2026}, author = {Liu, Z and Yang, H and Cui, J and Guan, Z and Gao, D and Feng, P and Yang, H and Li, W and Zhao, Y and Yang, Q and Zheng, X and Liu, Q and Geng, Z}, title = {White matter abnormalities in amyotrophic lateral sclerosis: a free water imaging study.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1899073}, pmid = {42597242}, issn = {1662-4548}, abstract = {OBJECTIVE: To investigate white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) using free-water-corrected diffusion tensor imaging (FW-DTI), compare its findings with those of conventional DTI, and examine the clinical correlations and preliminary diagnostic value of these metrics.<br><br>METHODS: 44 ALS patients and 42 healthy controls underwent multi-b-value diffusion MRI. Conventional DTI metrics (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AxD], radial diffusivity [RD]), free-water-corrected metrics (FW-FA, FW-MD, FW-AxD, FW-RD), and the free-water fraction (FWF) were calculated. Tract-based spatial statistics (TBSS) was used for voxelwise group comparisons. Correlations between clinical parameters, including disease progression rate (&#x394;FS) and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and DTI metrics were examined. A diagnostic nomogram was constructed using logistic regression based on imaging markers that showed significant differences between groups.<br><br>RESULTS: Conventional DTI identified white matter abnormalities in ALS-related regions, including corticospinal tract-related regions, the corpus callosum, and the cingulate gyrus. FW-DTI showed additional and partially distinct alterations, including changes in the fornix, bilateral superior corona radiata, anterior and posterior corona radiata, and the posterior limb of the internal capsule. The free-water fraction did not differ between groups. Correlation analysis revealed that &#x394;FS was negatively associated with FA in the left posterior limb of the internal capsule (r&#x202f;=&#x202f;-0.432), and the ALSFRS-R score was positively associated with FW-FA in the right anterior corona radiata (r&#x202f;=&#x202f;0.389). A diagnostic nomogram combining FA in the right cerebral peduncle and FW-FA in the right anterior corona radiata showed preliminary discriminative performance (area under the curve [AUC]&#x202f;=&#x202f;0.860).<br><br>CONCLUSION: FW-DTI may provide complementary model-derived information for characterizing ALS-related white matter alterations beyond conventional DTI. Specific regional metrics were associated with &#x394;FS and the ALSFRS-R score, and the preliminary diagnostic nomogram yielded an AUC of 0.860.}, }
@article {pmid42597576, year = {2026}, author = {Maeta, T and Kobayashi, K and Asano, K and Sato, T and Ito, S}, title = {Ruxolitinib-Associated Improvement in Post-transplant Air-Leak Syndrome Complicating Steroid-Dependent Organizing Pneumonia: A Case Report.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e112618}, pmid = {42597576}, issn = {2168-8184}, abstract = {Air-leak syndrome (ALS), including pneumothorax, pneumomediastinum, and subcutaneous emphysema, is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, no standard treatment has yet been established. Here, we report the case of a 60-year-old man with acute myeloid leukemia who underwent allogeneic HSCT. He developed chronic graft-versus-host disease (GVHD) and cryptogenic organizing pneumonia (COP) on day 126 after transplantation. Although initial corticosteroid therapy improved the COP, the relapse occurred during tapering, and repeated steroid treatment failed to achieve sustained disease control. The patient subsequently developed pneumomediastinum, consistent with ALS. Ruxolitinib treatment was initiated on day 265 for steroid-dependent chronic GVHD and organizing pneumonia. Following treatment, oxygenation improved, pneumomediastinum improved, and corticosteroids were successfully tapered and discontinued without COP recurrence. Serum Krebs von den Lungen-6 (KL-6) levels decreased in parallel with clinical and radiological improvement. The introduction of ruxolitinib is associated with improvements in ALS and enabled the discontinuation of steroids. Adverse events included cytopenia and mild liver dysfunction, consistent with known safety profiles. The patient died of acute respiratory failure after transfusion, which was not considered a direct complication of the ruxolitinib treatment. This case suggests that ruxolitinib may facilitate corticosteroid tapering and radiographic improvement of organizing pneumonia-associated ALS after allogeneic transplantation.}, }
@article {pmid42598001, year = {2026}, author = {Tan, Q and Ma, Y and Zhao, J and Hu, H}, title = {Mapping artificial intelligence in problem-based and case-based medical education: a bibliometric analysis (2019-2026).}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1901004}, pmid = {42598001}, issn = {2296-858X}, abstract = {INTRODUCTION: Problem-based learning (PBL) has been a cornerstone of medical education since its introduction at McMaster University in the 1960s. Since the public release of ChatGPT in November 2022, artificial intelligence (AI) tools have increasingly been applied to PBL and case-based learning (CBL) contexts, yet the research landscape at this intersection remains poorly characterized. This study aimed to map the growth trajectory, thematic structure, and collaboration networks of AI-PBL/CBL research from 2019 to 2026.<br><br>METHODS: A comprehensive search of Scopus and Web of Science was conducted on June 2, 2026, combining AI-related terms with PBL/CBL frameworks and medical education contexts. Using a PRISMA-guided bibliometric review workflow, 1,616 records were identified; after deduplication and eligibility screening, 735 unique publications (2019-2026, original articles, reviews, conference papers, and other eligible indexed document types) were included. Bibliometric analyses employed VOSviewer for network visualization (keyword co-occurrence, co-authorship, co-citation), CiteSpace for citation burst detection, and Bibliometrix for thematic mapping, three-field plot, and factorial analysis.<br><br>RESULTS: Publication output grew from 25 papers in 2022 to 254 in 2025, with 206 papers indexed by June 2, 2026. The United States (n = 70) and China (n = 64) led publication volume. Keyword co-occurrence analysis identified four thematic clusters: a central AI-focused cluster, a medical education and clinical reasoning cluster, a nursing and simulation-oriented cluster, and an educational technology cluster. Kung et al.'s 2023 study evaluating ChatGPT's performance on the USMLE was the most frequently co-cited reference (62 co-citations, betweenness centrality = 0.11). Thematic mapping positioned machine learning as a motor theme, while clinical reasoning, medical education, and self-directed learning appeared in the basic themes quadrant. The country/region collaboration network comprised 33 countries/regions and was led by the United States and China, although collaboration patterns remained uneven across regions.<br><br>CONCLUSION: To our knowledge, this is the first bibliometric study specifically focused on the intersection of AI technologies with PBL/CBL in health professions education. The findings reveal rapid growth after 2023, four distinct but interconnected research clusters, and a collaboration network led by the United States and China, with uneven regional participation. These results may inform curriculum design and research priorities in AI-enhanced medical education.}, }
@article {pmid42598675, year = {2026}, author = {van de Zande, NA and Ruiter, CCC and Polman, MA and Brama, SCM and Roos, RAC and Kremer, PHC and de Bot, ST}, title = {Tracing neuroinflammation in neurodegeneration: insights from a scoping review on biofluid biomarkers.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag289}, pmid = {42598675}, issn = {2632-1297}, abstract = {Neuroinflammation is increasingly recognized as a key pathological process in neurodegenerative disease and can be monitored using biofluid biomarkers. Objective biomarkers may aid diagnosis, prognosis and progression. We conducted a scoping review of neuroinflammation biomarkers across major neurodegenerative diseases covering the past 23 years, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, Lewy body dementia, multiple system atrophy and progressive supranuclear palsy. PubMed and Web of Science were systematically searched for observational studies from 2003 to 2025 reporting neuroinflammation biomarkers in adult human subjects. Included markers encompassed blood, cerebrospinal fluid, saliva and urine, providing possible complementary information. Original studies on non-neuroinflammatory mechanisms, cellular or post-mortem biomarkers, animal models, genetics and comparisons between diseases were excluded. Two reviewers independently screened articles; biomarkers reported in ≥3 independent cohorts per disease were analysed. A total of 388 studies were included, predominantly in Alzheimer's disease/mild cognitive impairment (n = 214) and Parkinson's disease (n = 92). Eight biomarkers were most frequently reported: IL-6, TNF-α, IL-1β, CRP/hs-CRP, IL-10, MCP-1, YKL-40 and neutrophil-to-lymphocyte ratio (NLR), measured in blood or cerebrospinal fluid (CSF) as indicators of inflammatory processes associated with neurodegeneration. Across biomarkers, the strength and scope of evidence varied. Most studies demonstrated higher biomarker levels in disease, with more advanced stages, greater clinical severity and faster progression. NLR showed the most consistent pattern across staging, severity and progression, but is currently under-represented across diseases. CSF YKL-40 generally increased with disease presence and advancement; IL-6 showed consistent increases in advanced stages and with severity, although significant results were limited; MCP-1, CRP and TNF-α were mostly linked to severity and progression; IL-1β and IL-10 remained largely inconsistent. Other markers, including GFAP, showed associations in Alzheimer's disease but remain underexplored in other neurodegenerative diseases. Variability across studies, including differences in biofluid source, assay sensitivity, population characteristics and statistical approaches, limits interpretability and comparability. Although neuroinflammation is elevated in neurodegenerative diseases and generally intensifies as these diseases progress, potentially contributing to downstream pathology, the precise timing, role and predictive value of these biomarkers remain uncertain. A subset of markers, including NLR, YKL-40 and GFAP, shows relatively consistent associations and may warrant further investigation across diseases. In clinical practice, neuroinflammation biomarkers could serve as complementary tools to capture inflammatory processes related to disease heterogeneity and progression. Future longitudinal studies tracking pre-symptomatic and early-stage individuals, with standardized approaches, are needed to define temporal dynamics and explore their utility for monitoring disease progression and therapeutic response.}, }
@article {pmid42599142, year = {2026}, author = {Etemadifar, M and Salari, M and Kashefi, M and Shams, Y and Heydari Sichani, M and Hojjatipour, F}, title = {Incidence and clinical characteristics of amyotrophic lateral sclerosis during the post-COVID-19 Period: a population-based study from Isfahan, Iran.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2718409}, pmid = {42599142}, issn = {1758-2032}, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Understanding the underlying causes would help further studies on the pathogenesis and treatments. Recent interest has emerged in evaluating whether the COVID-19 pandemic and vaccination have any influence on the epidemiological patterns of ALS.<br><br>MATERIALS &amp; METHODS: To assess this association in Isfahan, Iran, during the post-COVID-19 era, we conducted this retrospective study. Newly diagnosed ALS cases were identified, and demographic data, environmental exposures, comorbidities, vaccination history, and other aspects were collected.<br><br>RESULTS: A total of 63 patients were diagnosed with definite ALS, yielding an incidence rate of 0.74 per 100,000 person-years (95% CI: 0.57-0.94). The mean age was 59.7&#x2009;&#xb1;&#x2009;11.6&#x2009;years, and cases were predominantly male (73%). Of the 63 new ALS-diagnosed cases, 45% of patients reported probable prior COVID-19 infection, and 95.3% mentioned at least one dose of COVID-19 vaccination. Bulbar signs, including facial muscle weakness, tongue atrophy, and fasciculation, were present in 46% of cases, and emotional lability and cognitive decline were observed in 20.6%.<br><br>CONCLUSION: We showed a probable relation between COVID-19 infection and the epidemiology of ALS in post-COVID era. However, our results and symptom alterations require further investigation.}, }
@article {pmid42600830, year = {2026}, author = {Ayala, E and Puigdemasa, J and Platikanov, S and van Drooge, BL and Bedia, C}, title = {Contrasting neurotoxic pathways triggered by PM10 in relation with organic molecular markers in suburban and rural sites in Catalonia.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {}, number = {}, pages = {128961}, doi = {10.1016/j.envpol.2026.128961}, pmid = {42600830}, issn = {1873-6424}, abstract = {Air pollution, particularly particulate matter (PM), is a major driver of global morbidity and mortality, with increasing evidence linking it to neurological disorders. This study investigates the chemical composition and neurotoxic potential of PM collected simultaneously in three sites in Catalonia (Spain): Bellver de Cerdanya (rural background), Manlleu (suburban), and Mollet del Vallès (suburban-industrial). Fifty-four filter samples collected in 2022 were analyzed by GC-MS for 30 organic molecular tracers, including polycyclic aromatic hydrocarbons (PAHs) and levoglucosan. Extracts were tested in SH-SY5Y human neuroblastoma cells across six toxicity endpoints: cell viability, reactive oxygen species (ROS), acetylcholinesterase (AChE) activity, antioxidant response, xenobiotic response, and p53 activation (DNA damage response). Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) on the combined chemical-biological dataset resolved four components: a winter biomass burning component enriched in levoglucosan, dehydroabietic acid, and PAHs, inducing strong cytotoxicity, oxidative stress, and xenobiotic responses; a traffic component present throughout the year; a spring-summer secondary organic aerosol (SOA) component associated with selective AChE inhibition without cytotoxicity; and a summer primary organic aerosol (POA) component. Partial Least Squares (PLS) regression linked PM10 composition with toxicity responses. Five of six models were statistically significant (R[2]CV = 0.53-0.75), with the highest performance for ROS, p53 activation, and cell death (R[2]CV ≥ 0.62). Biomass burning markers and PAHs were the main predictors of oxidative stress and cytotoxicity, whereas biogenic SOA tracers showed low importance. These findings link specific PM10 sources to distinct neurotoxic effects and highlight the importance of controlling winter emissions.}, }
@article {pmid42600917, year = {2026}, author = {deAndrés-Galiana, EJ and Fernández-Martínez, JL and Morís, G}, title = {Identifying candidate therapeutic targets in amyotrophic lateral sclerosis through a transcriptome-wide machine-learning consensus approach for drug repurposing.}, journal = {Neuroscience}, volume = {614}, number = {}, pages = {163-179}, doi = {10.1016/j.neuroscience.2026.08.017}, pmid = {42600917}, issn = {1873-7544}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease for which effective disease-modifying therapies remain limited. This study aimed to derive internally recurrent ALS-associated transcriptional signatures and generate directionally interpretable drug-repositioning hypotheses using a consensus machine-learning framework. Two publicly available transcriptomic datasets from motor cortex (E-MTAB-2325) and blood (E-TABM-940) were analyzed using four feature-selection methods within 100 repetitions of 4-fold cross-validation. Probes recurrently selected in models achieving an accuracy of at least 0.90 were prioritized and examined using COGENA pathway enrichment and Connectivity Map drug-signature analysis. Fifteen qualifying models were obtained for the motor-cortex dataset and 55 for the blood dataset. No exact prioritized gene or probe identifier was shared between the two top-100 signatures, but pathway-level integration identified complementary evidence involving glial and immune regulation, proteostasis and vesicle trafficking, MAPK-related stress signaling, cytoskeletal and extracellular remodeling, and RNA-related processes. The motor-cortex dataset additionally emphasized astroglial support, glutamate handling, and inclusion-body regulation, whereas the blood dataset highlighted cytokine regulation and directionally heterogeneous immune, mitochondrial, and metabolic signals. Deferoxamine and disulfiram showed the clearest reversal-compatible profiles in motor cortex, whereas yohimbic acid and atovaquone showed reversal-compatible profiles in blood. Ciprofloxacin, prochlorperazine, and a compound group led by androsterone instead showed concordant connectivity. The results provide transparent, hypothesis-generating gene, pathway, and compound priorities, but they do not establish biomarkers, therapeutic efficacy, or clinical suitability and require validation in independent cohorts and experimental ALS models.}, }
@article {pmid42600995, year = {2026}, author = {Ataei, R and Amini, J and Sanadgol, N and Simon, AF and Duennwald, ML}, title = {Circular RNAs in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107574}, doi = {10.1016/j.nbd.2026.107574}, pmid = {42600995}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. Here, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). Here we provide a general overview of circular RNA metabolism and cellular functions. We then present our systematic literature review that identified ALS-associated circRNAs, followed by in silico analyses of 15 circular RNA candidates that were selected based on most compelling data regarding ALS. Our results revealed that several circular RNAs regulate ALS-related genes, such as unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein-RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins. Additionally, molecular docking analysis demonstrated that ALS-associated FUS variants significantly alter its binding affinity to circular RNAs. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins in ALS-affected CNS tissues. Collectively, our findings identify circRNAs as potential key contributors to ALS pathogenesis.}, }
@article {pmid42601592, year = {2026}, author = {Shijo, T and Suzuki, N and Warita, H and Ikeda, K and Kato, M and Aoki, M}, title = {Poor Prognostic Factors After Gastrostomy in Patients With Amyotrophic Lateral Sclerosis: A Two-Center Retrospective Cohort Study.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70378}, pmid = {42601592}, issn = {1097-4598}, support = {JPMH23FC1008//the MHLW/ ; }, abstract = {INTRODUCTION/AIMS: Percutaneous endoscopic gastrostomy (PEG) is widely used to manage dysphagia in patients with amyotrophic lateral sclerosis (ALS). However, some patients experience rapid clinical deterioration following the procedure. Prognostic factors specific to outcomes following PEG remain insufficiently defined.<br><br>METHODS: This two-center retrospective cohort study included 117 patients with ALS who underwent PEG prior to tracheostomy between April 2011 and June 2023. Cox proportional hazards modeling was used to identify independent prognostic factors following PEG. Explanatory variables included age, sex, onset site, percent of normal forced vital capacity (%FVC), disease duration from onset to PEG, and body mass index. Optimal cutoff values for continuous variables were determined using time-dependent receiver operating characteristic analyses.<br><br>RESULTS: Among six examined clinical variables, four were independently associated with worse outcomes after PEG placement as follows: male sex, spinal onset, lower %FVC at the time of PEG, and shorter duration from onset to PEG. Cutoff values were determined as %FVC <&#x2009;63% and disease duration <&#x2009;12&#x2009;months. Log-rank analyses confirmed significantly shorter post-PEG survival in patients meeting these criteria.<br><br>DISCUSSION: Poorer respiratory function and shorter duration from disease onset to PEG were strongly associated with worse prognosis after PEG. Male sex emerged as an independent prognostic factor, suggesting potential biological differences in disease progression after gastrostomy. These findings underscore the importance of comprehensive clinical evaluation when considering PEG in patients with ALS.}, }
@article {pmid42602697, year = {2026}, author = {Sgobbi, P and de Rezende Pinto, WBV and Seneor, DD and Orsini, M and Chieia, MAT and Oliveira, ASB}, title = {Update and recommendations on genetic testing for amyotrophic lateral sclerosis in clinical practice: a Brazilian expert view.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1928302}, pmid = {42602697}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/methods/standards ; Brazil ; Genetic Predisposition to Disease ; *Practice Guidelines as Topic/standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. Although most ALS cases occur sporadically, without a known family history of the disease, genetic factors play a major role in its pathogenesis through monogenic, oligogenic, or polygenic mechanisms. It is estimated that 10-15% of ALS cases occur in a familial setting; however, a specific monogenic cause cannot always be identified. Establishing the underlying genetic basis in both sporadic and familial ALS is essential, as it enables individualized and family genetic counseling, facilitates the early identification of at-risk or oligosymptomatic relatives, improves the prediction of gene-specific clinical trajectories, and, more recently, determines eligibility for gene-targeted therapies, such as tofersen for SOD1-associated ALS and ulefnersen, currently under clinical investigation, for FUS-associated ALS. Over the years, differing opinions have existed regarding the role of genetic testing in individuals diagnosed with ALS. However, accumulating clinical evidence has increasingly supported the timely and early implementation of genetic testing as part of the standard clinical management of patients with ALS. In this article, we present the perspective of leading Brazilian neurologists specializing in ALS care regarding the current role of genetic testing in clinical practice.}, }
@article {pmid42603254, year = {2026}, author = {Lietzen, LW and Jensen, RD and Chippendale, RZ and Vamdrup-Andersen, AS and Andersen-Ranberg, K and Andersen, LH}, title = {Supporting geriatric thinking and management: adaptation of the Geriatrics 5Ms to Danish healthcare context.}, journal = {European geriatric medicine}, volume = {}, number = {}, pages = {}, pmid = {42603254}, issn = {1878-7649}, abstract = {PURPOSE: Coordinated, person-centred care for older adults is often challenged by multimorbidity, functional decline, and fragmented care trajectories. While Comprehensive Geriatric Assessment (CGA) remains the gold standard, its implementation outside specialised geriatric settings is limited. The Geriatrics 5Ms framework (mind, mobility, medications, multicomplexity, and matters most) offers a structured and accessible alternative. We aimed to adapt the Geriatrics 5Ms to the Danish healthcare context.<br><br>METHODS: Using Moore et al.'s ADAPT guidance, we conducted an iterative adaptation process involving academics, clinicians, and patient representatives. The framework was professionally translated and refined through expert workshops and ad hoc consultations. Evaluation activities included focus groups, individual interviews, structured feedback from health professions education and primary and secondary care. Findings informed iterative revisions and development of a core content list to support implementation.<br><br>RESULTS: Direct transfer of the original Geriatrics 5Ms was not feasible due to organisational differences and cross-sectoral responsibilities in Danish healthcare. Adaptation resulted in a shift from a physician-centred decision-support tool to an interprofessional reference framework with simplified language and strong emphasis on everyday functioning, care transitions, and shared decision-making. Stakeholders valued the structured, person-centred approach and the potential for a shared cross-sectoral language but highlighted the need for context-specific versions and clear implementation strategies.<br><br>CONCLUSION: Stakeholders perceived the Danish adaptation of the Geriatrics 5Ms as relevant and potentially feasible across sectors. Future efforts should focus on structured context-sensitive implementation and education research to ensure sustainable integration into routine clinical practice.}, }
@article {pmid42604810, year = {2026}, author = {Littger, B and Lorenzl, S and Schuchter, P and Bublitz, S}, title = {An Encouragement to Broaden the Frame: Spiritual Care as a Complementary Perspective on Healthcare Professionals' Emotional Experiences in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70379}, pmid = {42604810}, issn = {1097-4598}, }
@article {pmid42595352, year = {2026}, author = {Gao, J and Chalitsios, CV and Bennett, D and Doherty, A and Turner, MR and Thompson, AG}, title = {Associations of self-reported and objectively measured physical activity and amyotrophic lateral sclerosis risk.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2026-339165}, pmid = {42595352}, issn = {1468-330X}, abstract = {BACKGROUND: The role of physical activity in the risk of amyotrophic lateral sclerosis (ALS) is debated. It is also unclear whether the association differs in people at high genetic risk of ALS.<br><br>METHODS: The strength and shape of the association between self-reported and device-measured physical activity and incident diagnosis of ALS in the UK Biobank cohort was analysed using Cox regression, adjusting for potential confounders. Cubic splines were used to assess non-linearity. Analyses were performed in the entire cohort and restricted to those with increased genetic risk due to C9ORF72 expansion carriage or C-allele homozygosity at rs12608932 in UNC13A.<br><br>RESULTS: Among 384&#x2009;836 participants with valid questionnaire data, the median age at recruitment was 57.0 years (IQR 50.0-63.0) and median follow-up was for 14.0 years (IQR 13.3-14.6), with 541 incident diagnoses of ALS. Higher self-reported physical activity was associated with a lower risk of ALS (HRhigh vs low=0.77, 95%&#x2009;CI 0.61 to 0.96). The relationship was non-linear, with lowest risk in those in the mid-range self-reported activity. Higher overall device-measured activity was also associated with a lower risk of ALS (HRper 1SD = 0.75, 95%&#x2009;CI 0.58 to 0.97, n=96&#x2009;570, 98 ALS events) but with a linear dose-response relationship. The association of physical activity with ALS was similar in individuals with C-allele homozygosity at rs12608932 in UNC13A and directionally consistent but not statistically significant in C9ORF72-HRE carriers (n=535, 56 ALS events).<br><br>CONCLUSION: Higher self-reported and device-measured overall physical activity were associated with a lower risk of ALS overall, but with a potentially non-linear dose-response relationship.}, }
@article {pmid42595353, year = {2026}, author = {Fang, F}, title = {Physical activity in ALS: friend or foe?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2026-339492}, pmid = {42595353}, issn = {1468-330X}, }
@article {pmid42595782, year = {2026}, author = {Hetz, C and Thielen, P and Fisher, J and Pasinelli, P and Brown, RH and Korsmeyer, S and Glimcher, L}, title = {Correction: The proapoptotic BCL-2 family member BIM mediates motoneuron loss in a model of amyotrophic lateral sclerosis.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41418-026-01701-0}, pmid = {42595782}, issn = {1476-5403}, }
@article {pmid42596010, year = {2026}, author = {Kamphausen, A and Pilz, M and Baumgärtel, M and Kubitz, JC and Engelen, C}, title = {Effect of an app-guided advanced cardiac life support algorithm on teamwork, non-technical skills, and workload in simulated in-hospital cardiac arrest: a randomized controlled feasibility trial.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {34}, number = {1}, pages = {}, pmid = {42596010}, issn = {1757-7241}, mesh = {Humans ; *Heart Arrest/therapy ; *Advanced Cardiac Life Support/methods ; Prospective Studies ; Feasibility Studies ; Female ; *Mobile Applications ; Male ; *Algorithms ; *Patient Care Team ; *Workload ; *Clinical Competence ; }, abstract = {BACKGROUND: In-hospital cardiac arrest carries high mortality despite advances in monitoring, rapid response systems, and adherence to advanced life support (ALS) guidelines. Digital decision-support tools, including mobile applications, are increasingly explored to improve guideline adherence, yet their impact on cognitive workload, team performance, and ALS performance remains uncertain.<br><br>METHODS: We conducted a prospective, randomized, simulation-based controlled feasibility trial with 40 interprofessional teams (80 participants) comparing ALS performance with and without the use of the 'CPR Leader' app. Two-person teams were randomized 1:1 to intervention or control and followed standardized in-hospital cardiac arrest scenarios (asystole and ventricular fibrillation). Primary outcomes included team performance (TEAM), non-technical skills (ANTS), and subjective workload (NASA-TLX). Secondary outcomes comprised objective resuscitation metrics, including time to rhythm analysis, defibrillation, medication administration, and chest compression quality.<br><br>RESULTS: Overall NASA-TLX scores were high but comparable between intervention and control group (mean 49.2&#x2009;&#xb1;&#x2009;13.6 vs. 54.1&#x2009;&#xb1;&#x2009;14.6; p&#x2009;=&#x2009;0.2), with higher effort reported in the app group and higher frustration in the control group. TEAM and ANTS scores showed no evidence of meaningful between-group differences. Across the two scenarios types, ALS performance metrics-including rhythm analysis, defibrillation, medication administration, and chest compression quality-were similar between groups, with the exception of earlier chest compression initiation in the control group during ventricular fibrillation.<br><br>CONCLUSIONS: In this exploratory randomized simulation study involving predominantly experienced in-hospital healthcare professionals, the use of a resuscitation support application did not demonstrate a clear improvement in adherence to guideline-recommended ALS algorithms or resuscitation performance compared with standard practice. These findings likely reflect the high level of participants' clinical experience and should not be generalized to novice providers, mixed-experience teams, prehospital settings, or training environments. Further studies are warranted to evaluate the potential benefits of cognitive aids in less experienced populations and in real-world clinical practice.<br><br>TRIAL NUMBER: None.}, }
@article {pmid42596024, year = {2026}, author = {Reeves, MM and Aviles Carpintero, S and Zanovello, M and Jansen-West, K and Yue, M and Calliari, A and Song, Y and Dunmore, J and Maroto Cidfuentes, C and Ball, S and Kachergus, JM and Killeen, HE and Rawlinson, B and Engelberg-Cook, E and DeTure, M and Day, GS and Graff-Radford, NR and Boeve, BF and Knopman, DS and Petersen, RC and Murray, M and Thompson, AE and Dickson, DW and Fratta, P and Petrucelli, L and Josephs, KA and Prudencio, M}, title = {The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.}, journal = {Alzheimer's research &amp; therapy}, volume = {18}, number = {1}, pages = {}, pmid = {42596024}, issn = {1758-9193}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; U54NS123743, R35NS097273//NIH/ ; R01NS120992, R01AG037491//NIH/ ; R01NS120992, U54NS123743//NIH/ ; MR/M008606/1 and MR/S006508/1//Lady Edith Wolfson Fellowship/ ; U54 NS123743/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U01AG006786/AG/NIA NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/complications ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; DNA-Binding Proteins/metabolism ; *Exons/genetics ; *Nerve Tissue Proteins/genetics ; Aged ; Brain/pathology/metabolism ; Aged, 80 and over ; Cohort Studies ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.<br><br>OBJECTIVE: To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.<br><br>METHODS: We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.<br><br>RESULTS: In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.<br><br>CONCLUSIONS: These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.}, }
@article {pmid42595324, year = {2026}, author = {Fustes, OJH and Teive, HAG}, title = {Amyotrophic lateral sclerosis (ALS): new insights 156 years after Charcot's masterful description.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {7}, pages = {1-4}, pmid = {42595324}, issn = {1678-4227}, mesh = {*Amyotrophic Lateral Sclerosis/history ; History, 19th Century ; Humans ; History, 20th Century ; }, abstract = {In 1869, Charcot and Alix Joffroy published the first detailed clinical and neuropathological description of amyotrophic lateral sclerosis (ALS), establishing the correlation involving muscle weakness, atrophy, spasticity, and degeneration of the lateral corticospinal tracts. Charcot unified the involvement of upper and lower motor neurons into a single clinical entity. His pioneering description was limited to the motor system, reflecting the scientific constraints of his time. Charcot interpreted ALS primarily as a disorder of the motor system, a conclusion consistent with the clinical and pathological methods available in the late nineteenth century. Neurological investigation at that time relied mainly on detailed clinical observation, anatomical correlation at autopsy, and relatively-simple physiological techniques. These approaches were well suited to identify motor dysfunction but were far less capable of revealing subtle cognitive or behavioral alterations. Currently, ALS is recognized as a multisystem neurodegenerative disorder. Thus, Charcot's historical contribution was crucial for the initial understanding of ALS, while modern perspectives acknowledge its broader clinical complexity beyond the motor system.}, }
@article {pmid42594668, year = {2026}, author = {Nakasako, J and Nishimoto, Y}, title = {Reply to the comment on "Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis".}, journal = {Journal of the neurological sciences}, volume = {490}, number = {}, pages = {126130}, doi = {10.1016/j.jns.2026.126130}, pmid = {42594668}, issn = {1878-5883}, }
@article {pmid42595080, year = {2026}, author = {Al-Badaineh, M and Josan, H and Imran, B and Ebeid, I and Mekhail, J and Abdou, M and Dagher, D and Ahmed, AF and Hantouly, A and Khan, M}, title = {Spin in Systematic Reviews on Patch-Augmented Rotator Cuff Repair: Prevalence, Predictors, and Methodological Implications.}, journal = {Journal of shoulder and elbow surgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jse.2026.07.030}, pmid = {42595080}, issn = {1532-6500}, abstract = {BACKGROUND: Rotator cuff tears are a major cause of shoulder pain and dysfunction, and surgical repair is often complicated by the risk of retear, especially in patients with large, massive, revision tears and high-risk patients. Biologic or synthetic patch augmentation has emerged to reinforce repair and potentially reduce retears. Despite many systematic reviews and meta-analyses on patch-augmented versus non-augmented repair, concerns remain regarding study heterogeneity, outcome variability, and spin in interpretation and reporting, particularly in abstracts. This study assessed the methodological quality and abstract spin.<br><br>METHODS: This systematic review was conducted in accordance with the Cochrane Handbook and PRISMA guidelines. On October 30, 2025, PubMed, Scopus, and Web of Science were searched for English-language systematic reviews and meta-analyses comparing patch- or graft-augmented versus non-augmented rotator cuff repair in clinical studies. Eligible reviews reported at least one clinical, patient-reported, or imaging-based outcome. Two reviewers independently performed duplicate study selection, data extraction, spin assessment, and methodological quality appraisal using Yavchitz et al.'s nine severe spin types and AMSTAR-2.<br><br>RESULTS: Sixteen reviews and meta-analyses were included in this study. Spin was identified in 81.3% (n = 13) of the abstracts. The types were 5 (62.5%), 3 (56.2%), and 8 (50.0%). Univariate analysis found no significant associations with the funding status (p = 0.36), quality (p = 1.00), or impact factor (p = 0.95). Each AMSTAR-2 flaw was associated with 61% more spin types (IRR 1.61; 95% CI 1.08-2.49; p = 0.02).<br><br>CONCLUSION: Spin is prevalent in the abstracts of systematic reviews on patch augmentation for rotator cuff repair, regardless of funding or journal impact factor. Although spin was widespread, poor methodological quality was linked to a greater spin burden rather than its presence. These findings highlight the importance of critically appraising systematic reviews, as spin may contribute to an overly favorable interpretation of the evidence and potentially influence clinical decision-making. Readers should interpret the conclusions cautiously and verify the claims against the full-text results.<br><br>LEVEL OF EVIDENCE: Research Methodology Study, Systematic Review.}, }
@article {pmid42595317, year = {2026}, author = {Oliveira, AC and Corrêa, TDS and Vieira, LF and Carvalho, IR and Chaul, DN and Almeida, AECG and Faria, VLG and Simamoto Júnior, PC and Morais, JF and Stelzer, FG and Goulart, IMB and Santos, DFD}, title = {Nocturnal polygraphy in neuromuscular disorders: is it a useful diagnostic tool?.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {7}, pages = {1-8}, pmid = {42595317}, issn = {1678-4227}, mesh = {Humans ; *Sleep Apnea, Obstructive/diagnosis/epidemiology/etiology/physiopathology ; *Neuromuscular Diseases/complications/physiopathology ; Female ; Prospective Studies ; Male ; *Polysomnography/methods ; Middle Aged ; Prevalence ; Adult ; Surveys and Questionnaires ; Aged ; }, abstract = {BACKGROUND: Patients with neuromuscular diseases (NMDs) have a high incidence of sleep-related breathing disorders. These include obstructive sleep apnea (OSA), which is characterized by recurrent episodes of upper airway obstruction during sleep, resulting in intermittent hypoxemia and sleep fragmentation. Obstructive sleep apnea may be more common in patients with NMDs than in the general population.<br><br>OBJECTIVE: To assess the prevalence of OSA through home polygraphy at a public university hospital during respiratory evaluations of patients with NMDs, and its contribution to the indication of non-invasive ventilation. It did not aim to validate a model for early indication.<br><br>METHODS: The present prospective study collected data over the period from May 2021 to June 2024, using medical records and tests such as spirometry to evaluate pulmonary respiratory function, home polygraphy, and sleep assessments using the Epworth Sleepiness Scale (ESS) and a symptom questionnaire.<br><br>RESULTS: A total of 74 patients were included, 64.7% (n&#x2009;=&#x2009;48) of whom had OSA. The most prevalent NMDs were muscular dystrophy (n&#x2009;=&#x2009;22; 29.7%), myasthenia gravis (n&#x2009;=&#x2009;13; 17.6%), and amyotrophic lateral sclerosis (ALS) (n&#x2009;=&#x2009;11; 14.9%). Apnea-hypopnea index (AHI) values were higher in the supine position (11.6&#x2009;&#xb1;&#x2009;12.6) compared to the AHI in the non-supine position (7.0&#x2009;&#xb1;&#x2009;14.1), which indicates, on average, a mild degree of OSA. The ESS revealed that 40.5% of patients had scores indicating excessive daytime sleepiness (EDS).<br><br>CONCLUSION: The findings reinforce the importance of early OSA diagnosis in patients with NMDs.}, }
@article {pmid42533617, year = {2026}, author = {Rasmussen, LK and Gomes Moreira, D and Okarmus, J and Simonsen, A and Meyer, M}, title = {Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/15548627.2026.2711596}, pmid = {42533617}, issn = {1554-8635}, abstract = {Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMFR/GP78: autocrine motility factor receptor; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATG: autophagy related; Aβ: amyloid beta; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMc: core autophagy machinery components; CSNK2/CK2: casein kinase 2; DUB: deubiquitinase; DNM1L/DRP1: dynamin 1 like; FKBP8: FKBP prolyl isomerase 8; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GLP-1: glucagon-like peptide 1; HD: Huntington disease; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IMM: inner mitochondrial membrane; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCHF5: membrane associated ring-CH-type finger 5; MCL1: MCL1 apoptosis regulator, BCL2 family member; MDV: mitochondria-derived vesicle; MFN1: mitofusin 1; MFN2: mitofusin 2; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; OMM: outer mitochondrial membrane; OMMAD: outer mitochondrial membrane-associated degradation; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PD: Parkinson disease; PE: phosphatidylethanolamine; PG: phagophore; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RHOT1/Miro1: ras homolog family member T1; ROS: reactive oxygen species; SIAH1: siah E3 ubiquitin protein ligase 1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TCA: tricarboxylic acid cycle; TFAM: transcription factor A, mitochondrial; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UPRmt: mitochondrial unfolded protein response; UPS: ubiquitin-proteasome system; USP30: ubiquitin specific peptidase 30; VCP: valosin containing protein; VDAC: voltage dependent anion channel; WIPI: WD repeat domain, phosphoinositide interacting.}, }
@article {pmid42589639, year = {2026}, author = {Wu, Y and Li, L and Tian, J and Liu, L and Du, K and Shao, Z and Cheng, T and Cao, X and Wang, T}, title = {RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.}, journal = {International journal of molecular sciences}, volume = {27}, number = {15}, pages = {}, pmid = {42589639}, issn = {1422-0067}, support = {STI2030-Major Projects-2022ZD0212600//National Science and Technology Innovation 2030 Major Projects of China/ ; 32271000//National Natural Science Foundation of China/ ; 32471008//National Natural Science Foundation of China/ ; 32300796//National Natural Science Foundation of China/ ; 23ZR1413800//Natural Science Foundation of Shanghai/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *RNA Stability ; *Protein Biosynthesis ; Humans ; RNA, Messenger/genetics/metabolism ; *Dipeptides/genetics/metabolism ; *Exosome Multienzyme Ribonuclease Complex/metabolism/genetics ; *DNA Repeat Expansion/genetics ; Induced Pluripotent Stem Cells/metabolism/cytology ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; }, abstract = {The RNA exosome plays a critical role in surveilling nuclear mRNA biogenesis and regulating co-translational mRNA decay in the cytoplasm. Unlike canonical translation, repeat-associated non-AUG (RAN) translation of a GGGGCC hexanucleotide repeat expansion (HRE) within an intron of the C9orf72 locus leads to the synthesis of neurotoxic dipeptide-repeat (DPR) proteins, contributing to the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis (C9-ALS/FTD). However, it remains unclear whether aberrant RAN translation is monitored and regulated co-translationally or how C9orf72 HRE (C9-HRE) mRNA is degraded during this process. Here, we demonstrate that RAN translation triggers the rapid decay of C9-HRE mRNA. During this process, the RNA exosome engages the translating ribosome-C9-HRE mRNA complex to mediate RAN translation-coupled mRNA decay. Moreover, overexpression of EXOSC3, a key subunit of the RNA exosome cap, promotes RAN translation-coupled decay of C9-HRE mRNA and suppresses DPR production. In iPSC-derived neurons, a reduction in EXOSC3 levels blocks C9-HRE mRNA decay in a translation-dependent manner, further confirming its role in RAN translation surveillance. These findings highlight the essential function of the RNA exosome, particularly EXOSC3, in mitigating RAN translation-associated toxicity and preventing pathological DPR production. This work provides insights into potential therapeutic strategies for C9-ALS/FTD and may have broader implications for other disorders involving RAN translation.}, }
@article {pmid42591225, year = {2026}, author = {Vöhringer, K and Müller, MS and Yildiz, CB and Zimmer-Bensch, G}, title = {DNMT1 as an environmental sensor: epigenetic pathways linking environmental exposures, sex hormone signaling, and vulnerability to neurodevelopmental and neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1883887}, pmid = {42591225}, issn = {1664-2295}, abstract = {DNA methyltransferase 1 (DNMT1) has classically been viewed as the canonical maintenance methyltransferase, yet accumulating evidence positions it as a multifaceted hub that integrates environmental, hormonal, and metabolic signals with chromatin regulation in the developing and adult brain. This review highlights DNMT1 as an environmentally responsive epigenetic sensor across the lifespan. We examine how psychosocial stress, early-life adversity, inflammation, nutritional and microbiome-derived metabolites, and environmental toxicants modulate DNMT1 expression, subcellular localization, and post-translational modifications, thereby reshaping DNA methylation landscapes in neurons and glia. We further discuss how sex hormone signaling, particularly estrogen receptor alpha α (ERα)-DNMT1 feedback loops, introduces sex-specific dimensions to epigenetic responsiveness, and how lncRNAs serve as intermediaries linking environmental cues to targeted DNMT1 recruitment at specific genomic loci. Building on this framework, we review how DNMT1 dysregulation contributes to neurodevelopmental and neuropsychiatric disorders-including schizophrenia, autism spectrum disorder, and depression-and to neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and DNMT1-associated monogenic neurodegenerative disorders. By positioning DNMT1 as a molecular interface between genetic predisposition, environmental exposure, and circuit-level vulnerability, this review highlights the need for integrated, sex-stratified, and longitudinal approaches to understanding epigenetic risk in neurological disease.}, }
@article {pmid42592079, year = {2026}, author = {Tu, S and Mahoney, CJ and Huynh, W and Vucic, S and Kiernan, MC}, title = {Cortical excitability stratifies neurochemical profiles in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag292}, pmid = {42592079}, issn = {2632-1297}, abstract = {Transsynaptic deficits arising from an imbalance in excitatory/inhibitory inter-neuronal circuitry have been extensively shown to underlie the phenomena of altered cortical motor excitability in patients with amyotrophic lateral sclerosis (ALS), with glutamate-induced excitotoxicity believed to represent a primary mechanism of ALS pathogenesis. In vivo evidence of glutamate abnormality in ALS patients, however, remains inconsistent, likely reflecting heterogeneity in the severity of underlying cortical dysfunction. The current study assessed the utility of short interval intracortical inhibition (SICI), a validated marker of upper motor neuron (UMN) dysfunction in ALS, to stratify cortical motor metabolite abnormalities, as determined by proton magnetic resonance spectroscopy ([1]H-MRS). Serial [1]H-MRS data were acquired over 2.5 years for two ALS participants with contrasting profiles of progressive motor dysfunction as a pilot study. Longitudinal monitoring of these participants demonstrated stable cortical motor metabolite concentrations in the participant with lower motor predominant disease presentation but progressive changes in glutamate-glutamine (Glx) and N-acetylaspartate (NAA) concentrations in the participant with a classical ALS presentation. Fifty-four participants (34 ALS; 20 control) were prospectively recruited for a formal study. All patients underwent threshold-tracking transcranial magnetic stimulation) and were classified as having high (>5.5%; H-SICI) or low (≤5.5%; L-SICI) cortical motor inhibition. Matching 3T single-voxel [1]H-MRS data were acquired from the hand region of the motor cortex for all participants at baseline, with a subset of patients (n = 10) longitudinally assessed at 6 months. Dissociable patterns of pathological change in NAA and Glx/NAA metabolites were observed at baseline and longitudinally in ALS. At baseline, L-SICI ALS participants with increased cortical motor excitability demonstrated a significant bilateral reduction in NAA and elevated Glx/NAA metabolite concentrations (P-values < 0.03), contrasting to H-SICI ALS participants, where the neurochemical concentration was preserved. At follow-up, H-SICI patients demonstrated a trend towards elevated Glx and Glx/NAA in the left motor cortex (P-values ≤ 0.06). In contrast, L-SICI patients demonstrated stable concentrations of Glx but further reductions in NAA ratio (P = 0.04). Cortical excitability and brain neurochemical profile abnormalities reflect evolving states of UMN dysfunction in ALS. Elevated Glx/NAA metabolite concentration underlies greater cortical motor dysfunction in ALS. Longitudinal [1]H-MRS holds potential prognostic utility for clinical monitoring of ALS disease trajectory.}, }
@article {pmid42592352, year = {2026}, author = {Vinceti, M and Ferrante, M and Filippini, T and Wise, LA and Urbano, T and Bedin, R and Gianferrari, G and Rapisarda, P and Pulvirenti, E and Oliveri Conti, G and Mandrioli, J}, title = {Central nervous system concentrations of nano- and microplastics and risk of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag296}, pmid = {42592352}, issn = {2632-1297}, abstract = {Growing evidence suggests that microplastics, particularly nanoplastics, may be neurotoxic. However, there are few studies of neurologic diseases, especially amyotrophic lateral sclerosis (ALS). In a hospital-based case-control study, we measured in vivo concentrations of nano- and microplastics (size 0.1-10 µm) in serum and CSF among 24 newly diagnosed cases of ALS and 20 controls. Adjusting for sex and age, we found a strong positive association between serum and CSF microplastic concentrations and higher microplastic concentrations in the CSF and serum of ALS cases compared with controls. In spline regression analyses, CSF microplastic concentrations showed a positive monotonic association with odds of ALS. Serum microplastic concentrations also showed a positive association with ALS, but only above a certain threshold. Among ALS cases, serum-but not CSF-microplastic concentrations were positively associated with neurofilament light chain, a biomarker of neuroaxonal damage. Given the case-control design, we cannot rule out reverse causation (i.e. that ALS-related factors caused greater bioaccumulation of microplastics) or the possibility that the association reflects changes in lifestyle or other chemical exposures. However, the observed pattern raises the possibility of an aetiologic role of nano- and microplastics in motor neuron degeneration and indicates higher CNS concentrations of these chemicals in ALS cases.}, }
@article {pmid42592497, year = {2026}, author = {Pal, S and Das, S and Biswas, S and Murugan, SD and Jana, NR and Chattopadhyay, AP and Singh, NDP}, title = {Exploring viscosity sensitivity of π-extended coumarin fluorogen-based PRPGs for precise photorelease of valproic acid: detection and defibrillation of TDP-43 aggregation.}, journal = {Chemical science}, volume = {}, number = {}, pages = {}, pmid = {42592497}, issn = {2041-6520}, abstract = {Alteration of cellular microenvironment viscosity by protein aggregation plays a crucial role as a biophysical parameter that reflects abnormal cellular behaviour, leading to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), etc. Herein, we report the design and development of a series of coumarin fluorogen-based photoremovable protecting groups (PRPGs, 5a-d) with variations in substitutions tethered with a π-extended linker that integrate viscosity sensing with visible-light-triggered release of bioactive molecules. By introducing π-extended conjugation and systematic substitution, the coumarin fluorogen-based PRPGs exhibit twisted intramolecular charge transfer (TICT)-based fluorescence modulation in response to microenvironmental viscosity. Comprehensive photophysical and photochemical investigations, supported by theoretical calculations, identified PRPG 5d as the most sensitive viscosity-responsive system with green-light absorption. Under viscous conditions, restricted bond rotation suppresses nonradiative decay and photoisomerization, enabling efficient photorelease of the neuroprotective agent valproic acid. The versatility of PRPG 5d was demonstrated in biologically relevant in vitro models, including TDP-43 protein aggregation and Parkinson's disease induced SH-SY5Y neuroblastoma cells. In both extracellular and intracellular neurodegenerative environments, increased viscosity was effectively sensed, triggering light-mediated valproic acid release and subsequent defibrillation. Overall, this work establishes coumarin fluorogen-based PRPGs as a promising platform for viscosity-guided, spatiotemporally controlled drug release, offering potential applications in the diagnosis and targeted therapy of neurodegenerative diseases.}, }
@article {pmid42592720, year = {2026}, author = {Żur-Wyrozumska, K}, title = {Severe hypersensitivity reaction during tofersen therapy in amyotrophic lateral sclerosis associated with the rare SOD1 p.Val120Phe mutation.}, journal = {Neurologia i neurochirurgia polska}, volume = {}, number = {}, pages = {}, doi = {10.5603/pjnns.113584}, pmid = {42592720}, issn = {0028-3843}, }
@article {pmid42592867, year = {2026}, author = {McFarlane, R and Anneser, J and Al-Chalabi, A and Chiò, A and Mcdermott, CJ and Meyer, T and Mora, G and Sermeus, W and Stavroulakis, T and Tappenden, P and Van Den Berg, LH and Winkler, AS and Galvin, M and Hardiman, O}, title = {The EQ-5D-5L in amyotrophic lateral sclerosis: an international longitudinal exploration as part of ALS-CarE.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2715921}, pmid = {42592867}, issn = {2167-9223}, abstract = {BACKGROUND: The EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) is widely used in health outcomes research, but its longitudinal performance in amyotrophic lateral sclerosis (ALS), particularly across international cohorts, remains poorly characterized. This study examined whether the EQ-5D-5L captures clinically meaningful change over time in ALS and how national value sets influence interpretation of that change.<br><br>METHODS: EQ-5D-5L data from 296 patients across six European ALS centers in five countries were analyzed over 18.6&#x2009;months (IQR 17.9-20.8). Baseline and follow-up assessments were compared using the Paretian Classification of Health Change and Health Profile Grids. Country-specific tariffs were applied to identical health-state transitions. Associations between EQ-5D measures and King's stage were assessed.<br><br>RESULTS: Overall health states worsened over time, although mixed change remained common (31.0%-39.0%), reflecting simultaneous improvement and deterioration across dimensions. Pain/discomfort and anxiety/depression were the only domains showing notable improvement at later follow-up. Mean health-state ranks worsened from 619.65 at baseline to 857.20 at follow-up. However, the apparent magnitude of progression differed substantially according to national tariff selection, with pooled mean utility change ranging from -0.081 under the Dutch tariff to -0.112 under the Italian tariff. Both EQ-5D index and visual analog scale scores correlated with progression according to the King's staging system.<br><br>CONCLUSIONS: The EQ-5D-5L captures plausible longitudinal deterioration in ALS, but interpretation is strongly influenced by valuation context. National tariffs may materially alter the apparent size of quality-of-life change in multinational ALS studies.}, }
@article {pmid42593908, year = {2026}, author = {Sanchez-Santos, C and Jimenez-Amor, A and Martinez-Gonzalez, L and Nozal, V and Martin-Morales, R and Aledavood, E and Bausela, D and Merrigan, K and Diaz-Palacios, K and Zhubi, R and Knapp, S and Garcia-Gonzalo, FR and Rodriguez-Cueto, C and Gil, C and de Lago, E and Martinez, A}, title = {Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.}, journal = {Journal of medicinal chemistry}, volume = {69}, number = {15}, pages = {19451-19481}, doi = {10.1021/acs.jmedchem.6c01882}, pmid = {42593908}, issn = {1520-4804}, support = {GA-202205-2023343//Association for Frontotemporal Degeneration/ ; FPU21/01392//Ministerio de Ciencia, Innovaci?n y Universidades/ ; PID2019-105600RB-I00//Ministerio de Ciencia, Innovaci?n y Universidades/ ; PID2023-149472NB-I00//Ministerio de Ciencia, Innovaci?n y Universidades/ ; CB06/05/0089//Instituto de Salud Carlos III/ ; CB06/07/1029//Instituto de Salud Carlos III/ ; CB18/05/00040//Instituto de Salud Carlos III/ ; 1097737//Structural Genomics Consortium/ ; }, mesh = {Animals ; *Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; Humans ; *Brain/metabolism/drug effects ; Mice ; Disease Models, Animal ; *TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry/pharmacokinetics ; Structure-Activity Relationship ; *Cognitive Dysfunction/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.}, }
@article {pmid42594043, year = {2026}, author = {Nair, T and Larson, T and Raymond, J and Horton, DK and Mehta, P}, title = {Motor Neuron Disease Mortality in the United States, 2010-2023: A demographic, geographic, and temporal analysis.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-24}, doi = {10.1159/000551599}, pmid = {42594043}, issn = {1423-0208}, abstract = {INTRODUCTION: Our objective was to calculate age-adjusted motor-neuron disease (MND) mortality rates in the United States, 2010-2023, by year, age, sex, race, origin, period, and state. Amyotrophic lateral sclerosis makes up almost 80% of all MNDs.<br><br>METHODS: Multiple cause mortality data was obtained from the National Center for Health Statistics (NCHS) for years 2010-2023. Cases were included if code G12.2, the code for MND listed in the International Classification of Disease, 10th Revision (ICD-10), was listed as a cause of death. Using the direct method, cases were age-adjusted to the 2000 U.S. Standard population and mortality rates were calculated.<br><br>RESULTS: The overall national MND associated mortality rate was 2.07 per 100,000 population (95% CI 2.06, 2.09). Rates were highest in those aged 80+ years (13.69, 95% CI 13.49, 13.89) at death, non-Hispanic (2.17, 95% CI 2.15, 2.18), and male (2.50, 95% CI 2.48, 2.52). Northern states had higher rates (2.26, 95% CI 2.23, 2.29) with a rate ratio of (1.05, (95% CI 1.04, 1.07) when compared to the middle state tier (2.14, 95% CI 2.12, 2.17, p<0.01). State rates ranged from 3.07 (95% CI 2.75, 3.42) in Vermont to 1.41 (95% CI 1.27, 1.57) in Hawaii. The average annual percentage change was -1.62, corresponding to a statistically significant negative trend.<br><br>CONCLUSION: MND associated mortality rates were higher among northern states, decedents who were male, White, or non-Hispanic, which is consistent with previous studies of U.S. MND mortality. Decreasing mortality rates may indicate longer patient life spans due to increased treatment options and care access, but further research is needed.}, }
@article {pmid42594177, year = {2026}, author = {Parisien, R}, title = {Epistemic Asymmetry Between Abstracts and Discussion Sections in the Orthopaedic Literature: A Corpus Analysis of 201 Publications.}, journal = {The Journal of bone and joint surgery. American volume}, volume = {}, number = {}, pages = {}, doi = {10.2106/JBJS.26.00433}, pmid = {42594177}, issn = {1535-1386}, abstract = {BACKGROUND: Abstracts and Discussion sections serve distinct functions: Abstracts are optimized for brevity and impact, while Discussion sections contain authors' most explicit engagement with uncertainty and the scope of inference. Whether these sections differ systematically in epistemic stance-the level of confidence or uncertainty with which findings are stated and qualified-has not been formally examined in the orthopaedic literature.<br><br>METHODS: All original research articles published in The Journal of Bone and Joint Surgery (JBJS) and Clinical Orthopaedics and Related Research (CORR) during the first half of 2025 were included (total, n = 201; JBJS, n = 153; CORR, n = 48). Editorials, reviews, letters, and case reports were excluded. The densities of hedges (markers of uncertainty and qualification) and boosters (markers of confidence and certainty) were measured per 1,000 words using an automated 233-item lexicon. The epistemic shift index (ESI) quantified the net difference in epistemic stance between sections, with a positive value indicating greater caution in the Discussion. Abstract limitation surfacing (ALS) indicated explicit acknowledgment of limitations in the Abstract.<br><br>RESULTS: Discussion sections contained 2.8 times the hedge density of Abstracts, and the ESI was positive in 176 (87.6%) of the 201 articles. The mean ESI was 7.8 (95% confidence interval, 6.9 to 8.8; t[200] = 16.39, p < 0.001; Cohen d = 1.15). Discussions carried more than double the hedge-to-booster ratio of Abstracts (3.58 versus 1.69, p < 0.001). The asymmetry did not differ by open-access status (p = 0.807) or journal (p = 0.142) but varied significantly by study design (Kruskal-Wallis p = 0.034), with the largest asymmetry in diagnostic studies and randomized controlled trials. Only 12 (6.0%) of 201 Abstracts acknowledged study limitations.<br><br>CONCLUSIONS: The Discussion sections of the orthopaedic research articles were substantially more epistemically cautious than their Abstracts across journals and access models. In most articles, the Abstract presented findings without caveat, with corresponding limitations appearing only in the Discussion. A limitation of this analysis is that epistemic stance was measured at the word and phrase level only. These findings have implications for clinical decision-making and for artificial intelligence systems trained on freely accessible Abstract text.}, }
@article {pmid42594365, year = {2026}, author = {Berry-Kilgour, N and Wiseman, R and Grundy, K}, title = {Prescribing and monitoring of riluzole in amyotrophic lateral sclerosis: a retrospective cohort study from Health New Zealand - Te Whatu Ora Waitaha Canterbury.}, journal = {The New Zealand medical journal}, volume = {139}, number = {1640}, pages = {23-30}, doi = {10.26635/6965.7367}, pmid = {42594365}, issn = {1175-8716}, mesh = {Humans ; Retrospective Studies ; *Riluzole/therapeutic use/adverse effects ; New Zealand ; *Amyotrophic Lateral Sclerosis/drug therapy ; Female ; Male ; Middle Aged ; Aged ; *Guideline Adherence/statistics &amp; numerical data ; *Drug Monitoring ; *Neuroprotective Agents/therapeutic use/adverse effects ; Practice Guidelines as Topic ; *Practice Patterns, Physicians'/statistics &amp; numerical data ; Spirometry ; Adult ; }, abstract = {AIM: This retrospective cohort study assessed adherence to the Motor Neurone Disease New Zealand best practice guidelines and Pharmac Special Authority criteria for riluzole in a Canterbury-based amyotrophic lateral sclerosis (ALS) cohort. Secondary objectives included reasons for not prescribing, side effects and treatment initiation relative to diagnosis.<br><br>METHOD: A retrospective cohort study was conducted using the Christchurch Hospital respiratory department's ALS database. Patients diagnosed between January 2020 and November 2024 were included. Electronic health records and Special Authority records were reviewed. Patients with incomplete data or non-motor neurone disease (MND) diagnoses were excluded.<br><br>RESULTS: Of 115 patients, 69 (60%) were prescribed riluzole. Less than 45% of patients had baseline blood tests, and pre-treatment spirometry was completed in 70% of patients. Delays in prescribing improved rates of baseline spirometry, but not blood test completion. Ongoing monitoring was poor, with less than 60% of patients completing recommended tests across all time points. Eight patients (11.6%) reported side effects, and three discontinued treatment following alanine aminotransferase derangement.<br><br>CONCLUSION: Adherence to recommended monitoring and Special Authority criteria for riluzole was inconsistent in this cohort. In the context of emerging evidence supporting broader survival benefit and reduced drug cost, further evaluation of current Special Authority prescribing criteria may be warranted.}, }
@article {pmid42594388, year = {2026}, author = {Griffin, AC and Zulman, DM}, title = {Digital Decisions: Enhancing Chronic Disease Self-Care Through Digital Health and AI-Enhanced Decision-Making.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e106648}, doi = {10.2196/106648}, pmid = {42594388}, issn = {1438-8871}, mesh = {Humans ; *Self Care ; Chronic Disease/therapy ; Digital Health ; *Decision Making ; *Artificial Intelligence ; Telemedicine ; }, abstract = {Advances in digital health have dramatically changed how patients engage with their health. Rather than relying solely on periodic clinical visits, patients now have access to smartphones, patient portals, wearable devices, and mobile apps that provide support for day-to-day self-care decisions. This commentary discusses the findings of Longhini et al's systematic review and meta-analysis on the effectiveness of digital health interventions, which found modest improvements in self-care monitoring but limited effects on self-care maintenance and management behaviors. Reflecting on these findings through the lens of dual-process theory, digital health technologies appear to be effective at supporting fast, intuitive processes, such as symptom monitoring, but are less effective at engaging slower, deliberative processes needed for complex decision-making and behavior change. Digital health technologies should evolve from primarily supporting routine self-care activities to enhancing patients' reflective decision-making processes for sustained behavior change. Emerging AI capabilities offer opportunities to strengthen and bridge these fast and slow cognitive processes by translating complex health information into actionable insights and facilitating patient-clinician communication. Realizing this potential requires careful attention to implementation, including integration into clinical workflows, patient and clinician education, and digital literacy. In addition, digital health teams should adopt standardized implementation frameworks and outcome measures to generate a more robust evidence base. Lastly, human-centered design, patient engagement, and safeguards addressing bias, privacy, and transparency are foundational to ensure that the rapid pace of digital health technology will continue to enhance patient self-care and health outcomes.}, }
@article {pmid42581415, year = {2026}, author = {Goehring, K and Abler, E and Vavra, J and Mayer, K and Dorst, J and Elmas, Z and Wiesenfarth, M and Richter, L and Petri, S and Regensburger, M and Reilich, P and Bjelica, B and Lumi, R and Süß, P and Tumani, H and Otto, M and Weishaupt, JH and Ludolph, AC and Oeckl, P}, title = {Blood SOD1 Activity in ALS Patients Receiving Tofersen Treatment.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78328}, pmid = {42581415}, issn = {1531-8249}, abstract = {OBJECTIVE: The antisense oligonucleotide tofersen is the first disease-modifying drug for SOD1-related amyotrophic lateral sclerosis (ALS) and was approved because of its ability to reduce SOD1 protein and neurofilament levels. The effect of tofersen on SOD1 activity is unclear but of clinical relevance because homozygous SOD1 mutations, linked to reduced SOD1 activity, cause severe motor neuron impairment and tofersen-induced reduction could be deleterious. Therefore, monitoring of SOD1 activity is urgently needed.<br><br>METHODS: SOD1 activity was analyzed in blood samples from a discovery (n&#x2009;=&#x2009;120) and a validation cohort (n&#x2009;=&#x2009;208), including controls, patients with sporadic ALS (sALS), C9orf72 mutation carriers (c9ALS), asymptomatic (SOD1-asym), and symptomatic SOD1 mutation carriers (SOD1-ALS). SOD1 activity was characterized in 18 patients receiving tofersen treatment.<br><br>RESULTS: SOD1 activity was significantly lower in both SOD1-asym (median&#x2009;=&#x2009;7.5&#x2009;U/mg, interquartile range [IQR]&#x2009;=&#x2009;7.0-9.0&#x2009;U/mg) and SOD1-ALS (median&#x2009;=&#x2009;7.9&#x2009;U/mg, IQR&#x2009;=&#x2009;7.1-9.1&#x2009;U/mg) relative to controls (median&#x2009;= 9.2&#x2009;U/mg, IQR&#x2009;=&#x2009;8.9-10.0&#x2009;U/mg, p&#x2009;<&#x2009;0.0001), c9ALS (median&#x2009;=&#x2009;9.4&#x2009;U/mg, IQR&#x2009;=&#x2009;8.9-10.2&#x2009;U/mg, p&#x2009;<&#x2009;0.0001) and sALS (median 9.5&#x2009;U/mg, IQR 8.8-9.9&#x2009;U/mg, p&#x2009;<&#x2009;0.0001). SOD1 activity was significantly lower in individuals with deleterious SOD1 variants than in individuals with neutral variants. During tofersen treatment, neurofilament and SOD1 protein levels decreased, whereas SOD1 activity remained stable.<br><br>INTERPRETATION: The data indicate that the positive tofersen treatment effect is independent of SOD1 activity. Lower SOD1 activity is specific to SOD1-ALS, already present in the asymptomatic phase and depends on the mutation type. Future studies should determine whether tofersen treatment affects cerebrospinal fluid (CSF) SOD1 activity. ANN NEUROL 2026.}, }
@article {pmid42581651, year = {2026}, author = {Vinceti, M and Till, C and Goodman, PJ and Filippini, T and Rothman, KJ and Thompson, IM}, title = {The selenium and vitamin E cancer prevention trial (SELECT): a secondary, post-intervention analysis on potential excess chronic disease incidence induced by selenium administration.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag189}, pmid = {42581651}, issn = {1476-6256}, abstract = {The potential for trace amounts of selenium supplements to prevent prostate cancer and other neoplasms was studied in SELECT, a randomized trial conducted in North America for 7-12 years. 34 887 eligible men age 55 or older were assigned to take either 200 μg selenium from L-selenomethionine, 400 IU vitamin E, both selenium and vitamin E, or placebo. The trial was stopped for futility and concerns about adverse effects. Subsequently, we used incidence and mortality data from Medicare through 2019 and the National Death Index through 2024 to investigate the extent to which selenium administration was associated with increased long-term risk of cancer and neurodegenerative disease, during 341 697 person-years of follow-up. Lung cancer showed little increased risk. Associations were near null for leukemia, non-Hodgkin lymphoma and Parkinson's disease, and there was a lower risk for melanoma and colorectal cancer. In contrast, we found a higher risk for Hodgkin lymphoma, multiple myeloma and amyotrophic lateral sclerosis, which has been associated with selenium overexposure in some nonexperimental studies. Though these latter associations were based on few cases, they were consistent with findings from a range of other studies, possibly indicating long-term adverse effects of this organic selenium compound. (Registration no. NCT00006392).}, }
@article {pmid42583074, year = {2026}, author = {Glynne-Jones, R and Mawdsley, S}, title = {The historical perspective on anal cancer therapy: what have we learnt, where did we fail?.}, journal = {ESMO gastrointestinal oncology}, volume = {13}, number = {Pt A}, pages = {100151}, pmid = {42583074}, issn = {2949-8198}, abstract = {Squamous-cell cancer of the anus is a rare entity. Fifty years ago, understanding the natural history was limited by the lack of an agreed staging system and a largely irrelevant but complex histological categorisation. Retrospective reports described a small number of patients, generally with small tumours, treated by diverse methods with limited follow-up. The use of therapeutic radiation was limited by observed acute toxicity. Some centres gained substantial experience with interstitial radiation, but knowledge and expertise regarding the natural history and optimal methods of treatment were difficult to accumulate and hand on. Radiotherapy (RT) with or without interstitial radiation as the primary treatment, chemoradiotherapy (CRT) both definitive and preoperative, local excision for residual after CRT and small margin carcinomas and 'prophylactic' groin dissections after radical surgery all had advocates in different centres. The dogma in Europe at the time favoured split-course treatments. Early experiments combining fluoropyrimidines and RT were refined with Nigro et al.'s landmark study in 1974. Subsequent regimens are variations and today CRT with concurrent fluoropyrimidines and mitomycin C is accepted as the standard primary treatment. Early randomised phase III trials proved CRT to be more effective than external beam RT alone, but uncertainty remained over the optimal integration of chemotherapy, the type of chemotherapy, the ideal RT doses and potential late effects. These questions were imperfectly addressed and led to subsequent pragmatic phase III trials testing the impact of induction and consolidation chemotherapy and dose escalation. We describe the historical perspective and examine the opportunities we failed to grasp.}, }
@article {pmid42583247, year = {2026}, author = {Klyk, C and Wohnrade, C and Petri, S and Haghikia, A and Körner, S and Volk, LH}, title = {Gold coast criteria but not neurofilaments improve diagnostic sensitivity in a specialized ALS university center.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {512-521}, pmid = {42583247}, issn = {2467-981X}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by upper and lower motor neuron loss. Diagnosing ALS may still be challenging due to the absence of specific biomarkers and requires thorough clinical evaluation, comprehensive electromyography (EMG), and exclusion of differential diagnoses by laboratory analyses and imaging. The Gold Coast criteria (GCC) replaced the revised El Escorial (rEEC) and Awaji criteria (AC), simplifying ALS diagnosis and standardizing communication with patients.<br><br>METHODS: This retrospective study compared the sensitivity of the GCC with the rEEC and AC in a specialized neuromuscular center.<br><br>RESULTS: 431 patients with suspected ALS were included, and 426 patients ultimately received an ALS diagnosis. The GCC showed higher sensitivity than both the rEEC and AC. The explorative inclusion of neurofilament levels into an extended diagnostic framework did not increase the sensitivity of rEEC and AC.<br><br>CONCLUSIONS: Continued clinical use of the GCC should be considered the standard for ALS diagnosis. Careful clinical and electrophysiological examination is particularly essential in this context, supplemented by biomarkers such as neurofilaments.<br><br>SIGNIFICANCE: This retrospective real-world study demonstrates a high sensitivity of the GCC in a specialized neuromuscular clinic.}, }
@article {pmid42583548, year = {2026}, author = {Suazo, JRP and Piuvezam, G and Pimenta, IDSF and Ferrándiz, LL and Ríos, MP and Castro-Delgado, R}, title = {Effectiveness of extended reality-based cardiopulmonary resuscitation training for healthcare students: A systematic review.}, journal = {Turkish journal of emergency medicine}, volume = {26}, number = {3}, pages = {223-233}, pmid = {42583548}, issn = {2452-2473}, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) is a lifesaving intervention where timely, effective actions improve survival. However, traditional Basic and Advanced Life Support (BLS and ALS) training often lacks realism, limiting preparedness among healthcare students. Extended Reality (XR) technologies, including Virtual, Augmented, and Mixed Reality, offer promising tools to enhance CPR training. The aim is to assess the effects of XR on CPR training outcomes among healthcare students.<br><br>METHODOLOGY: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines, PubMed/MEDLINE, EMBASE, CINAHL, Cochrane, Web of Science, and Scopus were searched for randomized controlled trials and quasi-experimental studies. Two reviewers independently extracted data, with disagreements resolved by a third. Risk of bias was evaluated using Cochrane ROB 2 and ROBINS-I. Due to heterogeneity, findings were synthesized narratively.<br><br>RESULTS: Eight studies from six countries were included. Evidence showed mixed outcomes: XR improved confidence and reduced anxiety in Basic Life Support and ALS training, but results on technical performance, including CPR knowledge and quality, were inconsistent. Variability in study design and concerns about bias limited generalizability.<br><br>CONCLUSION: XR shows potential as a valuable complement to traditional CPR training, particularly in blended learning approaches aligned with modern pedagogy. However, inconsistent findings highlight the need for standardized assessments, evaluation of long-term outcomes, and integration of haptic torso simulators to improve technical skills and clarify XR's role in resuscitation education.}, }
@article {pmid42584174, year = {2026}, author = {Wang, BN and Van Der Spek, RAA and Van Nispen Tot Sevenaer, JDAM and Van Vugt, JJFA and Munnik, FA and Bakker, MK and ,  and Van Es, MA and Van Den Berg, LH and Van Rheenen, W and Veldink, JH}, title = {Lessons from a systematic review of family-based studies in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2713969}, pmid = {42584174}, issn = {2167-9223}, abstract = {ALS is genetically heterogeneous, with many causal genes identified through family-based gene-discovery studies. To evaluate this progress, we systematically reviewed these studies and identified unresolved genomic regions across five pedigrees. Reexamination resolved two pedigrees, nominating FUS and SYNE1 as the causal genes. The remaining three pedigrees exhibited linkage to four unresolved regions, which we reanalyzed using large-scale genetic datasets. We found no convincing evidence for new ALS-causing variants in these regions. These unresolved regions originated from complex pedigrees-consanguineous, isolated, or containing only a few affected individuals-whereas successful linkage was observed in larger, multigenerational families with ALS. Our findings confirm that family-based methods are robust in typical ALS pedigrees but lack power in small pedigrees with few affected individuals or in phenotypically heterogeneous families. Given these challenges and the rare-variant architecture of ALS, we propose a 'super-pedigree' framework to identify extended families with ALS to discover shared genetic risk factors and help develop gene-based therapies.}, }
@article {pmid42585674, year = {2026}, author = {Godage, P and Giggins, OM and Doyle, J and Byrne, A}, title = {Integrating psychological support into gestational diabetes self-management: Development of a user-centred digital mindfulness programme.}, journal = {Women's health (London, England)}, volume = {22}, number = {}, pages = {17455057261473448}, doi = {10.1177/17455057261473448}, pmid = {42585674}, issn = {1745-5065}, mesh = {Humans ; *Mindfulness/methods ; Female ; *Diabetes, Gestational/psychology/therapy ; Pregnancy ; *Self-Management/methods/psychology ; Adult ; Qualitative Research ; Focus Groups ; Digital Media ; Stress, Psychological ; Needs Assessment ; User-Centered Design ; Digital Health ; Social Support ; }, abstract = {BackgroundGestational diabetes mellitus (GDM) presents significant psychological and behavioural challenges, with diagnosis often triggering stress, anxiety, and fear. Despite these burdens, structured psychosocial support remains limited within existing GDM care. Mindfulness-based interventions (MBIs) show promise for reducing distress in perinatal contexts, but few are tailored to the unique needs of individuals with GDM, and digital delivery remains rare.ObjectivesThis study aimed to develop a digitally delivered mindfulness programme tailored to the psychological needs of individuals with GDM using a user-centred, multi-phase design approach.DesignA qualitative, multi-phase participatory design study involving needs assessment and co-design workshops, guided by the Obesity-Related Behavioural Intervention Trials (ORBIT) model for behavioural intervention development and Loucks et al.'s evidence-based adaptation framework for Mindfulness-Based Programmes (MBPs).MethodsA qualitative needs assessment was conducted through focus groups with individuals with GDM (n=11) and healthcare professionals (n=4) to identify psychological experiences, mental health support, and the feasibility of a digital mindfulness intervention. Findings informed the initial mindfulness programme framework, which was further refined through participatory co-design workshops (n=10) and iterative tailoring of scripts and multimedia content.ResultsParticipants reported high levels of emotional distress following GDM diagnosis, citing a strong desire for brief, flexible, and supportive psychosocial interventions. Co-design feedback highlighted preferences for short audio-guided sessions, soft and calming voice characteristics, and seamless integration into daily routines. The final one-month programme comprised 20 mindfulness exercises, delivered via audio and video for integration within a holistic GDM self-management app.ConclusionA systematically developed, contextually relevant digital mindfulness programme may address critical gaps in GDM care, supporting psychological well-being and self-management.}, }
@article {pmid42585850, year = {2026}, author = {Alencar, MA and Gonçalves, JMW and D Allembert, D and Rangel, MFA and Gomes, PCF and de Souza, LC}, title = {Falls in people with amyotrophic lateral sclerosis: A prospective study.}, journal = {Brazilian journal of physical therapy}, volume = {30}, number = {5}, pages = {101623}, doi = {10.1016/j.bjpt.2026.101623}, pmid = {42585850}, issn = {1809-9246}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Falls are common and may lead to dependence, reduced quality of life, higher healthcare costs, and death. Few studies have examined falls in ALS.<br><br>OBJECTIVES: To investigate the frequency of falls in individuals with ALS with and without functional ambulation, and to identify predictors of falls at three and six months among those with functional ambulation.<br><br>METHODS: A longitudinal prospective study included 66 individuals with ALS. Falls were assessed through interviews at three- and six-month follow-ups. Demographic and clinical characteristics, functional capacity, lower limb strength, fatigue, mobility, and balance were assessed. Descriptive, bivariate, and logistic regression analyses were performed.<br><br>RESULTS: At baseline, 42 participants were ambulatory and 24 non ambulatory (wheelchair-dependent). Among ambulatory participants, 38 were assessed at three months (18 fallers, 47%) and 37 at six months (22 fallers, 59%). Among non-ambulatory participants, 22 were assessed at three months (4 fallers, 18%) and 20 at six months (2 fallers, 10%). Losses in both groups were due to death. Predictors of falls in the ambulatory group were lower limb strength (Odds Ratio [OR]: 0.844; p = 0.016) and fatigue (OR: 7.800; p = 0.037) at three months, and lower limb strength (OR: 0.856; p = 0.009) at six months.<br><br>CONCLUSION: Falls can occur across functional profiles in ALS and are most frequent among ambulatory individuals. These findings highlight the importance of assessing fall risk and considering strategies. In ambulatory participants, interventions focusing on lower limb strength and fatigue may contribute to fall prevention.}, }
@article {pmid42586199, year = {2026}, author = {Pecorari, C and Montagna, C and Cozzolino, M and D'Ambrosi, N and Benassi, B and Cirotti, C and Filomeni, G}, title = {Nuclear SOD1 links ATM-CHK2 signaling to ADH5/GSNOR transcription in SHSY-5Y SOD1[G93A] cellular models of ALS.}, journal = {Nitric oxide : biology and chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.niox.2026.08.001}, pmid = {42586199}, issn = {1089-8611}, abstract = {The activity of S-nitrosoglutathione reductase (ADH5/GSNOR) has been proposed being essential to limit oxidative stress and preserve mitochondrial quality control. Here we identify a redox-dependent ATM-CHK2-SOD1 signaling axis that drives ADH5/GSNOR transcription in SH-SY5Y cells expressing the ALS-associated SOD1[G93A] mutant. ATM-CHK2 activation promotes the interaction of SOD1 with CHK2, leading to SOD1 nuclear translocation and binding to the ADH5 promoter. Pharmacological inhibition of ATM or CHK2 abolishes these effects. ADH5/GSNOR overexpression protects cells from SOD1[G93A]-induced toxicity suggesting that the modulation of GSNOR activity may represent a potential strategy to restore redox homeostasis in ALS.}, }
@article {pmid42586267, year = {2026}, author = {Tognaccini, C and Thomas, LE and Ghanim, D and Ghebrial, M and Ansari, Z and Gupta, K and Wu, JJ}, title = {Comment on Chen et al.'s "Disparities of itch severity in outpatient clinics as measured by the ItchyQuant".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.07.127}, pmid = {42586267}, issn = {1097-6787}, }
@article {pmid42586268, year = {2026}, author = {Ghanim, D and Ghebrial, M and Tognaccini, C and Thomas, LE and Ansari, Z and Gupta, K and Wu, JJ}, title = {Comment on Gao et al.'s "A Multicenter, Randomized, Double-blinded, Placebo-Controlled Phase III Trial to Evaluate Efficacy and Safety of Picankibart in Moderate-to-Severe Plaque Psoriasis".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.06.151}, pmid = {42586268}, issn = {1097-6787}, }
@article {pmid42586271, year = {2026}, author = {Rundle, CW and Lukowiak, TM and Maher, IA}, title = {Response to Wang et al.'s: Cartilage grafts for alar reconstruction in nasolabial interpolation flap surgery may negatively affect breathing function and cosmesis: A retrospective study.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.07.126}, pmid = {42586271}, issn = {1097-6787}, }
@article {pmid42586272, year = {2026}, author = {Chen, RF and Chen, SC}, title = {Response to Tognaccini et al., "Comment on Chen et al.'s 'Disparities of itch severity in outpatient clinics as measured by the ItchyQuant'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.022}, pmid = {42586272}, issn = {1097-6787}, }
@article {pmid42586274, year = {2026}, author = {Shi, Y}, title = {Response to the letter by Ghanim et al, "Comment on Gao et al.'s 'A Multicenter, Randomized, Double-blinded, Placebo-Controlled Phase III Trial to Evaluate Efficacy and Safety of Picankibart in Moderate-to-Severe Plaque Psoriasis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.08.025}, pmid = {42586274}, issn = {1097-6787}, }
@article {pmid42586324, year = {2026}, author = {Palumbo, F and Iazzolino, B and Canosa, A and Manera, U and Vasta, R and Grassano, M and Ilardi, A and Cabras, S and Matteoni, E and Maccabeo, A and Pede, FD and De Mattei, F and Pellegrino, G and Minerva, E and Riva-Rovedda, F and Clari, M and Zocco, G and Pascariu, D and Testa, M and Arcari, M and Veronese, S and Chiò, A and Moglia, C and Calvo, A}, title = {Advance Care Planning in Amyotrophic Lateral Sclerosis: a retrospective population-based study.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.08.002}, pmid = {42586324}, issn = {1873-6513}, abstract = {BACKGROUND: . In recent decades, autonomy and self-determination in Amyotrophic Lateral Sclerosis (ALS), have gained increasing attention, and Advance Care Planning (ACP) has been incorporated into ALS guidelines. In Italy, Law 219 emphasizes the role of ACP in respecting patients' healthcare preferences. However, longitudinal data on ACP prevalence and impact remain limited.<br><br>AIM: . To assess the prevalence of ACP discussions in a population of ALS patients, their effectiveness in end-of-life management, and the impact of Law 219/2017.<br><br>METHODS: . Demographic and clinical data from the PARALS Register (2008-2020) were retrospectively examined, with particular focus on ACP discussions, tracheostomy preferences, and end-of-life outcomes.<br><br>RESULTS: . Of 1219 ALS patients, 655 (53.7%) had ACP discussions, with 90.8% concordance between expressed choices and outcomes. The ACP prevalence increased over time from 51.6% to 61.94% (p&#x202f;=&#x202f;0.025). Cognitive impairment, including fronto-temporal dementia and intermediate cognitive-behavioural impairment, and absence of NIMV use were negatively associated with ACP (p&#x202f;=&#x202f;0.029 and p < 0.001). Older age was associated with tracheostomy placement (p < 0.001). ACP discussion was positively associated with gastrostomy placement, Palliative Care activation, and home death.<br><br>CONCLUSIONS: . ACP plays a crucial role in ALS care, with high alignment between expressed choices and outcomes. Cognitive impairment reduced ACP participation, highlighting the need for earlier, tailored interventions. The ACP increase over the last decade reflects a growing emphasis on patient autonomy in Italy. Further efforts are needed to expand ACP adoption in ALS care, to support self-determination despite cognitive decline and disease progression.}, }
@article {pmid42586601, year = {2026}, author = {Chai, X and Zheng, Z and Wang, N and He, Q and Jia, Y and Wan, K and Zhu, S and Zhang, B and Niu, H and Zhai, Y and Zhao, J and Yang, Y}, title = {Real-world clinical characteristics of motor disorders for personalised brain-computer interfaces: phenotypic insights from a specialised clinic.}, journal = {Stroke and vascular neurology}, volume = {}, number = {}, pages = {}, doi = {10.1136/svn-2026-005290}, pmid = {42586601}, issn = {2059-8696}, abstract = {Motor dysfunction caused by neurological disorders such as stroke, spinal cord injury and amyotrophic lateral sclerosis has become a major global public health issue. Conventional rehabilitation approaches yield limited efficacy, highlighting the urgent need for innovative therapies. Brain-computer interface (BCI) technology offers a promising avenue for motor function restoration by decoding motor intentions and driving external devices or providing sensory feedback. However, current BCI development has predominantly emphasised technical performance metrics, lacking systematic investigation into the clinical characteristics of real-world patient populations. This disconnect between technological advancement and genuine clinical demands persists because existing studies often recruit idealised subjects while neglecting prevalent conditions like stroke and lack standardised assessments of clinically meaningful outcomes. Consequently, system designs frequently fail to align with patient-specific profiles. To address this gap, our study established a prospective BCI evaluation outpatient cohort, comprehensively collecting data from patients presenting with motor dysfunction throughout 2025. Among the total of 1641 patients with motor dysfunction, the majority were patients with chronic-phase stroke (1087, 66.24%). The cohort was primarily middle-aged, with a mean age of 45.93±11.23 years. The study further detailed patterns of muscle strength, joint range of motion and sensory impairments. The goal is to construct the first clinical profile characteristics to inform precise patient selection and guide personalised system design.}, }
@article {pmid42586726, year = {2026}, author = {Quasdorf, T and Brenner, S and Kramer, I and Kotkowski, K and Gutenberg, J}, title = {Developing organisational capacity building for person-centred dementia care in nursing homes: a multiphase co-design study protocol.}, journal = {BMJ open}, volume = {16}, number = {8}, pages = {e123820}, doi = {10.1136/bmjopen-2026-123820}, pmid = {42586726}, issn = {2044-6055}, mesh = {*Nursing Homes/organization &amp; administration ; Humans ; *Patient-Centered Care/organization &amp; administration ; *Dementia/therapy ; *Capacity Building/organization &amp; administration ; Research Design ; Organizational Culture ; Qualitative Research ; }, abstract = {INTRODUCTION: Person-centred dementia care (PCdC) is widely recognised as a core principle of high-quality dementia care and is embedded in national and international dementia care guidelines. However, translating PCdC into routine practice in nursing homes (NHs) continues to pose a significant challenge. This reflects both the theoretical complexity of PCdC and the fact that its delivery relies less on discrete care techniques and more on an underlying organisational culture and shared approach to care. Implementing PCdC therefore requires an organisational perspective that acknowledges the interplay between staff, leadership and organisational conditions. Although several approaches exist to strengthen organisational capacity for PCdC, NHs often lack guidance on how to identify and apply approaches that fit their specific context. This study aims to develop a toolbox that supports NHs in systematically building the organisational capacity required to implement and sustain PCdC in their specific context.<br><br>METHODS AND ANALYSIS: The toolbox will be developed through three consecutive studies:Study 1: An exploratory qualitative study of the perspectives of managers and staff in NHs on organisational capacity building (OCB) for implementing and sustaining PCdC.Study 2: A co-design study involving workshops to develop a first version of the OCB toolbox, informed by insights from a preliminary scoping review (conducted separately and published as a protocol on Open Science Framework) and Study 1.Study 3: A qualitative consensus-building study using a nominal group technique with stakeholders and PCdC experts to refine and finalise the OCB toolbox (validation phase).The toolbox development is conceptualised as the development of a complex intervention and will therefore be informed by O'Cathain et al's guidance for developing complex health interventions. While co-design principles guide the overall development process, Study 2 represents the dedicated co-design phase involving collaborative workshops, ensuring that the resulting OCB toolbox integrates research evidence with practice-based insights.<br><br>ETHICS AND DISSEMINATION: The Cantonal Ethics Committee Zurich confirmed that the study is exempt from formal ethical approval under the Swiss Human Research Act (Req-2025-00812). Findings will be disseminated through peer-reviewed publications, conference presentations and practice-oriented outputs, including a toolbox for NHs.}, }
@article {pmid42586744, year = {2026}, author = {Shijo, T and Suzuki, N and Warita, H and Ikeda, K and Namioka, Y and Kato, M and Aoki, M}, title = {Emergency Tracheostomy with Invasive Ventilation in Patients with Amyotrophic Lateral Sclerosis Increases Hospitalization Duration and Long-Term Complications.}, journal = {The Tohoku journal of experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1620/tjem.2026.J085}, pmid = {42586744}, issn = {1349-3329}, }
@article {pmid42587315, year = {2026}, author = {Farghaly, A and Al-Khateeb, LA and Kanaan, BM and Magdy, G and Khashoqji, MM and Tantawy, MA and Abbas, AEF}, title = {Spectrophotometric determination of cefepime and enmetazobactam in pharmaceutical formulations and human plasma using chemometric modeling, metaheuristic wavelength selection, and comprehensive sustainability assessment.}, journal = {BMC chemistry}, volume = {20}, number = {1}, pages = {}, pmid = {42587315}, issn = {2661-801X}, support = {R-2026-XX//Deanship of Postgraduate Studies and Scientific Research, Majma'ah University/ ; }, abstract = {The recently introduced cefepime-enmetazobactam (CEF-ENM) combination requires reliable analytical methods for pharmaceutical quality control and proof-of-concept bioanalytical evaluation. Existing methods are predominantly chromatographic and rely on large volumes of organic solvents, costly instrumentation, and high energy consumption. In this work, a UV spectrophotometric approach integrated with chemometric analysis was established for the simultaneous quantification of CEF and ENM in pharmaceutical formulations and processed post-extraction-fortified human plasma. Calibration samples were prepared according to the Brereton multilevel experimental design, whereas an independent external validation set was constructed using the Maximin Distance Design (MMD) algorithm. The analytical performance of six chemometric models (CLS, PCR, PLS, GA-PLS, FA-PLS, and MCR-ALS) was evaluated to resolve the severe spectral overlap between both analytes. Matrix-specific calibration models were developed for processed plasma samples. The developed models showed excellent analytical performance, with MCR-ALS providing the highest predictive accuracy and robustness. Sustainability was comparatively evaluated using the integrated Multi-color Assessment (MA) Tool together with complementary greenness metrics. The proposed method demonstrated superior overall sustainability compared with previously reported chromatographic methods while maintaining reliable quantitative performance. The proposed approach offers a rapid, cost-effective, and environmentally sustainable alternative for routine pharmaceutical quality control and proof-of-concept evaluation in processed post-extraction-fortified human plasma. Further comprehensive bioanalytical validation is warranted to support routine clinical application.}, }
@article {pmid42587774, year = {2026}, author = {Garza, TN and Abisambra, JF}, title = {The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.}, journal = {Cells}, volume = {15}, number = {15}, pages = {}, doi = {10.3390/cells15151365}, pmid = {42587774}, issn = {2073-4409}, support = {5T32AG061892-07/AG/NIA NIH HHS/United States ; 1R01AG075900-04/NH/NIH HHS/United States ; 1R01AG074584-05/NH/NIH HHS/United States ; 1R21AG093972-01/NH/NIH HHS/United States ; 5I50RX003000-07//United States Department of Veterans Affairs/ ; }, mesh = {Humans ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Stress Granules/metabolism ; *RNA/metabolism ; Animals ; RNA-Binding Proteins/metabolism ; }, abstract = {The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.}, }
@article {pmid42588274, year = {2026}, author = {Paynter, C and Mathers, S and Vogel, A and Cruice, M}, title = {Foregrounding Communication Access in Person-Centred Decision Making for People with Motor Neurone Disease: A Narrative Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {14}, number = {15}, pages = {}, doi = {10.3390/healthcare14152307}, pmid = {42588274}, issn = {2227-9032}, support = {1133541//NHMRC/MNDRA Postgraduate Scholarship/ ; FT220100253//Australian Research Council/ ; }, abstract = {Effective motor neurone disease (MND) management depends on patient and carer involvement in decisions about interventions and future care. Communication and cognitive impairments are common in MND and have under-recognised consequences for shared decision making and autonomy. This narrative conceptual review draws on empirical qualitative research with people living with MND and unpaid family carers and the literature specifically concerning shared decision making and communication in MND. Themes relating to communication, information use, and decision making styles were mapped onto an ALS/MND multidisciplinary decision making model. Enhancements to the model include expanding the decision making context beyond in clinical activity, embedding communication and cognitive skills and accommodations across stages, and acknowledging risks to collaborative decision making. Practical strategies for clinicians, healthcare services, people living with MND, and family carers are proposed to ensure that communication is foregrounded in-person-centred MND care. Observational and implementation research is required to evaluate and refine the proposed approaches.}, }
@article {pmid42588882, year = {2026}, author = {Faburrieta, RA and López Ruiz, BA and Rosas, U and Davis, KJ and Richards, CL and Banta, JA}, title = {Partial Reproducibility and Pleiotropic Epigenetic QTLs in Arabidopsis Recombinant Inbred Lines.}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {15}, pages = {}, doi = {10.3390/plants15152379}, pmid = {42588882}, issn = {2223-7747}, support = {DEB-1419960//U.S. National Science Foundation/ ; IOS-397 1556820//U.S. National Science Foundation/ ; //The University of Texas at Tyler/ ; //Universidad Nacional Aut&#xf3;noma de M&#xe9;xico/ ; //Mexican Academy of Sciences/ ; //Secretar&#xed;a de Ciencia, Humanidades, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; }, abstract = {Unlike conventional genetic polymorphisms, many induced epigenetic polymorphisms can be reset across generations, raising uncertainty about how consistently the same epigenetic loci and associated phenotypic effects can be recovered among independent studies. To address this problem, we designed our study specifically to maximize a lineage-matched, environmentally aligned cross-study comparability with the foundational work of Cortijo et al. by using seeds derived from the same epiRIL generation and grown under broadly similar environmental conditions. We mapped flowering time, as well as five non-flowering traits that had not previously been mapped in this epiRIL population: rosette diameter, basal branch number, lateral branch number, fruit number, and rosette leaf number. We detected significant epiQTLs for all traits except lateral branch number. We also reproduced a facsimile of the original computational pipeline. This design provides an approximate upper bound on expected reproducibility before additional generations of methylation resetting or divergence among seed stocks could substantially influence the results. We recovered two of Cortijo et al.'s previously reported epiQTLs, failed to recover another, and found a different one, with power analyses suggesting that the discrepancies may reflect statistical power. Within overlapping epiQTL intervals across the five traits that had significant intervals, we identified 69 candidate genes exhibiting gene body methylation. Overall, our results reproduced some but not all previous epiQTL signals when comparisons were made using closely matched source material under similar conditions.}, }
@article {pmid42573583, year = {2026}, author = {Yeow, A and Cleland, J and Soh, C and Balete, C}, title = {Sociotechnical Misalignments in Hospital AI System Implementation: Qualitative Case Study.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e87534}, pmid = {42573583}, issn = {1438-8871}, mesh = {Humans ; *Artificial Intelligence ; Qualitative Research ; }, abstract = {BACKGROUND: Implementing AI into real-world health care settings is known to be challenging, particularly regarding how well AI is embedded into the existing knowledge, practices, and procedures of a context. Understanding this process is critical for maximizing the successful implementation of AI tools and planning the time, costs, and resources needed for their successful implementation.<br><br>OBJECTIVE: This study sought to examine the contextual challenges of implementing an AI chatbot, ChatAI (which provided quick access to clinical and operational information without relying on the intranet), in a large tertiary government hospital by analyzing the impact of sociotechnical factors on its sustained use.<br><br>METHODS: We used an instrumental case study approach, utilizing interviews and meeting minutes. A total of 16 semistructured interviews were conducted with the implementation team and hospital staff who interacted with ChatAI. Interviews were audio-recorded and transcribed. Sociotechnical systems (STS) theory, specifically Davis et al's (2014) framework, was adopted to examine ChatAI's implementation and use.<br><br>RESULTS: Multiple misalignments among 5 of Davis et al's sociotechnical elements (goals, people, processes, technology, and infrastructure) limited ChatAI's user adoption and sustainability. Although the hospital's innovation center team attempted to address these initial misalignments, contextual changes such as new regulatory mandates, infrastructure changes, and evolving stakeholder practices introduced further misalignments between ChatAI and the hospital-eventually leading to its discontinuation.<br><br>CONCLUSIONS: This study highlights how sociotechnical misalignments can undermine the use and sustainability of large-scale implementation of AI systems. These findings will inform future efforts to implement AI tools in real-world health care settings, increasing awareness of the need to align sociotechnical dimensions of goals, people, processes, technology, and infrastructure. It highlights the particularly challenging aspect of aligning continually evolving infrastructure with regulatory requirements. Future research should focus on how infrastructure and infrastructure changes, as well as external regulatory requirements, influence AI implementation and use.}, }
@article {pmid42573824, year = {2026}, author = {Su, B and Li, L and Zheng, X and Ma, H and Li, X and Feng, X}, title = {Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42573824}, issn = {1364-6753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Sequestosome-1 Protein/genetics ; Male ; Middle Aged ; Pedigree ; Mutation, Missense ; Genetic Association Studies ; Adaptor Proteins, Signal Transducing/genetics ; }, abstract = {We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords ("amyotrophic lateral sclerosis") OR ("motor neuron disease") AND ("SQSTM1") to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C > T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget's disease.}, }
@article {pmid42573939, year = {2026}, author = {Khadilkar, V and Mondkar, S and Baalaaji, ARM and Bhutada, A and Dhongade, A and Lad, SS and Lad, P and Jain, MK and Patnaik, S and Sarkar, M and Shaikh, F and Sharma, M and Shetty, R and Upadhyay, N and Vohra, R and Wagle-Patki, S and Khadilkar, A and Patki, V and James, EJG and Shah, S and Bansal, A}, title = {A Multicenter Study for Validation of the New Pediatric Advanced Life Support Tape for Indian Children.}, journal = {Indian pediatrics}, volume = {}, number = {}, pages = {}, pmid = {42573939}, issn = {0974-7559}, abstract = {OBJECTIVE: Accurate weight estimation is essential for drug dosing and equipment selection in pediatric emergencies. A new Pediatric Advanced Life Support (ALS) tape was developed using Indian growth references. The present study was performed to validate its performance in critically ill children across multiple centers in India.<br><br>METHODS: A prospective, cross-sectional, multicenter observational study was conducted in 13 pediatric intensive care units (PICUs) across five zones of India in children aged&#x2009;<&#x2009;12&#xa0;years. Recumbent length was measured using the new ALS tape, and color-band-based estimated weight recorded. Weight was measured using a digital scale. The primary outcomes were bias, precision, and accuracy of the tape in predicting weight. Secondary outcomes included correlation between estimated and measured weight, agreement using Bland-Altman analysis, center-wise subgroup analyses, and interrater reliability for color-band assignment.<br><br>RESULTS: Out of 2740 children measured, 2253 were included in the final analysis. Correct color-band concordance was observed in 79.9% of children. Overall, 78.6% of estimates were within&#x2009;&#xb1;&#x2009;10% and 84.6% within&#x2009;&#xb1;&#x2009;15% of measured weight. The mean difference between estimated and measured weight was -&#x2009;0.6&#xa0;kg (0.08%). Lower color bands showed modest underestimation (13.1%), while higher bands showed mild overestimation (-&#x2009;10.3%). Regional concordance ranged from 65.9% to 91.4%. Interrater reliability demonstrated strong agreement (&#x3ba;&#x2009;=&#x2009;0.84; 95% CI 0.61, 1.00).<br><br>CONCLUSIONS: The Indianized Pediatric ALS tape demonstrated acceptable accuracy, minimal overall bias, and strong interrater reliability in critically ill Indian children. Although some variability was observed across regions and lower weight bands, the new ALS tape represents a practical and reasonably accurate indigenous alternative for emergency weight estimation in diverse PICU settings across India.}, }
@article {pmid42574200, year = {2026}, author = {Mirg, S and Elavarasi, A and Das, A and Vibha, D and Singh, RK and Parihar, J and Sharma, MC and Tripathi, M}, title = {Myofibrillar Myopathy with Pyramidal Signs Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Annals of Indian Academy of Neurology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aian.aian_1333_25}, pmid = {42574200}, issn = {0972-2327}, }
@article {pmid42574250, year = {2026}, author = {Tithi, SS and Cooper-Knock, J and Benatar, M and Wuu, J and Taylor, JP and Wu, G and Chen, W}, title = {CoCoRV-nf: a powerful and cost-effective tool for rare variant analysis leveraging external biobank sequence data identified new candidate predisposition genes in amyotrophic lateral sclerosis and neuroblastoma.}, journal = {Human molecular genetics}, volume = {35}, number = {17}, pages = {}, doi = {10.1093/hmg/ddag076}, pmid = {42574250}, issn = {1460-2083}, support = {R03OD039975/NH/NIH HHS/United States ; U54 NS092091/NH/NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Genetic Predisposition to Disease ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuroblastoma/genetics/pathology ; Biological Specimen Banks ; Cost-Benefit Analysis ; Genetic Variation/genetics ; *Software ; Genetic Association Studies ; }, abstract = {Although sequencing costs have steadily decreased with advances in technology, they remain high for large scale studies. The design of traditional individual-disease sequencing studies is either case only or cases with relatively few controls, resulting in potential loss of statistical power for discovery of disease associated genes. Here we show that for a given number of sequenced cases, a large control sample size is critical to maximize power for rare variant burden analysis. Furthermore, we have developed an end-to-end workflow based tool (CoCoRV-nf) to facilitate the use of external biobank sequence resources as controls. The modules include consistent variant QC, variant annotation, ancestry population prediction, and gene based burden analysis using summary genotype information, and combined analysis from multiple independent results. The tool supports exomes and genomes from gnomAD and All of Us as controls with preprocessed datasets. We apply the tool in two rare neurological diseases: amyotrophic lateral sclerosis and neuroblastoma. For each disease, two case cohorts are paired with gnomAD and All of Us data, respectively, followed by a combined analysis. Not only did we recapture known genes, but also, we identified new candidate genes for both diseases. By leveraging multiple large external biobank sequence data, we demonstrate the feasibility of using our tool to maximize statistical power to identify new disease predisposition genes.}, }
@article {pmid42574885, year = {2026}, author = {Inan, B}, title = {Comment on "Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis".}, journal = {Journal of the neurological sciences}, volume = {490}, number = {}, pages = {126131}, doi = {10.1016/j.jns.2026.126131}, pmid = {42574885}, issn = {1878-5883}, }
@article {pmid42575772, year = {2026}, author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT}, title = {Voice Disorders as Early Biomarkers of Cognitive Decline.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.07.037}, pmid = {42575772}, issn = {1873-4588}, abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.<br><br>RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).<br><br>CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.}, }
@article {pmid42576069, year = {2026}, author = {Saleem, M and Khan, MS and Syed Khaja, AS and Alraey, Y and Ahmad, I and Almuzaini, Y and AlShammari, A and Alshamamri, YM and Alharbi, T}, title = {Prevalence, antifungal susceptibility, and virulence determinants of Candida species causing vulvovaginal candidiasis in pregnant women in Saudi Arabia.}, journal = {Antonie van Leeuwenhoek}, volume = {119}, number = {9}, pages = {}, pmid = {42576069}, issn = {1572-9699}, support = {RGP.01/146/46//the Deanship of Research and Graduate Studies at King Khalid University/ ; }, mesh = {Humans ; Female ; *Candidiasis, Vulvovaginal/epidemiology/microbiology/drug therapy ; Saudi Arabia/epidemiology ; *Antifungal Agents/pharmacology ; Pregnancy ; Prevalence ; *Virulence Factors/genetics ; Microbial Sensitivity Tests ; *Candida/drug effects/pathogenicity/genetics/classification/isolation &amp; purification ; Adult ; Young Adult ; Adolescent ; *Pregnancy Complications, Infectious/microbiology/epidemiology ; Drug Resistance, Fungal ; Virulence ; }, abstract = {Vulvovaginal candidiasis (VVC) is a common opportunistic fungal infection of the female genital tract, primarily associated with Candida overgrowth influenced by host factors, hormonal changes, microbial imbalance, and environmental conditions. This study examined the prevalence, antifungal susceptibility, and virulence factors of Candida species in 440 pregnant women (ages 18-55) with vulvovaginitis and vaginal discharge at a Saudi Arabian hospital. The study was conducted from March 2022 to February 2023 at a tertiary hospital in Hail, Saudi Arabia, including 440 pregnant women with vaginitis. Vaginal swabs were cultured for Candida, with species identification and antifungal susceptibility testing performed using the Vitek-2 Compact system against five antifungals. Multiplex PCR was used to detect virulence genes (Hwp, Als, Sap, Hlp). Among them, 114 (25.9%) tested positive for Candida species, with Candida albicans being most prevalent (42.1%), followed by C. glabrata (19.3%) and C. tropicalis (12.3%). Most cases occurred during the second trimester (67%), with an average age of 27 years. Antifungal susceptibility testing showed that nystatin exhibited 49.1% susceptibility, 19.3% susceptible-dose dependence (SDD), and 31.6% resistance. Clotrimazole demonstrated 40.4% susceptibility, 26.3% SDD, and 33.3% resistance. Itraconazole showed 50.9% susceptibility, 28% SDD, and 21.1% resistance. Fluconazole exhibited 43.8% susceptibility, 8.8% SDD, and the highest resistance rate (47.4%). Voriconazole was the most effective antifungal agent, with 93% susceptibility, 3.5% SDD, and 3.5% resistance. Virulence analysis showed C. albicans had high Hwp (91.7%) and Sap (54.2%) gene detection, while C. glabrata and C. tropicalis exhibited elevated Hlp and Als levels, respectively. This study highlights the high prevalence of VVC in the second trimester and emphasizes the importance of virulence factors in pathogenicity. Voriconazole emerges as the most effective treatment, emphasizing the need for targeted diagnostics and therapies.}, }
@article {pmid42576087, year = {2026}, author = {Oyedokun, PA and Gbadero, JO and Ajao, DI and Olorunsesan, MD and Oyesiji, AI and Ayilara, GO and Ogunsina, MK and Justus, BS and Ademola, FM and Adetunji, EA and Okodio, PS and Amedu, NO}, title = {The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42576087}, issn = {1559-1182}, mesh = {*Oxidative Stress/physiology ; Humans ; Animals ; *Amino Acids/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Nerve Degeneration/metabolism/pathology ; Mitochondria/metabolism ; }, abstract = {Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca[2][+] influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.}, }
@article {pmid42576199, year = {2026}, author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F}, title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.}, journal = {Cellular &amp; molecular biology letters}, volume = {31}, number = {1}, pages = {}, pmid = {42576199}, issn = {1689-1392}, mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.}, }
@article {pmid42576610, year = {2026}, author = {Yang, Y and Yang, Y and Tang, Y and Yang, W}, title = {Myokines, Microbiota, and Neuroinflammation: Physical Activity Modulates the Gut-Brain Axis.}, journal = {Immunological investigations}, volume = {}, number = {}, pages = {1-28}, doi = {10.1080/08820139.2026.2689670}, pmid = {42576610}, issn = {1532-4311}, abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are increasingly recognized as disorders influenced not only by intrinsic neural pathology but also by systemic physiological networks, including the gut-brain axis. Emerging evidence highlights physical activity as a potent modulator of this bidirectional communication system, with muscle-derived signals particularly myokines, metabolites, and extracellular vesicles playing a central role.<br><br>METHODS: This narrative review synthesizes current knowledge on how exercise-induced molecular mediators influence gut microbiota composition, intestinal barrier integrity, immune signaling, and neuroinflammatory pathways. Findings were integrated across the disciplines of neuroscience, microbiology, and exercise physiology to evaluate mechanistic links between muscle-secreted factors and gut-mediated responses.<br><br>RESULTS: Mechanistic links exist between muscle-secreted factors such as irisin, cathepsin B, BDNF-inducing pathways, and lactate with microbial metabolites including short-chain fatty acids. These interacting pathways demonstrate a combined impact on neuroprotection, synaptic plasticity, and the modulation of disease progression in neurodegenerative conditions.<br><br>CONCLUSION: Physical activity represents a promising non-pharmacological strategy for modulating the gut-brain axis in neurodegenerative conditions. Understanding the interplay between muscle-derived signals and gut-mediated pathways may open new avenues for targeted interventions aimed at slowing or preventing neurodegenerative decline.}, }
@article {pmid42578424, year = {2026}, author = {Shen, D and Yang, X and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 536 young-onset amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2712723}, pmid = {42578424}, issn = {2167-9223}, abstract = {Objective: Young-onset amyotrophic lateral sclerosis (ALS), defined as symptom onset at or before 45 years, remains poorly characterized in Chinese patients. We aimed to describe its clinical and genetic features and compare them with adult-onset ALS. Methods: We retrospectively analyzed 536 young-onset ALS patients registered at Peking Union Medical College Hospital (2014-2022) alongside 1136 adult-onset patients (onset >45 years). Whole exome sequencing targeting 41 established ALS-related genes was performed in all young-onset patients. Results: Young-onset ALS accounted for 32.0% of the cohort, with a median onset age of 39.5 years (IQR 34.25-44.0). Compared with adult-onset patients, young-onset cases had less bulbar onset (14.2% vs. 19.5%, p = 0.008), more frequent predominant upper motor neuron phenotype (25.9% vs. 15.4%, p < 0.001), higher baseline ALSFRS-R scores (p < 0.001), slower progression (p = 0.001), and longer median survival (36 vs. 30 months, p = 0.009). Familial ALS was more common in the young-onset group (8.4% vs. 3.8%, p < 0.001). Rare variants were identified in 20.0% of young-onset patients across 32 genes; pathogenic or likely pathogenic variants were predominantly in SOD1 and FUS. Compared with adult-onset patients, SOD1 was proportionally more common in adult-onset disease, whereas FUS variants were markedly enriched among young-onset cases, suggesting age-dependent differences in genetic architecture. Conclusion: Young-onset ALS in China is characterized by a slower clinical course and a distinct genetic profile dominated by SOD1 and FUS, with near-absent C9orf72 expansions. Routine genetic testing and age-stratified trial design are warranted in this population.}, }
@article {pmid42578530, year = {2026}, author = {Zhou, Z and Ma, Y and Wang, L}, title = {Development and Psychometric Validation of the Chinese Online Disinhibition Scale for Adolescents.}, journal = {PsyCh journal}, volume = {15}, number = {4}, pages = {e70117}, pmid = {42578530}, issn = {2046-0260}, mesh = {Humans ; Adolescent ; *Psychometrics ; China ; Female ; Reproducibility of Results ; Male ; *Internet Addiction Disorder/psychology/diagnosis ; Surveys and Questionnaires ; *Internet ; *Cyberbullying/psychology ; *Adolescent Behavior/psychology ; }, abstract = {Online disinhibition significantly influences adolescents' communication and behaviors in digital environments, yet culturally adapted measurement tools remain limited in China. This study aimed to develop and validate a Chinese version of the Online Disinhibition Scale (ODS-C) based on Suler's (2004) theoretical framework. We translated and adapted Cheung et al.'s (2020) questionnaire through rigorous forward and backward translation protocols. Using a calibration sample (n = 686), we tested the scale's internal structure, reliability, and construct validity. A cross-validation sample (n = 687) was subsequently employed to verify and select the optimal internal structure of the ODS-C, assess measurement invariance across gender, and examine criterion validity based on relationships with internet addiction and cyberbullying perpetration. The final ODS-C demonstrated a hierarchical five-factor structure, in which dissociative anonymity and invisibility functioned as two distinct first-order factors subsumed under a higher-order anonymity factor, while the remaining four dimensions-asynchronicity, solipsistic introjection, dissociative imagination, and minimization of authority-operated as independent first-order factors. Results indicate that the ODS-C demonstrates high internal consistency, robust construct validity, and significant criterion validity. Evidence of measurement invariance confirmed the stability of the factor structure, loadings, and variances across genders. The ODS-C provides researchers and practitioners with a reliable and valid tool for assessing online disinhibition among Chinese adolescents, facilitating more culturally informed interventions and policies addressing digital behavior.}, }
@article {pmid42579090, year = {2026}, author = {Filippi, L and Nuvoli, S and Spanu, A and Palumbo, B}, title = {Mapping the Synaptome in Neurodegeneration: Emerging Clinical Applications of SV2A PET Imaging.}, journal = {Molecular diagnosis &amp; therapy}, volume = {}, number = {}, pages = {}, pmid = {42579090}, issn = {1179-2000}, support = {Ricerca Corrente//Ministero della Salute/ ; }, abstract = {Synaptic loss is a core pathological feature of neurodegenerative disorders and closely relates to cognitive and functional decline. Positron emission tomography (PET) targeting synaptic vesicle glycoprotein 2A (SV2A) has recently emerged as a promising tool for the indirect assessment of presynaptic alterations in the living human brain. This leading article discusses the evolving clinical landscape of SV2A PET across the neurodegenerative spectrum, emphasizing its translational trajectory and emerging applications. Current evidence spans Alzheimer's disease (AD), other dementias, movement disorders, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The literature is currently dominated by PET with [[11]C]UCB-J, while [[18]F]-labeled tracers, particularly [[18]F]SynVesT-1, are expanding clinical feasibility through longer half-life and broader distribution potential. Across disorders, PET consistently detected SV2A reductions that frequently correlated with cognition, disease severity, and complementary biomarkers, including amyloid, tau, glucose metabolism, and dopaminergic imaging. Although the field remains limited by small cohorts, heterogeneous quantification strategies, and incomplete longitudinal validation, SV2A PET is rapidly evolving into a promising translational tool for studying synaptopathies and monitoring disease progression.}, }
@article {pmid42580389, year = {2026}, author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q}, title = {Neuron-Derived Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Intervention Prospects.}, journal = {Pharmacological research}, volume = {}, number = {}, pages = {108383}, doi = {10.1016/j.phrs.2026.108383}, pmid = {42580389}, issn = {1096-1186}, abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.}, }
@article {pmid42580558, year = {2026}, author = {Armoundas, AA and Piperi, C}, title = {Epigenetic Drift and LINE-1 Activation in Aging Brain: Implications for Neurodegenerative Disease.}, journal = {Mechanisms of ageing and development}, volume = {}, number = {}, pages = {112235}, doi = {10.1016/j.mad.2026.112235}, pmid = {42580558}, issn = {1872-6216}, abstract = {Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.}, }
@article {pmid42580784, year = {2026}, author = {Souza, HJBC and Souza, KM and Dos Santos, MB and Silva, MAP and Grassi, TF and Destro, MV and Braz, MG}, title = {Evaluation of genetic instability in patients with amyotrophic lateral sclerosis.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {913}, number = {}, pages = {503953}, doi = {10.1016/j.mrgentox.2026.503953}, pmid = {42580784}, issn = {1879-3592}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Female ; Male ; Case-Control Studies ; Middle Aged ; *Genomic Instability ; Mouth Mucosa/pathology ; Micronucleus Tests ; Aged ; Chromosomal Instability ; Micronuclei, Chromosome-Defective ; }, abstract = {Genetic instability has been reported in several neurodegenerative diseases, such as Alzheimer's and Parkinson's, but only a few studies have addressed sclerosis. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Micronuclei (MNi) and nuclear buds (NBUDs) are established markers of chromosomal instability, yet no data are available regarding a possible link between genetic instability and ALS. The novelty of this case-control study lies in the assessment of genetic instability in oral exfoliated cells from ALS patients (n = 20) and matched controls (n = 20), contributing to the identification of potential novel markers related to the molecular pathogenesis of this severe disorder. Groups were matched for age, sex, and lifestyle (p > 0.05). No significant differences were observed in MNi or NBUD frequencies between groups (p > 0.05). These findings suggest no association between ALS and MN/NBUD frequencies in oral cells.}, }
@article {pmid42580829, year = {2026}, author = {Gaube, LM and Sparks, ED and Iten, M and Knapp, J and Fürholz, M and Schefold, JC and Hunziker Munsch, L and Hänggi, M and Krummrey, G and Müller, M and Hautz, WE}, title = {In-hospital cardiopulmonary resuscitation with balloon occlusion of the descending aorta: protocol of the randomised controlled CPReboa study.}, journal = {BMJ open}, volume = {16}, number = {8}, pages = {e119691}, doi = {10.1136/bmjopen-2026-119691}, pmid = {42580829}, issn = {2044-6055}, mesh = {Humans ; *Balloon Occlusion/methods ; *Cardiopulmonary Resuscitation/methods ; Prospective Studies ; *Heart Arrest/therapy/mortality ; *Aorta, Thoracic ; Randomized Controlled Trials as Topic ; Return of Spontaneous Circulation ; Female ; Adult ; }, abstract = {INTRODUCTION: Cardiac arrest (CA) remains a major health burden with poor survival and poor neurological outcomes despite decades of advances in resuscitation science. Although high-quality cardiopulmonary resuscitation is essential, it provides only limited cerebral and coronary perfusion, and current strategies relying on high-dose epinephrine may adversely affect cerebral microcirculation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a potential adjunct to improve coronary and cerebral perfusion without compromising microvascular blood flow. Although animal studies and small human case series suggest physiological and clinical benefits of REBOA in CA, randomised clinical trials are lacking.<br><br>METHODS AND ANALYSIS: This prospective, randomised controlled, single-centre clinical trial investigates the effect of REBOA during the treatment of CA. The planned study duration is 36&#x2009;months, with a total of 98&#x2009;patients to be randomised to either standard advanced life support (ALS) or ALS plus REBOA. Adult patients with an in-hospital CA, successful placement of a femoral artery introducer sheath and any electrical cardiac activity in the initial rhythm analysis are eligible for inclusion. Exclusion criteria comprise traumatic CA, asystole as the initial rhythm, pregnancy and CA occurring on intensive care units, in the operating room or in cardiac catheter laboratory. The primary outcome is sustained return of spontaneous circulation lasting for at least 20&#x2009;min. Secondary and exploratory outcomes include survival, neurological outcome, changes in aortic blood pressure, end-tidal CO&#x2082; and near-infrared spectroscopy values as well as causes of death and vascular complications related to the intervention. Statistical analyses will be performed on a modified intention-to-treat basis.<br><br>ETHICS AND DISSEMINATION: The study protocol (Version 2.1, 11.02.2026) was approved by the Cantonal Ethics Committee of Cantone Bern (2025-D0108). Study results will be disseminated through peer-reviewed journals.<br><br>TRIAL REGISTRATION NUMBER: NCT07434726.}, }
@article {pmid42581113, year = {2026}, author = {Jomova, K and Alomar, SY and Valko, R and Nepovimova, E and Kuca, K and Valko, M}, title = {Oxidative stress and inflammation in neurodegenerative disorders.}, journal = {Archives of toxicology}, volume = {}, number = {}, pages = {}, pmid = {42581113}, issn = {1432-0738}, abstract = {The brain's consumption of approximately 20% of the body's oxygen contributes to oxidative stress, a significant pathological factor in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This oxidative stress, linked to low levels of antioxidant enzymes, drives neuronal death by facilitating membrane peroxidation of fatty acids, proteins, and DNA. Alzheimer's disease is characterized by amyloid-beta (Aβ) plaque accumulation and hyperphosphorylated tau aggregates, both of which interact with mitochondria to generate reactive oxygen species (ROS). Aβ peptides bind metals such as iron and copper, catalyzing the formation of damaging hydroxyl radicals. Peripheral markers of oxidative damage, such as elevated malondialdehyde and protein carbonyls, are correlated with these processes in affected patients. In Parkinson's disease, the loss of dopaminergic neurons in the substantia nigra is associated with pathological iron accumulation and mitochondrial complex I dysfunction, which are worsened by misfolded α-synuclein and mutations in antioxidant genes such as PINK1 and Parkin. The autooxidation of dopamine also drives oxidative stress through the generation of hydrogen peroxide and reactive quinones. Huntington's disease involves the degeneration of medium spiny neurons in the striatum due to a polyglutamine repeat expansion in the huntingtin gene, which disrupts mitochondrial function and downregulates antioxidants, leading to excitotoxicity and ROS spikes. Amyotrophic lateral sclerosis primarily affects motor neurons due to the mutations in SOD1, which result in the production of aggregates that impair mitochondria and generate reactive nitrogen species (RNS), such as peroxynitrite. Mitigating oxidative stress in neurodegenerative disorders presents a considerable translational challenge. While low-molecular-weight antioxidant therapies for neurodegenerative disorders have shown promising results in preclinical and animal studies because they mitigate oxidative stress, their clinical efficacy is hampered by low bioavailability and difficulty in penetrating the blood‒brain barrier. To overcome these limitations, current medical research is focused on alternative delivery systems. Innovations such as nanoparticle-based drug delivery are being actively studied to help transport low-molecular-weight antioxidants across the blood‒brain barrier more safely and effectively. Several promising epidemiological trials linked high dietary intake of vitamins C and E to a reduced risk of Parkinson's disease, and plant-derived antioxidants such as polyphenols were explored for their ability to combat neuroinflammation and reduce cognitive decline. Refined oxidative stress-suppressing strategies involve the (ii) application of mitochondrial-targeted agents to preserve ATP production; (ii) boosting the Nrf2 pathway may trigger a cascade of detoxifying enzymes; (iii) supplementation with polyphenols such as quercetin, resveratrol, and curcumin can suppress oxidative stress and dampen microglial activation (neuroinflammation); (iv) and the use of substances affecting the bidirectional network linking oxidative stress and autophagy can clear ROS-generating components. Despite some promising epidemiological data, translating oral or systemic antioxidant therapy into effective clinical treatments for humans requires further effort. A survey of current knowledge of oxidative stress and antioxidant therapy in neurodegenerative diseases is the main subject of this review.}, }
@article {pmid42581131, year = {2026}, author = {Rahim, A and Zubair, SM and Ahamed, M and Das, S and Patel, R and Debnath, B and Porel, P}, title = {cGAS-STING as a Neuroimmune Traffic Molecule: Unraveling Pathogenic Mechanisms and Therapeutic Potential in Neurological Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {}, pmid = {42581131}, issn = {1557-1904}, mesh = {Humans ; cGAS-STING Signaling Pathway ; Animals ; *Nucleotidyltransferases/metabolism/immunology ; *Membrane Proteins/metabolism/immunology ; *Nervous System Diseases/immunology/metabolism/drug therapy ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; }, abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential cytosolic DNA-sensing system that plays an important role in the regulation of innate immune and inflammatory responses in the central nervous system (CNS). It was first discovered as a promising antiviral defense cascade and has since been shown to execute broader functions in neuroinflammation and neurodegeneration. The pathway can become hyperactive with the release of endogenous DNA from damaged nuclei, mitochondria, or genomic instability, leading to chronic production of type I interferon (TI-IFN), various pro-inflammatory cytokines, and eventually contributing to chronic neuroinflammatory diseases. Recent studies have found that dysregulated cGAS-STING signaling is associated with several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), stroke, and age-related neurodegeneration. In the CNS, chronic activation of this pathway leads to activation of microglia, oxidative stress, breakdown of the blood-brain barrier (BBB), impaired function of the synapses, and neuronal death. Mitochondrial dysfunction and cytosolic release of mitochondrial DNA (mtDNA) further promote inflammatory signaling, thus perpetuating neurodegeneration. This review highlights the molecular and pathological mechanisms of cGAS-STING signaling in a broader aspect of neurological disorders and appraises the novel therapeutics already under development to inhibit this pathway to regulate neuroinflammation and enhance neurological outcomes.}, }
@article {pmid42581247, year = {2026}, author = {Zhang, X and Zhang, L and Chen, L and Yu, W and Zhao, Y and Huang, Y and Xu, Z}, title = {LXR Pathway Activation by T0901317: A Novel Potential Experimental Strategy for ALS-Related Cognitive and Motor Impairments via Suppression of Necroptosis-associated RIPK1/RIPK3/MLKL Markers.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42581247}, issn = {1559-1182}, mesh = {Animals ; *Liver X Receptors/metabolism/agonists ; *Sulfonamides/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/metabolism/complications/drug therapy/physiopathology ; Fluorocarbons ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Benzenesulfonamides ; Mice, Transgenic ; *Hydrocarbons, Fluorinated/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Humans ; *Necroptosis/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism/complications ; DNA-Binding Proteins/metabolism ; Biomarkers/metabolism ; Male ; Mice ; Motor Neurons/metabolism/drug effects/pathology ; }, abstract = {To investigate the effects and mechanism of a synthetic LXR agonist, T0901317, on neuronal necroptosis-related signaling pathways in NSC-34 mouse neuronal cells transfected with the TDP-43-A315T plasmid, TDP-43-A315T transgenic mice of amyotrophic lateral sclerosis (ALS). SWATH proteinomics analysis was used to compare ALS patients with cognitive impairment (CI) and non-cognitive impairment (NOCI). TDP-43 abnormal aggregation and necroptosis-related protein expression were assessed with immunofluorescence and western blotting, while apoptosis and inflammatory cytokines were measured through TUNEL assay and ELISA, muscle and motor neuron degeneration were examined with H&amp;E and Toluidine Blue staining. Additionally, the Y-maze and Rotarod tests were used to evaluate cognitive and motor functions. Our study indicates that the LXR pathway was more downregulated in the ALS patients with cognitive impairment. RIPK1, p-RIPK3, and p-MLKL protein levels were upregulated in the TDP-43-A315T plasmid-transfected neuron cells and the TDP-43-A315T transgenic mouse model. The LXR agonist T0901317 reduced the abnormal aggregation of TDP-43 protein and downregulated the protein levels of RIPK1, p-RIPK3, and p-MLKL in vivo and in vitro. Furthermore, T0901317 attenuated motor neuron death and ameliorated muscle degeneration in TDP-43-A315T mice. T0901317 significantly prolonged survival, ameliorated cognitive and motor deficits, and shifted microglial activation marker profiles. The beneficial effects of T0901317 were abolished by LXR antagonist GSK 2033, accompanied by upregulation of necroptotic signaling. The neuroprotective effects of activating LXR may involve the regulation of the RIPK1-RIPK3-MLKL axis and TDP-43 aggregation.}, }
@article {pmid42566133, year = {2026}, author = {Thompson, JC and Kobylecki, C and Jones, M and Haigh, J and Larbey, M and Langheinrich, TC and Thomasson, R and Richardson, AMT and Snowden, JS}, title = {Frontotemporal dementia with right temporal predominance: a clinical comparison with left-predominant FTD.}, journal = {Journal of neurology}, volume = {273}, number = {9}, pages = {}, pmid = {42566133}, issn = {1432-1459}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnostic imaging/pathology/psychology/classification ; Female ; Male ; *Temporal Lobe/pathology/diagnostic imaging ; Middle Aged ; Aged ; Retrospective Studies ; Neuropsychological Tests ; Magnetic Resonance Imaging ; *Functional Laterality/physiology ; Atrophy ; }, abstract = {BACKGROUND: The right-temporal variant of frontotemporal dementia (FTD) is well characterised. Whether it should be considered a distinct clinical entity, separate from other syndromes of FTD, remains an open question. The study addressed the issue through a retrospective comparison of clinical characteristics of patients with predominant atrophy in right or left anterior temporal lobe (R-ATL vs. L-ATL).<br><br>METHODS: Patients were identified from a clinical database, diagnosed with FTD, and reported to show temporal lobe atrophy on imaging. Fifty-one patients were selected in whom independent ratings of atrophy were greatest in right or left anterior temporal lobe. Presenting symptoms, cognitive and behavioural characteristics, neuropsychological findings, and diagnostic classification were recorded.<br><br>RESULTS: Difficulty recognising people, impaired decision-making, perseverative preoccupations, disinhibition, and loss of empathy characterised the R-ATL group, in keeping with the previous reports. There was, however, overlap in cognitive and behavioural symptomatology in R-ATL and L-ATL, and sensitivity and specificity values were modest. Group differences diminished with disease progression. The most common clinical classification at first assessment in both groups was semantic dementia (SD), with other patients being classified as behavioural-variant FTD (bvFTD), FTD with amyotrophic lateral sclerosis or mixed FTD/SD. Not all patients with L-ATL met criteria for semantic variant primary progressive aphasia (svPPA).<br><br>CONCLUSIONS: The data question the notion that R-ATL and L-ATL presentations are separate entities. We argue that a common diagnostic framework for the two is warranted, with classification being based on cognitive/behavioural characteristics rather than neuroradiological grounds.}, }
@article {pmid42567782, year = {2026}, author = {Risby-Jones, G and Lee, JD and Fung, JN}, title = {Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2026.07.002}, pmid = {42567782}, issn = {1878-108X}, abstract = {Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.}, }
@article {pmid42568821, year = {2026}, author = {Okano, H}, title = {From neural development to regenerative medicine: A research journey in stem cell biology, spinal cord repair, and iPSC-based drug discovery.}, journal = {Regenerative therapy}, volume = {33}, number = {}, pages = {101157}, pmid = {42568821}, issn = {2352-3204}, abstract = {This commemorative article reflects on a research journey spanning neural development, stem cell biology, regenerative medicine, and iPSC-based drug discovery. My early work focused on RNA-mediated regulation in the nervous system, including studies on myelin basic protein gene regulation and the identification and functional characterization of the RNA-binding protein Musashi. These studies contributed to the conceptual foundation of neural stem cell biology and helped establish methods for identifying and isolating neural stem/progenitor cells, including those present in the adult human brain. Building on this foundation, my colleagues and I pursued translational research in spinal cord injury, ranging from analyses of injury pathophysiology and molecular interventions to preclinical studies using rodent and non-human primate models. These efforts ultimately led to the first-in-human clinical study of induced pluripotent stem cell-derived neural stem/progenitor cell transplantation for subacute spinal cord injury. In parallel, we developed patient-derived iPSC platforms for neurological disease modeling and drug discovery, particularly for amyotrophic lateral sclerosis, where iPSC-based screening identified Ropinirole as a therapeutic candidate and enabled reverse translational research linking cellular phenotypes with clinical responses. Looking ahead, I argue that the future of regenerative therapy will depend on the continued integration of developmental biology, stem cell science, disease modeling, rehabilitation, and clinical translation to address unmet medical needs in disorders of the central nervous system.}, }
@article {pmid42568823, year = {2026}, author = {Ding, M and Lu, J}, title = {The Influence of Applied Voltage on Drying Kinetics, Quality, and Mathematical Modeling of Ginger During Electrohydrodynamic (EHD) Drying.}, journal = {Food science &amp; nutrition}, volume = {14}, number = {8}, pages = {e72218}, pmid = {42568823}, issn = {2048-7177}, abstract = {This paper systematically evaluated the effects of electrohydrodynamic (EHD) on the drying characteristics, color, texture, moisture state, volatile components, and drying kinetics model of ginger. The results showed that EHD significantly increased the drying rate, rehydration rate, and effective moisture diffusion coefficient (D eff) of ginger. Among all the evaluated parameters, a voltage of 17 kV can produce the highest quality ginger. The drying rate of the 21 kV treatment group was 4.48 times higher than that of the control group (CG). ln[MR] showed a highly linear relationship with time (R [2] > 0.9). Among the ten thin-layer drying kinetics models, Midilli et al.'s model performed the best. Under 17 kV conditions, the best color retention was achieved for dried ginger. EHD drying significantly improved the texture of ginger. LF-NMR results showed a significant decrease in free water and an increase in bound water. Compared with the CG group, EHD showed good retention of most terpenoid compounds in dry ginger. SwissADME predicted six volatile compounds with good drug-like properties. Based on this study, it has been confirmed that the EHD technology has a good application in the ginger industry, providing theoretical support and experimental basis for the further expansion of EHD technology in the field of food drying.}, }
@article {pmid42569815, year = {2026}, author = {Kondo, A and Hokkoku, K and Kanbayashi, T and Nakayama, T and Sasaki, T and Matsuno, H and Iguchi, Y and Fukutake, T and Ando, T and Kamiyama, T and Kim, P and Hasegawa, T and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {"Abductor Sparing": A New Selective Involvement in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70374}, pmid = {42569815}, issn = {1097-4598}, support = {JP22K15738//Japan Society for the Promotion of Science/ ; 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; 26K10419//Ministry of Education, Science, Sports and Culture of Japan/ ; 20FC1030//Ministry of Health, Labour and Welfare of Japan/ ; }, abstract = {INTRODUCTION/AIMS: Various signs of selective muscle involvement have been reported in amyotrophic lateral sclerosis (ALS) but such studies for the lower limbs are scarce. We formed a preliminary impression that hip abductors (Ab) are often preserved in ALS. We named this phenomenon "abductor sparing", and this study aimed to verify our findings.<br><br>METHODS: Patients with a confirmed diagnosis of ALS (ALS group) and patients with pyramidal weakness other than ALS (pyramidal group) were retrospectively identified. Medical Research Council (MRC) scores of 10 muscle groups in the lower limbs were evaluated. The proportion of patients with weakness (MRC score 4 or less) was compared between different groups.<br><br>RESULTS: We enrolled 61 patients in the ALS group and 27 patients in the pyramidal group. The most frequently weak muscle groups in both groups were big toe extensors and hip flexors. Ab was the third (70%) in the pyramidal group, whereas it was weak only in 30% of patients with ALS. This held true also for patients with ALS with shorter duration or less severity. "The lower limb flexor pattern", i.e., flexor muscles being weaker than extensor muscles, was observed both in ALS and pyramidal groups.<br><br>DISCUSSION: Patients with ALS generally showed similar muscle weakness patterns to those with pyramidal syndrome, except for abductor sparing. The reason for the latter phenomenon is unclear. Abductor sparing may be useful for early diagnosis of ALS, although larger studies with blinded evaluators are needed to confirm these findings.}, }
@article {pmid42570648, year = {2026}, author = {Ye, P and Guo, B}, title = {Identification of Glycolysis-Related Diagnostic Biomarkers for Amyotrophic Lateral Sclerosis Using Machine Learning.}, journal = {Clinical laboratory}, volume = {72}, number = {8}, pages = {}, doi = {10.7754/Clin.Lab.2025.250766}, pmid = {42570648}, issn = {1433-6510}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism/blood ; *Biomarkers/metabolism/blood ; *Glycolysis/genetics ; *Machine Learning ; Predictive Learning Models ; Boosting Machine Learning Algorithms ; Blood Glucose/analysis/metabolism ; }, abstract = {BACKGROUND: Glycometabolism has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), yet the precise molecular mechanisms underlying this association remain poorly understood. The identification of reliable biomarkers for ALS diagnosis represents a critical unmet need in clinical practice, as early detection and intervention could significantly improve patient outcomes.<br><br>METHODS: We employed a comprehensive analytical approach combining two-sample Mendelian randomization analysis to investigate the causal relationship between blood glucose levels and ALS. Additionally, we integrated differential expression analysis, multiple machine learning algorithms, and correlation analyses to identify potential diagnostic biomarkers for ALS. The machine learning framework utilized gradient boosting tree methodology to construct predictive models, with performance evaluation conducted through cross-validation procedures.<br><br>RESULTS: Mendelian randomization analysis demonstrated a significant negative causal relationship between blood glucose levels and ALS risk. Through bioinformatic analysis and machine learning approaches, we successfully identified candidate genes and constructed a high-performance predictive model using gradient boosting tree methodology, achieving an average area under the curve (AUC) of 0.8782 in cross-validation. Validation studies utilizing both bulk and single-cell RNA sequencing datasets revealed that COL5A1 and VCAN genes play significant roles in ALS pathogenesis, likely through their involvement in glycolytic pathways.<br><br>CONCLUSIONS: Our findings provide novel insights into the molecular mechanisms linking glycometabolism and ALS, while identifying potential diagnostic biomarkers for the disease. The identified genes, COL5A1 and VCAN, represent promising targets for further investigation in ALS pathogenesis. However, the clinical translation of these findings requires validation through additional datasets and prospective clinical trials to establish their diagnostic utility and therapeutic potential.}, }
@article {pmid42572287, year = {2026}, author = {Okunomiya, T and Sakasai, T and Tsukita, K and Shimizu, R and Okusa, A and Adachi, M and Tomita, S and Tanaka, A and Kondo, T and Imamura, K and Inoue, H}, title = {Generation of mutant human SOD1 knock-in mouse lines at the Rosa26 locus as a platform for developing genome-editing therapies for amyotrophic lateral sclerosis.}, journal = {Experimental animals}, volume = {}, number = {}, pages = {}, doi = {10.1538/expanim.26-0040}, pmid = {42572287}, issn = {1881-7122}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, resulting in progressive paralysis and death within a few years of symptom onset. Although current treatments modestly slow the disease progression, effective disease-modifying and curative therapies remain an urgent unmet need. SOD1 mutations are one of the major genetic causes of familial ALS. The p.Leu127Ser (L126S) and p.Gly94Ser (G93S) variants are clinically relevant pathogenic variants for which appropriate animal models are needed for preclinical evaluation of gene-editing therapies. However, most existing SOD1 models rely on high copy overexpression of mutant SOD1. Therefore, animal models carrying a single copy mutant human SOD1 allele are required for evaluating the in vivo efficacy of genome editing therapies. Here, we used CRISPR/Cas9-mediated homology-directed repair to generate a knock-in mouse line at the Gt(ROSA)26Sor (Rosa26) locus carrying a single-copy, 11-kb human SOD1 genomic fragment, including all exons and introns, with the L126S mutation. The Rosa26-hSOD1[L126S] mice did not develop ALS-like phenotypes during the limited observation period. However, they faithfully retained a single-copy mutant human SOD1 genomic allele, providing a valuable preclinical platform for evaluating genome-editing therapies. We also generated Rosa26-hSOD1[G93S] mice carrying the SOD1 G93S mutation with comparable efficiency. Together, these mutant human SOD1 knock-in mouse lines provide a versatile and clinically relevant platform for the preclinical evaluation of genome-editing therapies targeting heterozygous SOD1 mutations.}, }
@article {pmid42572464, year = {2026}, author = {Cannedy, S and Lesser, R and Yano, EM and Hamilton, AB and Fenwick, KM}, title = {Staff Perspectives on Optimising Organisational Responses to Patient-Initiated Workplace Violence.}, journal = {Journal of advanced nursing}, volume = {}, number = {}, pages = {}, doi = {10.1111/jan.70713}, pmid = {42572464}, issn = {1365-2648}, support = {PPO 21-272//US Department of Veterans Affairs/ ; RCS 05-195//US Department of Veterans Affairs/ ; RCS 21-135//US Department of Veterans Affairs/ ; }, abstract = {AIMS: To identify existing and ideal practices for responding to patient-initiated workplace violence in the US Veterans Health Administration.<br><br>DESIGN: Cross-sectional, descriptive qualitative design.<br><br>METHODS: Qualitative interviews with staff (n&#x2009;=&#x2009;31) in eight veteran healthcare facilities located in the western United States (2023-2024). Guided by Spelten et&#xa0;al.'s model of strategies to reduce patient-initiated workplace violence, thematic analysis examined post-incident interventions with patients and identified recommendations for improvement.<br><br>RESULTS: Educating and setting limits with patients varied by facility. Most respondents were unaware of patient education/support that occurred post-incident. Respondents disagreed about the role that patients' clinical status should play; some wanted more leeway for certain patients (e.g., those diagnosed with dementia) and others wanted a consistent response (regardless of clinical status) to create a culture of respect.<br><br>CONCLUSION: Patient education and limit-setting are important elements in addressing patient-initiated workplace violence, but they are inconsistently used. Offering resources to patients is underutilised. Staff have differing perspectives on what constitutes ideal post-incident interventions for medically complex patients.<br><br>When responding to patient violence, healthcare systems may benefit from clear and consistently implemented protocols and tailored educational interventions and support for different patient populations (e.g., dementia). Staff may benefit from guidance on balancing patient care with limit-setting during encounters with medically complex patients.<br><br>IMPACT: We examined existing practices for responding to patient-initiated workplace violence and staff suggestions for improvement in a large healthcare system. Participants wanted additional and consistent patient interventions; opinions varied on how patient clinical status and intent should shape organisational responses. Staff can benefit from consistently implemented protocols for responding to patient violence. Healthcare systems may need to provide staff guidance on balancing patient care with limit-setting.<br><br>REPORTING METHOD: SRQR guidelines for qualitative studies.<br><br>No patient or public contribution.}, }
@article {pmid42572514, year = {2026}, author = {Sheehy, TP and Sia, T and Morgan, PE and Zhao, Y and Mathieson, SR and Gibb, RM and Smith, AA and Wools, CA}, title = {Relationship between neck weakness in motor neurone disease and respiratory function: a retrospective study.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2705867}, pmid = {42572514}, issn = {1758-2032}, abstract = {AIMS: The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor.<br><br>METHODS: This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables.<br><br>RESULTS: MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC&#x2009;<50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8&#x2009;months (IQR 10&#x2009;months; range 0 to 60&#x2009;months) with bulbar onset the quickest, median of 7&#x2009;months (IQR 7&#x2009;months, range 0 to 43&#x2009;months).<br><br>CONCLUSIONS: The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival.}, }
@article {pmid42560418, year = {2026}, author = {León-Ruiz, M and Castañeda-Cabrero, C and Benito-León, J}, title = {Response to "Palpebral ptosis as the initial symptom of amyotrophic lateral sclerosis": the potential usefulness of cortical excitability and motor band sign as biomarkers of upper motor neuron degeneration.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {9}, pages = {}, pmid = {42560418}, issn = {1590-3478}, }
@article {pmid42561134, year = {2026}, author = {Ehn, E and Thonberg, H and Nennesmo, I and Lindstrand, A and Kvarnung, M and Graff, C}, title = {Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.}, journal = {Human molecular genetics}, volume = {35}, number = {16}, pages = {}, doi = {10.1093/hmg/ddag072}, pmid = {42561134}, issn = {1460-2083}, mesh = {Humans ; *Whole Genome Sequencing/methods ; *Neurodegenerative Diseases/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; C9orf72 Protein/genetics ; DNA Copy Number Variations/genetics ; Male ; Middle Aged ; Alzheimer Disease/genetics/diagnosis ; Genetic Predisposition to Disease ; Frontotemporal Dementia/genetics/diagnosis ; Aged ; DNA Repeat Expansion/genetics ; Adult ; Polymorphism, Single Nucleotide ; Phenotype ; }, abstract = {Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.}, }
@article {pmid42561511, year = {2026}, author = {Al Ojaimi, Y and Dupuis, A and Palla, M and Lanznaster, D and Hergesheimer, R and Galineau, L and Serriere, S and Chami, AA and Martineau, P and Alouane, T and Marouillat, S and Dupuy, C and Schneider, BL and Veyrat-Durebex, C and Masse, F and Trovero, F and Andres, CR and Corcia, P and Vourcʼh, P and Blasco, H}, title = {Intrabody B1 targeting TDP-43 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01032}, doi = {10.1016/j.neurot.2026.e01032}, pmid = {42561511}, issn = {1878-7479}, abstract = {TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS), yet no therapeutic strategy effectively targets its upstream molecular consequences. Here, we investigated whether the anti-TDP-43 intrabody scFv B1 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model, and whether these effects translate into functional benefit after symptom onset. Using phage display, we previously identified single-chain variable fragments (scFvs) binding TDP-43, including the candidate therapeutic scFv B1. In NSC-34 motor neuron-like cells overexpressing human wildtype TDP-43, B1 reduced NF-κB activation, consistent with disruption of TDP-43-driven inflammatory signaling. For in vivo assessment, B1 was delivered via AAV-CAP.B10 after symptom onset in the hTDP-43(WTxA315T) transgenic mouse model, enabling neuro-specific expression. Two cohorts were analyzed - longitudinal (nine months) and terminal (six months post-treatment) - through behavioral testing, PET imaging, metabolomics, transcriptomics, and plasma biomarker analyses. B1 achieved robust CNS expression and modulated several disease-relevant molecular pathways. RNA-sequencing revealed attenuation of NF-κB-related inflammatory signatures and partial normalization of metabolic and trophic gene expression. Metabolomic profiling identified shifts toward wild-type-like levels in oxidative stress, mitochondrial, and membrane phospholipid metabolites. Despite these molecular effects, symptomatic B1 administration did not improve motor behavior or reduce plasma neurofilament light chain (NfL) concentrations. Notably, plasma TDP-43 levels were stabilized, indicating systemic target engagement. Collectively, scFv B1 modulates upstream pathogenic processes associated with TDP-43 proteinopathy but is insufficient to reverse established neurodegeneration after symptom onset, underscoring the need for earlier and likely combinatorial intervention strategies in ALS.}, }
@article {pmid42561943, year = {2026}, author = {Rostalski, H and Hietanen, T and Hoffmann, D and Heikkinen, S and Huber, N and Dhingra, A and Rodriguez-Nieto, S and Kuulasmaa, T and Ohtonen, S and Jäntti, H and Pekkala, V and Leskelä, S and Mäkinen, P and Katisko, K and Hartikainen, P and Lehtonen, &#x160; and Solje, E and Koistinaho, J and Malm, T and Portaankorva, AM and Natunen, T and Martiskainen, H and Takalo, M and Hiltunen, M and Haapasalo, A}, title = {C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {103026}, doi = {10.1016/j.stemcr.2026.103026}, pmid = {42561943}, issn = {2213-6711}, abstract = {C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.}, }
@article {pmid42561977, year = {2026}, author = {Helmold, B and Armon, C and Benatar, M and Bertorini, T and Bromberg, M and Brown, A and Cadavid, JM and Carbunar, O and Carter, GT and Crayle, J and Feldman, E and Foucher, J and Glass, J and Greenstein, E and Jhooty, S and Jiang, N and Kochen, NN and McDermott, C and Olby, N and Pattee, G and Porter, D and Premasari, A and Rao, A and Ratner, D and Staats, K and Tito, E and Vieira, F and Wicks, P and Bedlack, R}, title = {ALSUntangled #84 - ivermectin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2026.2714724}, pmid = {42561977}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.}, }
@article {pmid42562736, year = {2026}, author = {Chan, SC and Tung, CW and Chang, CY and Su, CC and Chen, YC and Wu, PM and Tung, CY and Chen, SF and Kuo, HY and Cheng, PH and Chen, CM and Yang, SH}, title = {Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00970}, doi = {10.1016/j.neurot.2026.e00970}, pmid = {42562736}, issn = {1878-7479}, abstract = {Mutant C9orf72 has been extensively studied as a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, and is also known to generate Huntington's disease (HD)-like phenocopies. However, despite this strong disease association, the role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration remains largely unexplored. HD is a neurodegenerative disease, and characterized by the accumulation of misfolded mutant Huntingtin (mHTT) and impaired proteostasis, yet the upstream mechanisms driving ubiquitin-proteasome system (UPS) dysfunction are not fully understood. Here, we identify a previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models. Analysis of public transcriptomic datasets reveal context-dependent C9ORF72 expression changes across HD-related human datasets, while C9orf72 levels are increased in R6/2 mouse brain lysates. Functional analyses reveal that overexpression of wt-C9orf72 increases mHTT aggregation and is accompanied by increased apoptotic signaling and reduced cell viability. Unbiased proteomic profiling identifies Stat1 as a key downstream effector. Mechanistically, wt-C9orf72 promotes Stat1 activation and nuclear translocation, leading to transcriptional upregulation of Isg15, a ubiquitin-like modifier. Elevated Isg15 disrupts UPS function, resulting in accumulation of polyubiquitinated proteins and impaired proteasomal degradation. Importantly, genetic suppression of Stat1 or Isg15 significantly attenuates C9orf72-associated mHTT aggregation, supporting a functional C9orf72-Stat1-Isg15 axis. Consistent with these cell-based findings, Stat1, phosphorylated Stat1 and Isg15 levels are elevated in the cortex and striatum of R6/2 HD mouse brains. Collectively, our findings identify a novel wt-C9orf72-Stat1-Isg15 axis that promotes proteasomal dysfunction and mHTT aggregation, providing new insights into wt-C9orf72-associated protein homeostasis.}, }
@article {pmid42562773, year = {2026}, author = {Zheng, X and Zhang, N and Wang, L and Zhao, H and Liu, C and Wang, J and Zhao, W and Zhao, J and Yang, P and Robinson, L and Hunt, L and Lokken, A and Lin, L and Nelson, PT and Kofler, J and Xie, H and Xia, H and Mao, Q}, title = {A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlag085}, pmid = {42562773}, issn = {1554-6578}, support = {GC-202008-2020689//Alzheimer's Drug Discovery Foundation/ ; R21AG080502/AG/NIA NIH HHS/United States ; R21AG088509/AG/NIA NIH HHS/United States ; R01AG097508/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.}, }
@article {pmid42562776, year = {2026}, author = {Wan, Y and Gao, C and Li, J and Luan, M and Lu, Y and Wang, J and Yang, B and Zheng, J and Yuan, Y and Wei, J and Wang, Z and Deng, J}, title = {Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlag013}, pmid = {42562776}, issn = {1554-6578}, support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we found that repeated administration of neural stem cell-derived extracellular vesicles (NSC-derived EVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model of ALS. Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.}, }
@article {pmid42564086, year = {2026}, author = {Zhang, G and Li, Z and Yao, X and Ding, M and Liu, X}, title = {Observed changes in clinical proxy measures of airway protection after cervical epidural spinal cord stimulation in neurological disorders: a preliminary retrospective case series.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1875581}, pmid = {42564086}, issn = {1664-2295}, abstract = {OBJECTIVES: Although spinal cord stimulation (SCS) has been investigated for cough and respiratory motor output after neurological injury, its relationship with clinical proxy measures of airway protection remains unclear. We explored observed changes in aspects of airway protection after cervical SCS in patients with neurological disorders.<br><br>MATERIALS AND METHODS: We retrospectively analyzed six patients who underwent cervical SCS for spinal cord injury, amyotrophic lateral sclerosis, or disorders of consciousness. Clinical proxy measures included the Semi-quantitative Cough Strength Score (SCSS), Functional Oral Intake Scale (FOIS), Water Swallow Test (WST), and Chinese Swallowing Quality of Life Questionnaire (cSWAL-QoL). SCSS was available for all six patients, whereas FOIS, WST, and cSWAL-QoL were limited to the four conscious patients. SCSS, FOIS, and WST were descriptively compared across preoperative, stimulation ON, and stimulation OFF conditions when clinically permissible. cSWAL-QoL was compared between preoperative and postoperative follow-up.<br><br>RESULTS: During active stimulation, SCSS scores were higher in all six patients, with the median score changing from 3.0 preoperatively to 4.0 during stimulation ON (nominal p&#x202f;=&#x202f;0.031). SCSS was also higher during stimulation ON than OFF (4.0 vs. 3.0; nominal p&#x202f;=&#x202f;0.031). Among the four conscious patients, FOIS changed from 4.0 to 5.0 and WST changed from 3.5 to 2.5 during stimulation ON, while cSWAL-QoL changed from 91.0 to 151.5 postoperatively. No stimulation-related adverse events occurred.<br><br>CONCLUSION: Clinical proxy measures related to airway protection showed exploratory state-associated changes during cervical epidural SCS, particularly in cough-strength scores. These preliminary findings do not establish efficacy or mechanism.}, }
@article {pmid42564438, year = {2026}, author = {Diovu, EO and Nnadi, CO and Paul-Chima, UO}, title = {Pharmaceutical wastewater irrigation and metabolite-based environmental pharmacognosy: a perspective on quality and safety risks for medicinal plants.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1878168}, pmid = {42564438}, issn = {1663-9812}, abstract = {Medicinal plants are increasingly cultivated in agroecosystems irrigated with treated or untreated wastewater, biosolids and contaminated surface water. Pharmaceutical residues are recognised contaminants of emerging concern, but their implications for botanical-drug quality, therapeutic consistency and safety remain insufficiently characterised. This Perspective argues that pharmaceutical wastewater irrigation is a plausible yet underexamined driver of metabolite reprogramming in medicinal plants. Chronic exposure to antibiotics, non-steroidal anti-inflammatory drugs, antiepileptics, antidepressants, hormones and transformation products may alter secondary metabolism through oxidative stress, xenobiotic detoxification, rhizosphere microbiome disturbance and modified nutrient signalling. These processes may change phenolic, flavonoid, alkaloid, terpenoid, glycoside and volatile metabolites that underpin pharmacognostic quality and ethnopharmacological reliability. Medicinal plants may also accumulate parent pharmaceuticals, transformation products and, under some conditions, microbial signatures associated with antibiotic resistance. Building on Carter et al.'s source-pathway-receptor framework and Helmecke et al.'s regulatory risk synthesis, we shift attention from residue burden to how exposure history alters the medicinal metabolome. Evidence from antibiotic-induced metabolite changes in Pinellia ternata supports this proposition, while indicating compound- and context-specific effects. We advance a balanced position: metabolite reprogramming is biologically credible, but food-crop studies often report de minimis residue risks and inconsistent rhizosphere-resistome effects. Future work should integrate wastewater profiling, matched controls, targeted and untargeted metabolomics, transformation-product discovery, microbiome analysis, digestion and bioaccessibility testing, bioactivity assays and probabilistic mixture-risk assessment.}, }
@article {pmid42565285, year = {2026}, author = {Semendric, I and Munn, Z and Jenkins, T and Edwards, A and Tull, V and Travlos, V and Hutchinson, K and Krikheli, L and Sheers, N and Hall, LA and Chua, P and Hatch, N and Allcroft, P and Werth, B and Saffrett, A and Yoong, J and Cooper, L and Signorelli, M and Farrugia, E and Devenney, E and Douglas, A and Gibb, A and Macshane, M and Gardiner, M and Collins, A and Yang, J and Rogerson, B and Schultz, D and Lim, D and Fisher, F and Herz, H and Puckering, H and Swain, I and Cameron, J and Donnelly, L and Davis, L and Anderson, L and Acampora, M and Heatley, R and Taubert, S and Sheehy, T and Sia, T and Aiyappan, V and Huynh, W and Stern, C and , }, title = {Issues in the clinical assessment and management of people living with motor neurone disease (MND): a survey of Australian healthcare professionals.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2710550}, pmid = {42565285}, issn = {2167-9223}, abstract = {Objective: To inform the development of the Australian MND Guideline, this study aimed to identify challenges Australian healthcare professionals (HCPs) face in the clinical assessment and management of people living with MND (plwMND) including where practice varies from evidence or is underrepresented in the literature and challenges that arise when supporting non-MND specialists. Methods: An anonymous online survey was developed on Qualtrics (Provo, UT) and distributed in July 2025 to members of the Australian MND Guideline Clinical and Content Advisory Group. Demographic data were analyzed using descriptive statistics and verbatim responses were analyzed thematically to a pre-defined framework of guideline scopes and topics. Results: Fifty HCPs, predominantly allied health professionals, completed the survey (55% response rate). HCPs reported diagnostic delays, difficulties accessing timely multidisciplinary support, and challenges coordinating care, particularly outside MND clinic catchment areas. HCPs perceived uncertainty in respiratory support, nutrition, saliva management, and psychological and cognitive care. Variations from guidance reflected gaps and inconsistencies in the evidence base, the need for individualized care, and systemic constraints including funding, workforce shortages, and inequities in access. Non-MND specialists sought guidance on prognosis, referral pathways, symptom management, and end-of-life care. Conclusion: This survey identified areas of clinical practice uncertainty and variability in the clinical assessment and management of plwMND from the perspective of Australian HCPs. These findings will inform the development of the Australian MND Guideline, including prioritization of topics and questions, and consideration of areas where expert consensus is required.}, }
@article {pmid42558984, year = {2026}, author = {Pourasghari, M and Babaie, S and Markazi-Movaghar, R and Salehpour, S and Eftekharsadat, B and Farshbaf-Khalili, A}, title = {The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Stem cells international}, volume = {2026}, number = {}, pages = {4122493}, pmid = {42558984}, issn = {1687-966X}, abstract = {BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products.<br><br>METHODS: The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I [2] statistics, and subgroup analyses were conducted based on treatment duration and dosing.<br><br>RESULTS: A pooled analysis (treatment group: n&#x2009;=&#x2009;93; control group: n&#x2009;=&#x2009;90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the &#x2265;10&#x2009;&#xd7;&#x2009;10[6] and <10&#x2009;&#xd7;&#x2009;10[6] dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n&#x2009;=&#x2009;88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups.<br><br>CONCLUSION: Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.}, }
@article {pmid42559389, year = {2026}, author = {Murray, G and Dupuis, M and Hagan, J and Laroche, M and Peters, J}, title = {Arbeitnehmer:innen als Klima-Akteure: Was können Gewerkschaften gegen den Klimawandel unternehmen? Einleitung.}, journal = {Transfer (Brussels, Belgium)}, volume = {32}, number = {2}, pages = {141-151}, doi = {10.1177/10242589261467970}, pmid = {42559389}, issn = {1024-2589}, }
@article {pmid42559804, year = {2026}, author = {Bonde, JP and Skaaby, S and Flachs, EM and Dollard, M and Keyes, K and Rosengren, A and Mehlum, IAS and Mikkelsen, S}, title = {Lavigne-Robichaud et al: Job strain and ischemic heart disease: the balance of methodological bias and implications for prevention. Author reply.}, journal = {Scandinavian journal of work, environment &amp; health}, volume = {}, number = {}, pages = {}, doi = {10.5271/sjweh.4324}, pmid = {42559804}, issn = {1795-990X}, abstract = {We appreciate Lavigne-Robichaud et al`s critical remarks (1) to our systematic review addressing the epidemiological evidence for causal relations between job strain and the risk of ischemic heart disease (IHD) (2). Their main concern relates to the strength of the hypothesized association between job strain and IHD and, by extension, the magnitude of the population attributable fraction. They argue that our overall conclusion places too much emphasis on biases that inflate risk estimates and underrates biases that attenuate estimates towards the null. However, we believe it is premature to discuss in detail the strength of associations before a causal link is established with reasonable confidence. The main objective of our review was to evaluate the epidemiological evidence that observed associations are indeed causal. We concluded that the current evidence neither substantiates nor excludes a causal association for several reasons, including, but not limited to, the presence of inflating or deflating biases (2). That said, we appreciate the opportunity to discuss the sources of bias raised by Lavigne-Robichaud et al (1). First, it is argued that dichotomizing exposure into "high" and "no-high" job strain deflates risk estimates because a subgroup of the no-high job strain group (passive jobs with low demands and low control) might also be associated with increased risk. However, others have found that results are broadly similar when different non-strain groups are used as reference (3). Thus, at present, the evidence for effects of passive jobs is not strong enough to deviate from the parsimonious use of "all others" as reference. Second, the notion that the pooled risk estimate may be attenuated by sex because women develop IHD at older ages than men is supported by our review indicating slightly lower risk estimates among women. However, the confidence intervals substantially overlap [(2), table 4] and the small difference, if valid, may be due to several other factors and thus considered of minor importance. Third, the use of job-exposure matrices (JEM) is not associated with attenuated risk estimates if the average exposure in the job groups is close to the true average (4). This condition is probably violated in most instances and may lead to attenuated risk estimates if the exposure misclassification is non-differential. However, misclassification may depend on potential confounders (eg, sex, socioeconomic status and psychosocial and lifestyle factors) in ways that inflate or deflate risk estimates. Note also that the JEM studies do not provide the independent assessment of exposure that is needed for stronger conclusions to be drawn. This is because most studies are based on JEM established by population-based questionnaire studies. We consider the lack of independent exposure assessment a major obstacle for causal inference. Fourth, we agree that the prospective cohort study design in principle eliminates recall bias caused by later occurring manifest disease. But it is not obvious that subclinical or early stages of the disease cannot confound the association, potentially leading to inflated risk estimates even in prospective studies (3). Fifth, self-reported psychosocial work exposures are inherently vulnerable to respondents` individual interpretations, particularly when they are asked to rate the intensity or frequency of subjective experiences. We acknowledge the references provided by Lavigne-Robichaud et al, but these studies do not rule out potential confounding by personality (5, 6). The influence of social context, attitudes, life experiences and personality traits remains unresolved and likely constitute bias regardless of study design (7). We are aware that our review may be misused to discourage sound efforts to improve the psychosocial work environment. While this unfortunate risk is inherent to all critical appraisals of the literature, we believe it remains incumbent on researchers to provide the most evidence-based assessments possible so that we can collectively endeavor to improve science. References 1. Lavigne-Robichaud M, Landsbergis P, Brisson C, Sembajwe G, Gilbert-Ouimet M, Li J, Milot A, Trudel X. Job strain and ischemic heart disease: the balance of methodological bias and implications for prevention. Response to: Bonde JP et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology. Scand J Work Environ Health - online first. https://doi.org/10.5271/sjweh.4315. 2. Bonde JP, Skaaby S, Flachs EM, Dollard M, Keyes K, Rosengren A et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology. Scand J Work Environ Health 2026 Jul;52(4):360-70. https://doi.org/10.5271/sjweh.4299. 3. Kivimäki M, Nyberg ST, Batty GD, Fransson EI, Heikkilä K, Alfredsson L et al.; IPD-Work Consortium. Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data. Lancet 2012 Oct;380(9852):1491-7. https://doi.org/10.1016/S0140-6736(12)60994-5. 4. Armstrong BG. Effect of measurement error on epidemiological studies of environmental and occupational exposures. Occup Environ Med 1998 Oct;55(10):651-6. https://doi.org/10.1136/oem.55.10.651. 5. Spector PE, O'Connell BJ. The contribution of personality traits, negative affectivity, locus of control and Type A to the subsequent reports of job stressors and job strains. J Occup Organ Psychol 1994;67:1-2. https://doi.org/10.1111/j.2044-8325.1994.tb00545.x. 6. Shipley BA, Weiss A, Der G, Taylor MD, Deary IJ. Neuroticism, extraversion, and mortality in the UK Health and Lifestyle Survey: a 21-year prospective cohort study. Psychosom Med 2007 Dec;69(9):923-31. https://doi.org/10.1097/PSY.0b013e31815abf83. 7. Kasl SV. Measuring job stressors and studying the health impact of the work environment: an epidemiologic commentary. J Occup Health Psychol 1998 Oct;3(4):390-401. https://doi.org/10.1037/1076-8998.3.4.390.}, }
@article {pmid42560011, year = {2026}, author = {Abrar, F and Martin, DDO}, title = {Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/15548627.2026.2711593}, pmid = {42560011}, issn = {1554-8635}, abstract = {SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.}, }
@article {pmid42556722, year = {2026}, author = {Jiang, H and Ding, L and Yang, C and Guo, G and Zhong, C and Ma, Z and Zhu, H and Zhang, J and Luo, Y and Liu, Z and Liu, R and Ding, Y}, title = {Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {113394}, doi = {10.1016/j.jbc.2026.113394}, pmid = {42556722}, issn = {1083-351X}, abstract = {EphA4 signaling is a key negative regulator of axonal regeneration and a genetic modifier of amyotrophic lateral sclerosis (ALS), making EphA4 an attractive but mechanistically underexplored therapeutic target. Although EphA4-targeting nanobodies have shown inhibitory potential, the structural principles governing their binding and inhibitory mechanisms remain largely unknown. Here, we report high-resolution crystal structures of the EphA4 ligand-binding domain (LBD) in complex with four nanobodies (Nb50, Nb53, Nb57, and Nb60), resolved at 1.34-2.21 Å. Nb50, Nb53, and Nb57 competitively engage the canonical ephrin-binding pocket through deep CDR3 insertion, directly mimicking ephrin recognition. In contrast, Nb60 adopts a previously unrecognized binding mode, contacting two EphA4 molecules at noncanonical sites in the crystal structure through framework-dominated interactions and supporting a structural model for steric and allosteric restriction of ephrin access. Integrated biophysical analyses reveal distinct thermodynamic and kinetic signatures underlying these binding mechanisms. Together, our findings uncover unexpected structural diversity in nanobody-mediated EphA4 recognition and provide a framework for rational development of EphA4-targeted modulators for ALS and related neurodegenerative conditions.}, }
@article {pmid42556956, year = {2026}, author = {Rahman, U and Yang, SC}, title = {Management of Anastomotic Leaks: Endoscopic, Interventional, and Surgical Strategies.}, journal = {Advances in surgery}, volume = {60}, number = {1}, pages = {259-270}, doi = {10.1016/j.yasu.2026.03.017}, pmid = {42556956}, issn = {1878-0555}, mesh = {Humans ; *Anastomotic Leak/therapy/surgery/etiology ; }, abstract = {Anastomotic leaks (ALs) are a significant source of morbidity and mortality. Every step should be implemented to prevent AL, including careful patient selection, optimizing patient's clinical and nutritional status, and ensuring proper technique. The appropriate management of an AL depends on several factors, such as patient's clinical status, the type of surgery, location of the AL, induction therapies, and the resources available. Surgeons should be familiar with the armamentarium of treatment modalities available to manage AL and use a patient-tailored approach when selecting the most appropriate treatment.}, }
@article {pmid42557952, year = {2026}, author = {Acharya, A and Thurman, M and Sutar, D and Olasunkanmi, OI and Malik, JR and Dyavar, SR and Végvári, &#xc1; and Byrareddy, SN}, title = {In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.}, journal = {Journal of medical virology}, volume = {98}, number = {8}, pages = {e71086}, pmid = {42557952}, issn = {1096-9071}, support = {R01DA05284/NH/NIH HHS/United States ; R01DA061678/NH/NIH HHS/United States ; }, mesh = {*Pericytes/virology/metabolism ; *Astrocytes/virology/metabolism ; Humans ; *Signal Transduction ; *HIV Infections/metabolism/complications/virology ; *SARS-CoV-2/physiology ; *Coinfection/virology/metabolism ; *Neurodegenerative Diseases/metabolism/virology ; *COVID-19/metabolism/complications/virology ; Proteomics ; Microglia/virology/metabolism ; Post-Acute COVID-19 Syndrome ; Virus Replication ; Proteome ; }, abstract = {Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.}, }
@article {pmid42558399, year = {2026}, author = {Okethwangu, D and Venkateswaran, M and Ario, AR and Nabatanzi, S and Asio, E and Ocom, F and Okot, CL and Nyisomeh, A and Nankabirwa, V and Rutebemberwa, E and Mayega, RW and Kiwanuka, SN}, title = {Resilience as recovery: stakeholder perspectives on Uganda's health system response to infectious disease shocks.}, journal = {Frontiers in health services}, volume = {6}, number = {}, pages = {1888814}, pmid = {42558399}, issn = {2813-0146}, abstract = {BACKGROUND: The conceptualization, definition, and measurement of health system resilience remain contested, hindering policy integration. Country-specific empirical evidence from sub-Saharan Africa, where infectious disease shocks recur, is limited. This study explored how national-level Ugandan stakeholders conceptualize health system resilience to infectious disease shocks and its attributes.<br><br>METHODS: We conducted a descriptive exploratory qualitative study using semi-structured key informant interviews with 15 purposively selected national-level stakeholders from the Ministry of Health, academia, and development and implementing partners between May and July 2025. Data were analyzed using a hybrid deductive-inductive (abductive) thematic analysis approach, drawing on Kruk et al.'s and the WHO's resilience frameworks while remaining open to emergent themes. Reporting follows the Consolidated Criteria for Reporting Qualitative Research (COREQ).<br><br>RESULTS: Participants conceptualized resilience across five capacities: preparedness, absorptive, adaptive, transformative, and recovery. Recovery-dominated narratives prevailed, while transformative capacity was least articulated, indicating a system oriented toward "bouncing back" rather than reform: A resilient system in Uganda is one that anticipates and prepares for infectious disease shocks; absorbs them while sustaining essential services; adapts through innovation and operational adjustment; recovers core functioning; and institutionalizes learning to transform structures, financing, and service delivery models in preparation for future shocks. Seven interconnected attributes were identified: (1) governance and leadership, (2) preparedness, (3) service delivery, (4) community involvement, (5) adaptability, (6) collaboration and partnerships, and (7) soft skills. Governance and leadership emerged as foundational; preparedness, service delivery, community involvement, adaptability, and collaboration as structural; and soft skills (trust, communication, cultural sensitivity) as relational enablers.<br><br>CONCLUSIONS: From the perspective of national-level actors, Uganda's health system is predominantly reactive, with recovery prioritized over transformation. Strengthening resilience requires institutionalizing learning, anticipatory financing, empowered subnational structures, and multisectoral partnerships. Future research should triangulate these perspectives with subnational, frontline, and community voices.}, }
@article {pmid42558527, year = {2026}, author = {Li, S and Cao, T and Zhang, Q}, title = {Oxidative stress as a driver of organelle cascade damage in neurological diseases.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1892923}, pmid = {42558527}, issn = {1663-4365}, abstract = {As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.}, }
@article {pmid42314945, year = {2026}, author = {Goldberg, MS and Lebwohl, MG}, title = {Response to Baharuddin et al.'s Comment on ''The 487-gene expression profile test guides systemic therapy selection to improve outcomes for patients with atopic dermatitis: Results from a prospective trial''.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.06.061}, pmid = {42314945}, issn = {1097-6787}, }
@article {pmid42549923, year = {2026}, author = {Takahashi, M and Abe, T and Fujii, M}, title = {Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.}, journal = {Molecular and cellular biology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/10985549.2026.2705871}, pmid = {42549923}, issn = {1098-5549}, abstract = {Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.}, }
@article {pmid42550987, year = {2026}, author = {Waters-Harvey, B and Kane, K and Griffiths, AW and Smith, G and Bartlett, CM and Sproson, L and Smith, S and Starkey, J and Clift, A and Stavroulakis, T and Hobson, E and Mayberry, E and O'Cathain, A and Bidder, C and Kennedy, K and Gibson, J and McDermott, C and Knox, L}, title = {Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e96327}, pmid = {42550987}, issn = {1929-0748}, mesh = {Humans ; *Motor Neuron Disease/therapy/psychology ; Amyotrophic Lateral Sclerosis/therapy ; England ; United Kingdom ; Wales ; }, abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this.<br><br>OBJECTIVE: The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders.<br><br>METHODS: This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool.<br><br>RESULTS: The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice.<br><br>CONCLUSIONS: By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home.}, }
@article {pmid42551425, year = {2026}, author = {Petrescu, J and Gouveia Roque, C and Jackson, CA and Daly, AC and Butti, Z and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and Gebremedhin, B and McDade, K and Gregory, JM and Bonneau, R and Smith, C and Phatnani, H}, title = {Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2026.07.008}, pmid = {42551425}, issn = {1097-4172}, abstract = {Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.}, }
@article {pmid42551655, year = {2026}, author = {Toyama, G and Koide, S and Yamagishi, T and Washida, A and Hanyu, R and Onodera, O and Sugai, A}, title = {Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107560}, doi = {10.1016/j.nbd.2026.107560}, pmid = {42551655}, issn = {1095-953X}, abstract = {Nuclear depletion and cytoplasmic mislocalization of TDP-43 are central pathological features of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 protein levels are normally maintained by autoregulation through its native 3' untranslated region (3' UTR), but whether this feedback remains protective during chronic cytoplasmic bias is unclear. To address this, we engineered full-length human TDP-43 carrying an N-terminal nuclear export signal (NES) while retaining the native 3' UTR autoregulatory module. In HEK293T cells, NES insertion imposed cytoplasmic bias and promoted detergent-insoluble TDP-43 species. In differentiated SH-SY5Y cells, nuclear splicing defects and autoregulatory changes scaled with export-biased load; detergent-insoluble accumulation was already detectable within a low-load range, defined by whole-cell RIPA-soluble exogenous TDP-43 ≤ 30% of endogenous levels. Human iPSC-derived neurons showed a comparable cytoplasmic shift, discrete TDP-43-immunoreactive foci, and TDP-43-dependent splicing defects. Endogenous TARDBP depletion provided a functional rescue test: nuclear-competent WT-TDP-43-3' UTR restored TDP-43-dependent nuclear readouts, whereas NES-TDP-43-3' UTR did not. In the NES condition, weakened autorepression increased transgene-derived TARDBP transcripts, but the added output failed to expand the soluble, splice-competent pool and instead partitioned into insoluble fractions. Increasing soluble NES-TDP-43 to endogenous-equivalent levels likewise did not normalize splicing, indicating that abundance alone is insufficient when output remains export-biased. These findings support a model in which persistent export bias converts native TARDBP autoregulation into maladaptive feedback: compensatory output is uncoupled from productive nuclear recovery and diverted toward cytoplasmic insoluble/fragmented species.}, }
@article {pmid42551865, year = {2026}, author = {Dalle, S and Vanderbeke, K and Burg, T and Schouten, M and Lauriks, W and Hersmus, N and Van Den Bosch, L and Koppo, K}, title = {Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1[G93A] Mice.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {17}, number = {4}, pages = {e70357}, pmid = {42551865}, issn = {2190-6009}, support = {G086823N//Fonds Wetenschappelijk Onderzoek/ ; 12Z8622N//Fonds Wetenschappelijk Onderzoek/ ; 11PRA24N//Fonds Wetenschappelijk Onderzoek/ ; PDMt1/24/001//Onderzoeksraad, KU Leuven or KU Leuven Research Council/ ; }, mesh = {Animals ; Female ; Mice ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Endocannabinoids/metabolism ; Disease Models, Animal ; *Superoxide Dismutase-1/genetics ; *Lipid Metabolism ; *Muscle Fibers, Slow-Twitch/metabolism ; }, abstract = {BACKGROUND: Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type-specific ECS changes in ALS.<br><br>METHODS: Female hSOD1[G93A] transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56-138&#x2009;days of age; n&#x2009;=&#x2009;7-8/group). Endocannabinoids, N-acyl-ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC-MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS-related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (n&#x2009;=&#x2009;5/group; ~63&#x2009;years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (n&#x2009;=&#x2009;10-11/group), and survival, body weight, welfare and motor function were assessed longitudinally.<br><br>RESULTS: ALS caused severe atrophy in the predominantly fast-twitch TA muscle (-76.5%; p&#x2009;<&#x2009;0.01), while the slow-twitch soleus was largely preserved (-14.4%; p&#x2009;<&#x2009;0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy- and epoxy-fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p&#x2009;=&#x2009;0.03) and multiple N-acyl-ethanolamine congeners (+76-102%; p&#x2009;<&#x2009;0.05), reduced 2-arachidonoylglycerol (-28%; p&#x2009;=&#x2009;0.06), increased CB1 receptor expression (+93%; p&#x2009;<&#x2009;0.01) and dynamic, age-dependent regulation of FAAH (presymptomatic: -68%; p&#x2009;=&#x2009;0.04, symptomatic: +21%; p&#x2009;=&#x2009;0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p&#x2009;=&#x2009;0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; pFDR&#x2009;=&#x2009;0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: Muscle type-specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.}, }
@article {pmid42552039, year = {2026}, author = {Venu, G and A, VP and Justin, A}, title = {Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {113-143}, doi = {10.1016/bs.irn.2026.05.014}, pmid = {42552039}, issn = {2162-5514}, mesh = {Humans ; *PPAR gamma/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Signal Transduction/physiology ; Animals ; *Huntington Disease/metabolism ; }, abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.}, }
@article {pmid42552041, year = {2026}, author = {Khodve, G and Raval, S and Banerjee, S}, title = {Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {199-229}, doi = {10.1016/bs.irn.2026.05.015}, pmid = {42552041}, issn = {2162-5514}, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy ; *Aging/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/metabolism/immunology ; *Brain-Gut Axis/physiology ; Probiotics ; Brain/metabolism ; }, abstract = {The human gut microbiota represents a complex ecosystem of trillions of microorganisms with profound implications for neurological health. Emerging evidence demonstrates that dysbiosis, an imbalance in microbial composition and function, plays a crucial role in the pathogenesis of neurodegenerative diseases and age-related cognitive decline. This chapter summarizes current knowledge of the microbiota-gut-brain axis (MGBA) and elucidates how intestinal microbes and their metabolites communicate with the central nervous system via neural, immune, endocrine, and metabolic pathways. We examine the mechanistic links between gut dysbiosis and specific neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Multiple sclerosis (MS). Furthermore, we explore age-related changes in the microbiota and their contributions to neuroinflammation, immunosenescence, and cognitive decline. Finally, we evaluate therapeutic interventions targeting the microbiota, including probiotics, prebiotics, synbiotics, and dietary modulation as promising strategies to prevent and ameliorate neurodegenerative pathology. The chapter provides a comprehensive summary of how microbiota-targeted approaches may delay ageing and neurodegeneration.}, }
@article {pmid42552132, year = {2026}, author = {Labrèche, F and Prud'homme, P and Gagnon, M and Dupré, N and Gravel, S}, title = {Occupational exposure to pesticides increases the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Occupational and environmental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1136/oemed-2025-110662}, pmid = {42552132}, issn = {1470-7926}, abstract = {OBJECTIVE: To systematically review the evidence on the association between occupational exposure to pesticides and the risk of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A systematic search, conducted in eight bibliographic databases for publications between 1990 and 2025, identified observational studies estimating the risk of ALS after occupational pesticide exposure. Study quality was assessed using the WHO Risk of Bias (RoB) assessment instrument for systematic reviews, with the ROBINS-E (RoB in non-randomised studies of exposure) tool domains of bias. Pooled risk estimates were produced using random-effects models with restricted maximum likelihood, heterogeneity was assessed with I&#xb2; statistics, and meta-regressions and publication bias explored with funnel plots and Egger's test.<br><br>RESULTS: Eight case-control studies (1734 cases) were retained for meta-analysis from 767 initially screened articles. 'Ever' occupational exposure to pesticides was associated with an increased risk of ALS (n=6 studies, pooled OR (pOR)=1.6; 95% CI 1.1, 2.2; I&#xb2;=57%), for combined sexes. The risk for exposure to herbicides was slightly greater (pOR=1.7, I[2]=0.0%) than for exposure to insecticides or fungicides (pORs=1.6, I[2]=0.0%). Based on three studies, ever exposure to high levels of pesticides was associated with a higher risk (pOR=2.7; 95% CI=1.4, 5.0) than exposure to low levels (pOR=1.9; 95% CI=1.0, 3.7). Self-reported exposure assessment methods and older publication dates (<2015) were statistically significant predictors of the effect size.<br><br>CONCLUSION: Despite the small number of studies and some heterogeneity, our results add to the evidence suggesting that occupational exposure to pesticides may increase the risk of ALS.}, }
@article {pmid42552521, year = {2026}, author = {Aradhya, L and Lath, V and Sirur, FM and Balakrishnan, JM and Hebbar, A and Shetty, AK}, title = {Evaluation of safety, comfort, and design ergonomics in ambulance retrieval vehicles: a survey in Southern India.}, journal = {International journal of emergency medicine}, volume = {19}, number = {1}, pages = {}, pmid = {42552521}, issn = {1865-1372}, abstract = {BACKGROUND: Ambulance interior design influences the safety, comfort, and operational efficiency of Emergency Medical Services (EMS) personnel. However, evidence regarding ergonomic challenges faced by EMS providers in the Indian prehospital setting remains limited.<br><br>OBJECTIVE: To evaluate EMS personnel perspectives on ambulance ergonomics, safety, comfort, and factors affecting patient care during transport.<br><br>METHODS: A multicentre, cross-sectional survey-based observational study was conducted among Emergency Medical Technologists (EMTs) and paramedics, recruited by convenience sampling, who were involved in patient transport using standard Advanced Life Support (ALS) ambulances across Southern India. Data on ergonomic challenges, safety concerns, occupational injuries, and patient-care factors were collected using a questionnaire developed from existing literature and refined through focused-group discussion and expert content review. Data were analysed using descriptive statistics and chi-square tests in jamovi.<br><br>RESULTS: A total of 130 EMS providers participated. Limited patient-cabin space (60%) and difficulty accessing equipment (50%) were the most frequently reported factors affecting safety and comfort. Half of the respondents reported concerns regarding EMT seat positioning during patient care. Uneven roads (49.23%) and sudden vehicle breakdowns (41.53%) were the leading causes of transport-related injuries. CPR was the procedure most commonly associated with injuries to the care giver (53.84%), while back pain was the predominant occupational health hazard (57.69%). Significant associations were observed between work experience and perceptions of ambulance ergonomics, injury mechanisms, patient safety concerns, and occupational health hazards (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: EMS personnel reported substantial concerns regarding ambulance ergonomics, particularly seat positioning, equipment accessibility, cabin workspace, and occupational safety. These findings emphasize the importance of further ergonomic research in ambulance design to enhance operational ease during in transit care while assuring provider and patient safety.}, }
@article {pmid42553257, year = {2026}, author = {Ammar, FI and Aljahdali, E and Alshrif, A and Alshareef, A and Faidah, D and Almohammadi, M and Makkawi, S}, title = {Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1876331}, pmid = {42553257}, issn = {1664-2295}, abstract = {BACKGROUND: Neurological disorders are associated with considerable morbidity and healthcare impact. Therapeutic plasma exchange (TPE) is an intervention that removes pathogenic antibodies, immune complexes, and other plasma constituents from circulation. Previous studies have suggested that TPE could be associated with improved outcomes in selected neurological disorders.<br><br>OBJECTIVES: To evaluate functional outcomes following therapeutic plasma exchange in patients with selected neurological disorders at National Guard Health Affairs (NGHA) in Jeddah, Saudi Arabia.<br><br>METHODS: This retrospective cohort study analyzes 133 patients diagnosed with various neurological disorders who received TPE between August 2015 and December 2022 at NGHA. Diagnoses included multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barr&#xe9; syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AE), and other neurological conditions including amyotrophic lateral sclerosis (ALS), transverse myelitis, cerebellar ataxia, paraneoplastic neurologic syndrome, polymyositis, and central nervous system (CNS) infections. The effectiveness of TPE was assessed using the Modified Rankin Scale (mRS) before and 90&#x202f;days following the final TPE session. Statistical analysis included Wilcoxon signed-rank tests and Mann-Whitney U test, with significance set at (p&#x202f;<&#x202f;0.05).<br><br>RESULTS: Significant improvements in mRS scores were observed following TPE for MS, MG, and GBS (all p&#x202f;<&#x202f;0.001), as well as for NMOSD (p&#x202f;=&#x202f;0.008), CIDP (p&#x202f;=&#x202f;0.007), and AE (p&#x202f;=&#x202f;0.018), but not in other neurological disorders (p&#x202f;=&#x202f;0.234). Overall mortality was 6.8%, with no TPE-related deaths. Comorbidities among deceased patients included hypertension, diabetes mellitus, malignancy, chronic kidney disease, and cardiovascular disease.<br><br>CONCLUSION: TPE was associated with improved functional outcomes in selected neurological disorders. Comorbidities were common among patients with poorer outcomes. Due to the retrospective design and potential confounding factors, causal inferences cannot be established. Further prospective studies are warranted to evaluate the role of TPE and optimize patient selection.}, }
@article {pmid42553297, year = {2026}, author = {Li, Q and You, M}, title = {Targeting mitochondria for the treatment of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1835506}, pmid = {42553297}, issn = {1662-4548}, abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.}, }
@article {pmid42554090, year = {2026}, author = {Silva, STD and de Souza, AA and de Melo, LP and de Oliveira Cacho, R and de Holanda, LJ and Ortiz, LDN and Dourado Júnior, MET and Farias, IB and Gonçalves, F and Nagem, DAP and de Medeiros Valentim, RA and Lindquist, ARR and Ribeiro, TS}, title = {Evidence-based physiotherapy recommendations for the management of motor aspects in amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/17582024.2026.2713034}, pmid = {42554090}, issn = {1758-2032}, abstract = {AIM: To provide evidence-based recommendations for the physiotherapy management of Amyotrophic Lateral Sclerosis (ALS).<br><br>MATERIALS AND METHODS: Evidence-based recommendations were developed by a multidisciplinary team, including PhDs and master's-level researchers, physicians, and experienced physiotherapists specializing in neurological rehabilitation.<br><br>RESULTS: After the selection process, 23 studies were included. Eighteen recommendations addressing motor aspects in ALS were formulated.<br><br>CONCLUSIONS: Therapeutic exercise should be considered to improve or maintain ALSFRS-R scores in people with ALS. However, the effects of other interventions examined in this study remain uncertain with respect to motor aspects.}, }
@article {pmid42554285, year = {2026}, author = {Benussi, A and Bracca, V and Premi, E and Cantoni, V and Palacino, F and Saccavini, A and Cotelli, MS and Binetti, G and Manenti, R and Alberici, A and Gasparotti, R and Ashton, NJ and Zetterberg, H and Blennow, K and Ghidoni, R and Borroni, B}, title = {Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {8}, pages = {e71722}, pmid = {42554285}, issn = {1552-5279}, support = {//University of Brescia, Italy/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; }, mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood ; Aged ; Middle Aged ; Neurofilament Proteins/blood ; Disease Progression ; Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Supranuclear Palsy, Progressive/pathology ; }, abstract = {BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.<br><br>METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.<br><br>RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.<br><br>CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.}, }
@article {pmid42554695, year = {2026}, author = {Krajewski, TJ and Koch, GG}, title = {Randomization-based covariance analysis for hypothesis testing of treatment comparisons based on restricted mean survival time with categorized time-to-event data.}, journal = {Journal of biopharmaceutical statistics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/10543406.2026.2699854}, pmid = {42554695}, issn = {1520-5711}, abstract = {This paper introduces randomization-based analysis of covariance (RB-ANCOVA) for hypothesis testing of restricted mean survival time (RMST) differences between two randomized treatments in trials with categorized time-to-event data. RMST treatment differences over a prespecified time period are clinically meaningful and avoid assumptions like proportional hazards. The proposed method tests the strong null hypothesis that each participant's time-to-event would remain unchanged regardless of treatment assignment. Covariate adjustment is achieved by constraining baseline covariate means to be equal across arms, which reduces variance. The follow-up period is partitioned into mutually exclusive intervals, and RMST is approximated as the area under the survival curve. Under the strong null hypothesis, the joint asymptotic covariance structure of RMST and covariate means is known and used to construct a chi-squared test statistic for the covariate-adjusted RMST difference. The method accommodates stratified trial designs and supports hypothesis testing over single or several time intervals, enabling testing within internal intervals. The difference in RMSTs over an interval can be divided by its length to yield an average survival rate difference. Additionally, the approach allows the computation of essentially exact p-values via re-randomization. We illustrate the method with data from a randomized, placebo-controlled trial evaluating a test treatment for amyotrophic lateral sclerosis. This method provides a hypothesis testing approach for RMST treatment differences that leverages RB-ANCOVA to adjust for their correlations with baseline covariate differences. Under the strong null hypothesis, it enables hypothesis testing with clear control of Type I error and reduced variance without relying on model-based assumptions.}, }
@article {pmid42554905, year = {2026}, author = {Colín-Martínez, E and Ramírez-Jarquín, UN and Tapia, R and Arias, C}, title = {Inhibition of Glutamate Decarboxylase in the Spinal Cord Induces Motor Deficits and Motor Neuron Degeneration.}, journal = {Neurotoxicity research}, volume = {44}, number = {4}, pages = {}, pmid = {42554905}, issn = {1476-3524}, support = {IN206719//Direcci&#xf3;n General de Asuntos del Personal Acad&#xe9;mico, Universidad Nacional Aut&#xf3;noma de M&#xe9;xico/ ; A1-S12135//Secretar&#xed;a de Ciencia, Humanidades, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; }, mesh = {Animals ; *Glutamate Decarboxylase/metabolism/antagonists &amp; inhibitors ; *Spinal Cord/drug effects/pathology/enzymology ; *Motor Neurons/drug effects/pathology/enzymology ; *Enzyme Inhibitors/toxicity/pharmacology ; *Nerve Degeneration/pathology/chemically induced/enzymology ; Male ; Rats ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {Motor neuron (MN) diseases such as amyotrophic lateral sclerosis (ALS) are characterized by the loss of cortical and spinal MNs. Although the precise mechanisms of MN degeneration are still unknown, downregulation of GABAergic circuits has been identified in both ALS patients and transgenic models of the disease. GABA synthesis depends on the activity of the enzyme glutamate decarboxylase (GAD), of which two isoforms are known: GAD65 and GAD67. To study the effects of decreased GABA synthesis on spinal cord motor function, we analyzed the effects of administering three selective inhibitors of GAD: 3-mercaptopropionic acid (MPA), a competitive inhibitor of GAD, thiosemicarbazide (TSC), and pyridoxal phosphate γ-glutamyl hydrazone (PLPGH), two GAD cofactor blockers. A single dose of any of these inhibitors did not affect motor behavior or MN morphology. However, subchronic (3 days) and chronic (10 days) administration of MPA, TSC or PLPGH in rats caused motor alterations and cellular changes, including episodic myoclonus-like movements, flaccidity in the ipsilateral phalanges, loss of 35-50% of MNs, reactive astrogliosis and decreased GAD activity. These findings suggest that chronic inhibition of GAD can lead to MN degeneration and further suggest that GABA metabolism in the spinal cord may participate in the mechanisms that cause MN death in patients with neurodegenerative diseases such as ALS.}, }
@article {pmid42555669, year = {2026}, author = {Hubbard, I and Dubnau, J}, title = {Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.}, journal = {PLoS genetics}, volume = {22}, number = {8}, pages = {e1011909}, doi = {10.1371/journal.pgen.1011909}, pmid = {42555669}, issn = {1553-7404}, abstract = {The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.}, }
@article {pmid42556002, year = {2026}, author = {Tekan, &#xdc;Y and Aksoy, E and Kargın, F and Küçük, RS and Saltürk, C and Çiyiltepe, F and Yavuz, D and Güngör, G and Adıgüzel, N and Karakurt, Z}, title = {Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {153}, number = {}, pages = {112228}, doi = {10.1016/j.jocn.2026.112228}, pmid = {42556002}, issn = {1532-2653}, abstract = {BACKGROUND: Patients with chronic neurological diseases (CND) are at increased risk of pulmonary complications that often require ICU admission. This study aimed to identify clinical factors associated with ICU mortality and long-term survival in patients with CND who developed acute respiratory failure (ARF).<br><br>METHODS: This retrospective cohort study was conducted in a level III respiratory ICU. Patients with pre-existing CND admitted to the ICU with ARF were included. ICU mortality was analyzed using multivariable logistic regression. Long-term survival after ICU discharge was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. Mortality timing was further characterized using hazard function analysis.<br><br>RESULTS: A total of 220 patients were included; the most common neurological diagnoses were dementia (37.3%), stroke (22.7%), and amyotrophic lateral sclerosis (14.1%). ICU mortality was 33.6%. Higher APACHE II scores were independently associated with increased ICU mortality (OR 1.076 per point increase; 95% CI 1.029-1.126; p&#xa0;<&#xa0;0.001). Long-term survival differed significantly by post-discharge respiratory support strategy, with Kaplan-Meier analysis demonstrating more favorable survival patterns among patients receiving home non-invasive mechanical ventilation (NIMV) (p&#xa0;=&#xa0;0.003). In Cox regression analysis, age, home NIMV, and feeding modality at discharge were independently associated with long-term outcomes. Survival analyses revealed an early clustering of deaths within the first months after ICU discharge, particularly among patients with dementia.<br><br>CONCLUSIONS: In patients with CND, acute physiological severity was the main determinant of ICU mortality, whereas long-term survival after ICU discharge was poor, with deaths clustering within the first months thereafter. Post-discharge respiratory support and nutritional management should be individualized according to the expected clinical trajectory and patient values.}, }
@article {pmid42547788, year = {2026}, author = {Wo, XM and Zhang, GM}, title = {Interpreting the clinical utility and generalizability of a multitask perioperative prediction model.}, journal = {NPJ digital medicine}, volume = {9}, number = {1}, pages = {}, pmid = {42547788}, issn = {2398-6352}, abstract = {This Matters Arising comments on Yoon et al.'s multitask gradient boosting model for predicting acute kidney injury, postoperative respiratory failure and in-hospital mortality after non-cardiac surgery. We ask for clarification on the clinical decision context and threshold ranges in the decision curve analyses, the absolute impact of the model for rare outcomes, and calibration and potential recalibration in external cohorts to support implementation.}, }
@article {pmid42547898, year = {2026}, author = {Domke, N and Geue, K and Schlichte, I and Ullsperger, M and Meyer, T and Petri, S and Schreiber, S and Vielhaber, S and Junne, F and Vogt, S}, title = {Depressive symptoms in amyotrophic lateral sclerosis: associations with quality of life, disease progression and perceived social support-a German multicenter study.}, journal = {BMC psychology}, volume = {14}, number = {1}, pages = {}, pmid = {42547898}, issn = {2050-7283}, mesh = {Humans ; *Social Support ; *Quality of Life/psychology ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Female ; Male ; Disease Progression ; Cross-Sectional Studies ; Middle Aged ; *Depression/psychology ; Aged ; Germany ; Adult ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease. Patients with ALS are at increased risk of developing depressive symptoms. A clearer understanding of the associations between depressive symptoms, disease progression, health-related quality of life and perceived social support is needed to advance intervention-oriented research and improve psychosocial care in ALS.<br><br>METHODS: In a multicenter cross-sectional study, patients with ALS were asked to complete patient-reported outcomes (PROs) to evaluate depressive symptoms (ALS-Depression-Inventory, ADI-12), health-related quality of life (ALS-Assessment-Questionnaire, ALSAQ-5/ALSAQ-40), physical functioning (ALS-Functional Rating Scale-Extension, ALSFRS-EX) and perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS). To evaluate associations between demographic/clinical variables and PROs, we performed Pearson's, Spearman's, and partial correlation analyses. In addition, a multiple regression was run to identify predictors of depressive symptoms. Comparisons of patient groups were performed with chi-squared tests for categorical variables and Student t-tests or one-way analysis of variance (ANOVA) for continuous variables, followed by post-hoc tests.<br><br>RESULTS: Out of the 150 patients examined, 60% reported depressive symptoms, with half of them exhibiting clinically relevant depressive symptoms. Depressive symptoms were significantly associated with disease progression (r&#x2009;=&#x2009;.466, p&#x2009;<&#x2009;.001), various aspects of health-related quality of life (mobility: r&#x2009;=&#x2009;.394, activities of daily living: r&#x2009;=&#x2009;.268 and emotional well-being: r&#x2009;=&#x2009;.793, all p&#x2009;<&#x2009;.001), the MSPSS sum score (partial r&#x2009;=&#x2009;-.234, p&#x2009; =&#x2009;.007), and the ALSFRS-EX sum score (r&#x2009;=&#x2009;-.352, p&#x2009;<&#x2009;.001). Patients with depressive symptoms reported significantly more physical impairments (p&#x2009;=&#x2009;.002) and less perceived social support by their families (p&#x2009;=&#x2009;.016) and friends (p&#x2009;<&#x2009;.001) compared to patients without depressive symptoms.<br><br>CONCLUSIONS: Depressive symptoms are prevalent in patients with ALS and are closely associated with faster disease progression, reduced physical functioning, poorer health-related quality of life, and lower perceived social support. Further studies, particularly using qualitative methods, are needed to elucidate protective factors, clarify psychosocial mechanisms, and support the conceptualization of specialized and integrated psychosocial care for patients with ALS in Germany.}, }
@article {pmid42548030, year = {2026}, author = {Matsuki, Y and Bokuda, K and Morishima, R and Kawazoe, T and Kimura, H and Takahashi, K and Nakayama, Y and Shimizu, T}, title = {Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70371}, pmid = {42548030}, issn = {1097-4598}, support = {22H03398//JSPS KAKENHI/ ; }, abstract = {INTRODUCTION/AIMS: Sensory cortical hyperexcitability, reflected by enlarged median nerve somatosensory evoked potentials (SEPs), has been reported in amyotrophic lateral sclerosis (ALS) and is associated with shorter survival. This study investigated whether similar changes involve the ulnar nerve representation within the hand area of the primary somatosensory cortex and examined their relationship with survival.<br><br>METHODS: Ninety-nine patients with sporadic ALS and 42 healthy controls were retrospectively studied. Sensory nerve action potentials (SNAPs) and SEPs were recorded following median and ulnar nerve stimulation. SNAP amplitudes and the peak-to-peak amplitudes between N20 and P25 (N20p-P25p) were compared between groups. Patients were followed until death or tracheostomy, and associations between SEP amplitudes and survival were analyzed using Kaplan-Meier and Cox proportional hazards analyses.<br><br>RESULTS: SNAP amplitudes did not differ between patients and controls. In contrast, patients with ALS showed larger N20p-P25p amplitudes for both median and ulnar nerve SEPs. N20p-P25p amplitudes were positively correlated between the two nerves, and the ulnar-to-median amplitude ratio did not differ from controls. Patients with ulnar N20p-P25p&#x2009;&#x2265;&#x2009;4.89&#x2009;&#x3bc;V had significantly shorter survival than those with lower amplitude (log-rank test, p&#x2009;=&#x2009;0.035). Multivariate Cox analysis identified increased N20p-P25p amplitude as an independent predictor of shorter survival for both nerves.<br><br>DISCUSSION: Sensory cortical hyperexcitability in ALS extends beyond the median nerve to the ulnar nerve hand area of the somatosensory cortex. Its association with survival supports the notion that sensory cortical dysfunction represents a fundamental pathophysiological feature of ALS and a potential electrophysiological prognostic marker.}, }
@article {pmid42548241, year = {2026}, author = {Konarbayeva, Z}, title = {Rheological and Technological Design of Texture-Modified Food Systems for Dysphagia Management in Amyotrophic Lateral Sclerosis.}, journal = {Journal of texture studies}, volume = {57}, number = {4}, pages = {e70105}, pmid = {42548241}, issn = {1745-4603}, mesh = {*Deglutition Disorders/etiology/diet therapy ; *Amyotrophic Lateral Sclerosis/complications ; *Rheology ; Humans ; Viscosity ; *Food Technology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is frequently accompanied by progressive dysphagia, weight loss, and hypermetabolism, which complicate the maintenance of adequate nutritional status. For these patients, food systems must not only provide sufficient energy and protein within a limited volume but also exhibit textural and rheological properties that support safe swallowing. This review analyzes technological and rheological approaches to the design of texture-modified food systems for nutritional support in ALS. Particular attention is given to apparent viscosity, shear-thinning behavior, yield stress, structural homogeneity, and storage stability as parameters affecting bolus formation, swallowing safety, and product performance. The relevance of the International Dysphagia Diet Standardization Initiative framework for classifying food textures and liquid consistencies is also considered. The review further examines the functional and technological roles of animal- and plant-based raw materials, including regional raw materials, in the formulation of energy-dense and structurally stable foods. Proteins, lipids, hydrocolloids, starch gels, and polysaccharide networks are discussed as key components for controlling texture, viscosity, gelation, emulsion stability, and nutritional density. Technological strategies such as homogenization, emulsification, protein-based structuring, hydrocolloid thickening, high-pressure homogenization, and 3D food printing are considered in relation to their potential for developing safe, acceptable, and locally adaptable products for patients with ALS-related dysphagia. The findings highlight the need to integrate food texture science, rheological control, nutritional adequacy, sensory acceptability, and regional availability in the development of clinically relevant texture-modified foods.}, }
@article {pmid42548317, year = {2026}, author = {Hwang, JJ and Donnelly, TT and Davidson, S and Raffin Bouchal, S}, title = {Between Denial and Delay: Barriers to Accessing Nonpharmacological Interventions for Seniors With Mild-to-Moderate Dementia in Canada.}, journal = {Qualitative health research}, volume = {}, number = {}, pages = {10497323261468186}, doi = {10.1177/10497323261468186}, pmid = {42548317}, issn = {1552-7557}, abstract = {Dementia is a growing public health concern in Canada, yet timely access to nonpharmacological interventions (NPIs) for persons with dementia (PWDs) remains poorly understood. This critical ethnographic study explored factors influencing access to NPIs among private-dwelling seniors with mild-to-moderate dementia and their family/friend care partners (CPs) in Alberta, Canada. Guided by McLeroy et al.'s Ecological Perspective and Habermas' Critical Social Theory, we conducted 53 semi-structured interviews with eight PWDs and 21 CPs across 20 families. Reconstructive, thematic analysis revealed 10 interrelated factors across socioecological domains: intrapersonal (denial, acceptance, and perceived benefits), interpersonal (support from CPs, physicians, and case managers), organizational (program acceptability and accessibility), community (stigma), and policy (funding constraints). Findings illuminate how systemic conditions such as market-driven care models and fragmented care pathways intersect with lifeworld dynamics, including stigma and relational coping, to shape families' navigation of NPIs. While PWDs relied on their CPs for information and coordination of NPIs, CPs encountered significant informational and navigational barriers. Program invisibility, lengthy referrals, and limited capacity compounded inequities, often leaving families to cope in isolation or seek privatized alternatives. Stigma operated subtly yet systematically, reinforcing therapeutic nihilism, evidence-practice gaps, and policy stagnation. These findings highlight the need to reconceptualize two widely used and valued services, adult day programs and companion care, within a rehabilitative, nonpharmacological framework, strengthen anticipatory guidance, and invest in early, equitable care pathways. Addressing system-lifeworld tensions is essential for dementia care that promotes dignity, connection, and quality of life.}, }
@article {pmid42548517, year = {2024}, author = {Palm, A and Grote, L and Einarsson, J and Hansson, D and Ljunggren, M and Sundh, J and Ekström, M}, title = {Evolution of Home Mechanical Ventilation in Sweden Over 27 Years: Changing Trends in Incidence, Prevalence, and Patient Characteristics - The Population-Based the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) Study.}, journal = {CHEST pulmonary}, volume = {2}, number = {4}, pages = {100108}, pmid = {42548517}, issn = {2949-7892}, abstract = {BACKGROUND: Home mechanical ventilation (HMV), noninvasive ventilation and invasive ventilation outside a hospital setting, is a key treatment to improve outcomes in chronic hypoventilation.<br><br>RESEARCH QUESTION: What are the temporal trends observed over 27 years in Sweden regarding the incidence, prevalence, diagnostic spectrum, and patient characteristics associated with HMV?<br><br>STUDY DESIGN AND METHODS: This was a national population-based longitudinal analysis of the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) study of patients initiating HMV between 1996 and 2022. Time trends stratified by the underlying diagnosis group (lung disease, predominantly COPD, restrictive thoracal diseases, obesity hypoventilation syndrome [OHS], neuromuscular diseases, amyotrophic lateral sclerosis, and other neurologic disorders) were analyzed using linear regression models.<br><br>RESULTS: We included 10,555 patients aged&#xa0;&#x2265; 16 years (mean age 63 [SD, 15] years; 50%&#xa0;women). Between 1996 and 1998 and 2020 and 2022, the HMV incidence increased threefold to 7 per 100,000 people, and the prevalence increased sixfold to 33 per 100,000 people. The most common indication for incident HMV shifted from restrictive thoracal diseases (35%&#xa0;in 1996-1998 to 3%&#xa0;in 2020-2022) to lung disease (14%&#xa0;to 31%), OHS (23%&#xa0;to 33%), and amyotrophic lateral sclerosis (4%&#xa0;to 14%) by 2020 to 2022 (P&#xa0;< .001). The proportion of women increased from 47%&#xa0;to 54%&#xa0;(P&#xa0;< .013) and the age at initiation of HMV increased from 58 [SD, 15] to 66 [SD, 14] years (P&#xa0;< .001). Lung function measured as vital capacity at treatment start increased significantly in all diagnosis groups except for OHS, where both vital capacity and FEV1 decreased. In the registry's first and last 3-year periods, the proportion of patients ventilated invasively decreased from 10%&#xa0;to 2%&#xa0;(P&#xa0;< .001).<br><br>INTERPRETATION: In the 27 years until 2022, the incidence and prevalence of HMV in Sweden have increased markedly, patient demographics have changed, and use of invasive ventilation has decreased. The average age of patients initiated on HMV has increased, but treatment is started earlier in the disease trajectory.}, }
@article {pmid42548788, year = {2026}, author = {Erazo, D and Hesters, A and Bruneteau, G and De La Cruz, E and Bernard, E and Grapperon, AM and Le Masson, G and Cintas, P and Soriani, MH and Guy, N and Cassereau, J and Camdessanché, JP and Genestet, S and Corcia, P and Pittion, S and Danel, V and Filliatre, M and Choumert, A and Jacquin-Piques, A and Salachas, F and Esselin, F and Bohic, A and Lautrette, G and Attarian, S and Catteau, J and Guissart, C and Vincent, MC and Mouzat, K and Temple, M and Vourc'h, P and Couratier, P}, title = {Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).}, journal = {Mayo Clinic proceedings. Innovations, quality &amp; outcomes}, volume = {10}, number = {5}, pages = {100739}, pmid = {42548788}, issn = {2542-4548}, abstract = {OBJECTIVE: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort.<br><br>PATIENTS AND METHODS: Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline.<br><br>RESULTS: In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 &#xb1; 0.5 at baseline to 0.22 &#xb1; 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 &#xb1; 9.0 pg/ml at baseline to 29.2 &#xb1; 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03).<br><br>CONCLUSION: Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.}, }
@article {pmid42549498, year = {2026}, author = {Iijima, N and Hagiwara, Y and Ishii, S and Kaneko, W and Araga, T and Yamano, Y}, title = {Quantitative Assessment of Tongue Atrophy in Amyotrophic Lateral Sclerosis Using Transoral Tongue Ultrasonography (TOTU): A Retrospective Single-Center Study.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70370}, pmid = {42549498}, issn = {1097-4598}, support = {25ek0109735//Japan Agency for Medical Research and Development/ ; 25fk0108733//Japan Agency for Medical Research and Development/ ; 25bm1423033//Japan Agency for Medical Research and Development/ ; 25ek0109617//Japan Agency for Medical Research and Development/ ; 25ek0109759//Japan Agency for Medical Research and Development/ ; 25FC1012//Ministry of Health, Labour and Welfare/ ; JP25K02584//Japan Society for the Promotion of Science/ ; JP24K10542//Japan Society for the Promotion of Science/ ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by bulbar dysfunction, in which tongue atrophy contributes to dysarthria and dysphagia. Conventional tongue assessments rely on inspection, palpation, or electrophysiological testing but are limited by subjectivity and invasiveness. A rapid, objective, and repeatable imaging-based method for evaluating tongue size would be valuable. We quantified tongue atrophy in ALS using a standardized protocol for transoral tongue ultrasonography (TOTU) and assessed discrimination.<br><br>METHODS: This retrospective, cross-sectional study included 15 patients with ALS and 15 controls who underwent TOTU. Using standardized mid-sagittal images, tongue cross-sectional area (cm[2]) and tongue thickness (mm) were measured three times per subject and averaged. Associations with age, body mass index (BMI), disease duration, and ALS Functional Rating Scale-Revised (ALSFRS-R) scores were explored. Discrimination was evaluated using receiver operating characteristic (ROC) analyses.<br><br>RESULTS: Both tongue cross-sectional area (6.26&#x2009;&#xb1;&#x2009;1.37 vs. 9.44&#x2009;&#xb1;&#x2009;1.02&#x2009;cm[2]) and tongue thickness (31.47&#x2009;&#xb1;&#x2009;3.0 vs. 39.44&#x2009;&#xb1;&#x2009;1.39&#x2009;mm) were significantly lower in the ALS group than in controls (both p&#x2009;<&#x2009;0.001). These indices showed no significant associations with age, BMI, disease duration, or ALSFRS-R scores. ROC analyses showed high discriminative ability, with an area under the curve of 0.982 for tongue cross-sectional area and 1.000 for tongue thickness.<br><br>DISCUSSION: Standardized TOTU enables rapid, quantitative, noninvasive assessment of tongue size and reliably detects tongue atrophy in ALS, supporting bedside evaluation of bulbar involvement.}, }
@article {pmid42549723, year = {2026}, author = {Buthelezi, U and Lubuzo, B and Tingen, M and Chiya, H and Gigaba, SG and Goeieman, B and Ramotsela, S and Luvuno, Z}, title = {Adapting a United States cancer education programme for South Africa: A participatory, culturally tailored approach using Card's Seven-Step adaptation framework.}, journal = {African journal of primary health care &amp; family medicine}, volume = {18}, number = {1}, pages = {e1-e10}, doi = {10.4102/phcfm.v18i1.5442}, pmid = {42549723}, issn = {2071-2936}, mesh = {Humans ; South Africa ; *Neoplasms/prevention &amp; control ; Primary Health Care ; United States ; Community-Based Participatory Research ; *Health Education/methods/organization &amp; administration ; Implementation Science ; Female ; }, abstract = {BACKGROUND: South Africa faces a growing cancer burden characterised by late-stage presentation, limited screening uptake and disparities in access to cancer education. While evidence-based cancer education programmes developed in high-income countries demonstrate effectiveness, direct transfer without contextual modification may compromise relevance and acceptability within resource-constrained health settings.<br><br>AIM: &#xa0;To systematically adapt the United States (US)-based Cancer-Community Awareness Access Research Education (c-CARE) programme as a multi-cancer education intervention for implementation within the South African primary health care (PHC) context using Card et al.'s seven-step adaptation framework.<br><br>SETTING: &#xa0;The adaptation was conducted in KwaZulu-Natal (iLembe District) and Gauteng (Johannesburg), South Africa, in collaboration with provincial Departments of Health, community health workers, traditional health practitioners and faith-based leaders.<br><br>METHODS: &#xa0;This implementation science study employed Participatory Action Research integrated with Card's framework to guide a structured adaptation process (January 2023 - January 2024). Thirty-eight consultative meetings were conducted to review programme materials, identify linguistic, cultural and structural mismatches and implement iterative revisions while preserving core intervention components.<br><br>RESULTS: &#xa0;Key adaptations included the addition of cervical cancer as a priority module; incorporation of South African epidemiological data and referral pathways; translation into isiZulu and Sesotho; integration of mental health, spirituality and palliative care content; and restructuring of delivery to align with the South African Health System. Core evidence-based content, modular design and interactive pedagogical strategies were retained.<br><br>CONCLUSION: &#xa0;Framework-guided adaptation enabled contextual recalibration of c-CARE while maintaining fidelity to core components.Contribution:&#xa0;This study provides a transparent model for adapting evidence-based cancer education interventions for culturally diverse, resource-constrained PHC systems.}, }
@article {pmid42538773, year = {2026}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Matteoni, E and Maccabeo, A and Cabras, S and Pellegrino, G and Minerva, E and Giudici, AD and Passidomo, V and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A}, title = {Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70720}, pmid = {42538773}, issn = {1468-1331}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Universit&#xe0; e della Ricerca/ ; 20228N7573//Ministero dell'Universit&#xe0; e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//HORIZON EUROPE Framework Programme/ ; DIG-ALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/complications/psychology/physiopathology ; Middle Aged ; Aged ; Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; *Cognitive Dysfunction/etiology/physiopathology ; Executive Function/physiology ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs).<br><br>METHODS: Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3&#x2009;months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria.<br><br>RESULTS: Thirty-two PLS patients were included (mean disease duration, 25&#x2009;months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia.<br><br>INTERPRETATION: Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.}, }
@article {pmid42539086, year = {2026}, author = {Lee, BH and Chan, J and Leung, YY and McMillan, CT and ,  and Song, Y and Amado, DA and Wang, K}, title = {Dissecting the relationship between haplotypes around ATXN2 CAG repeats and the number of CAA interruptions by long-read sequencing.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.11.26348169}, pmid = {42539086}, abstract = {BACKGROUND: CAG repeat expansions in ATXN2 are implicated as risk factors for several neurological diseases, including spinocerebellar ataxia type 2 (SCA2) when >=33 CAG repeats are present, and amyotrophic lateral sclerosis (ALS) when 27-33 CAG repeats are present. However, how haplotypes around the repeats and CAA interruptions within the repeats are associated with disease phenotypes remains poorly understood. Previous studies on haplotypes around ATXN2 were limited to SNPs very close to the repeats (<5kb) or were based on statistical inference only.<br><br>METHODS: Here, we used long-read sequencing on the Oxford Nanopore Technologies (ONT) platform to simultaneously infer haplotypes around ATXN2 , the number of CAG repeats, and the number of CAA interruptions, along with NYGC ALS Consortium NGS dataset. We further sequenced 41 individuals (EUR = 39) with neurological diseases with intermediate repeats by ONT.<br><br>RESULTS: We found that haplotypes around ATXN2 and the number of interruptions show ethnicity-specific and ALS-specific distribution. Three CAA interruptions are present at low prevalence (&#x223c;1%) in control populations in multiple ancestry groups, but high prevalence (&#x223c;55%) in ALS individuals with intermediate repeats. Furthermore, we examined 159 individuals with ALS (&#x223c;90% European ancestry) with intermediate ATXN2 repeats and found a unique haplotype in ALS individuals with three CAA interruptions, which can be tagged by an SNV, rs148019457. We also validated that the rs148019457-G allele is only present in haplotypes with three CAA interruptions.<br><br>CONCLUSIONS: In summary, our study shows that 3 CAA interruptions are rarely seen in healthy controls but are common in those with expanded ATXN2 CAG repeats who have neurological disorders, and that rs148019457 tags a specific haplotype with 3 CAA interruptions within expanded ATXN2 CAG repeats in individuals of European ancestry. These results have implications for the development of precision genomic medicine for neurological disorders, and the tag SNP may help identify those with interruptions from existing population genotyping data.}, }
@article {pmid42539252, year = {2026}, author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, E and Asher, MJ and Isaacs, A and Garner, AL and Todd, PK}, title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.16.739042}, pmid = {42539252}, issn = {2692-8205}, abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks global cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global increase in start codon stringency in neurons as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with a cytoplasmic redistribution of eIF1 in neurons and is reversed with neuronal overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and selectively enhances cap-dependent RAN translation. Taken together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis and neuronal translational regulation.}, }
@article {pmid42539319, year = {2026}, author = {Zhou, Y and Luster, CB and Pinto, SM and Feigel, ED and Paganoni, S and Izzy, S and Zafonte, RD and Giacino, JT and Hammond, FM and Daneshvar, DH}, title = {Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis Mortality: A Traumatic Brain Injury Model Systems Study.}, journal = {Neurotrauma reports}, volume = {7}, number = {}, pages = {2689288X261450846}, pmid = {42539319}, issn = {2689-288X}, abstract = {Emerging evidence suggests that amyotrophic lateral sclerosis (ALS) mortality is elevated following traumatic brain injury (TBI), reflecting a consequence of potential prodromal ALS, though the temporal patterns and underlying mechanisms remain unclear. We aimed to evaluate ALS mortality among individuals with TBI and examine temporal patterns. This study leveraged a retrospective cohort study of 20,250 individuals with complicated mild-to-severe TBI enrolled in the TBI Model Systems (TBIMS) from 1987 to 2024, with a cumulative 198,662 person-years (mean [standard deviation] = 9.8 [7.1] years) of follow-up. Standardized mortality ratios (SMRs) were calculated using the National Institute for Occupational Safety and Health Life Table Analysis System R package, adjusting for age, sex, race, and calendar year. Secondary analyses evaluated temporal patterns and injury severity differences in ALS mortality. Among 4,313 decedents in TBIMS, 11 died of ALS, representing significantly elevated mortality from ALS (SMR = 2.39; 95% confidence interval [CI]: 1.19-4.27) compared with the general population. Time-stratified analyses showed elevated ALS mortality within 2 years post-injury (SMR = 4.30; 95% CI: 1.17-11.01), but not after 2 years (SMR = 1.90; 95% CI: 0.76-3.92). Elevated ALS mortality was also observed within 2 years post-injury among those with severe TBI (SMR = 5.00; 95% CI: 1.03-14.61) and when including individuals with ALS at admission (SMR = 6.45; 95% CI: 2.37-14.04). ALS mortality was higher in the TBIMS cohort than in the general population, and this association was confined to within 2 years of injury. This pattern suggests potential reverse causality, whereby some TBIs in the cohort may have occurred in the setting of prodromal or pre-symptomatic ALS. Further investigation into TBI as a sign of subclinical ALS is warranted.}, }
@article {pmid42540536, year = {2026}, author = {Wang, S and Lin, Y and Che, Y and Zhao, J and Xu, L and He, W and Zhang, W}, title = {Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.}, journal = {Archives of medical science : AMS}, volume = {22}, number = {3}, pages = {1663-1677}, pmid = {42540536}, issn = {1734-1922}, abstract = {INTRODUCTION: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.<br><br>MATERIAL AND METHODS: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I[2] statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.<br><br>RESULTS: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.<br><br>CONCLUSIONS: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.}, }
@article {pmid42541368, year = {2026}, author = {Hirano, Y}, title = {Long-term trajectories of physical, psychological, and psychosocial experiences among people living with amyotrophic lateral sclerosis using tracheostomy invasive ventilation: An 18-year longitudinal study.}, journal = {Journal of health psychology}, volume = {}, number = {}, pages = {13591053261474390}, doi = {10.1177/13591053261474390}, pmid = {42541368}, issn = {1461-7277}, abstract = {Advances in respiratory care have enabled people living with amyotrophic lateral sclerosis (PALS) using tracheostomy invasive ventilation (TIV) to live for many years with the disease. However, longitudinal evidence describing their psychosocial trajectories remains limited. This study explored the long-term trajectories of three PALS using TIV through repeated face-to-face assessments over an approximately 18 year period. Psychological state, subjective physical symptoms, and hope followed similar patterns across participants, worsening after illness onset and reaching their lowest levels between diagnosis and TIV initiation before improving and becoming increasingly individual over time. Perceived psychological support and sources of joy peaked after TIV initiation before fluctuating, whereas perceived financial status remained relatively stable. These findings demonstrate a shared pattern of early adaptation followed by increasingly individual long-term trajectories, providing a foundation for trajectory-informed holistic care.}, }
@article {pmid42541567, year = {2026}, author = {Estevez-Fraga, C and Alvarez-Velasco, R and Afroz, T and Costa, MR and Jovičić, A and Yeh, FL and McColgan, P and Malaspina, A and McCampbell, A}, title = {Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42541567}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by motor neuron degeneration leading to early mortality. Despite advances in understanding genetic and molecular contributors, effective disease-modifying therapies for sporadic ALS are of limited utility. The identification of the accumulation of TAR DNA-binding protein 43 (TDP-43) in 97% of total ALS cases represents a critical pathogenic hallmark. This review examines key biological mechanisms underlying TDP-43 pathology, emerging therapeutic strategies, and evolving approaches to clinical trial design and biomarker development. TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction. Therapeutic strategies targeting these pathways are currently under investigation. Additional approaches aim to ameliorate TDP-43 gain-of-function through cytoplasmic TDP-43 aggregation or modulating processes such as stress responses and RNA metabolism, although clinical translation has been challenging. Advances in biomarkers, including neurofilament light chain and cryptic exon-derived peptides, provide tools for developing efficient clinical trials. However, heterogeneity in disease progression and limitations of available clinical endpoints complicate trial design. Integration of biological insights with biomarker-driven patient stratification and optimized trial methodologies is essential to improve clinical trial outcomes. Emerging biomarkers may enable earlier diagnosis, monitoring of therapeutic response, and personalized treatment approaches. Continued alignment of biological discovery with innovative clinical trial design holds promise for advancing effective therapies and transforming the future of ALS.}, }
@article {pmid42541645, year = {2026}, author = {Chu, M and Tan, M and Gan, X and Cui, S and Shi, L}, title = {Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42541645}, issn = {1559-1182}, mesh = {*Microglia/metabolism/pathology/drug effects ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; *Mitochondria/metabolism/pathology/drug effects ; Animals ; }, abstract = {Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.}, }
@article {pmid42542073, year = {2026}, author = {Oriquat, G and Rizaev, J and Abdulqader, AF and Kadhim, AA and Jamuna, KV and Singhal, D and Bainsal, N and Mansurova, N}, title = {Gut microbiota and brain health: Disease-specific pathways and emerging therapeutic strategies.}, journal = {Multiple sclerosis and related disorders}, volume = {113}, number = {}, pages = {107407}, doi = {10.1016/j.msard.2026.107407}, pmid = {42542073}, issn = {2211-0356}, abstract = {The microbiota-gut-brain axis (MGBA) has emerged as a dynamic, bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS) through neural, immune, endocrine, and metabolic mechanisms. Increasing evidence indicates that alterations in gut microbial communities are associated with a wide range of neurological disorders; however, the strength of this association varies across diseases, and many mechanistic observations still rely predominantly on experimental models rather than human studies. This review provides an overview of current evidence regarding the role of the gut microbiota in maintaining CNS homeostasis, with particular emphasis on intestinal barrier function, immune modulation, vagal and enteric communication, and the generation of biologically active microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitter-related compounds. Studies in both clinical and experimental settings have reported disease-specific microbial signatures in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorders, and amyotrophic lateral sclerosis. In parallel, microbiota-directed interventions-including probiotics, prebiotics, dietary approaches, fecal microbiota transplantation, and strategies targeting microbial metabolites-have produced encouraging findings in preclinical studies and early-stage clinical investigations. Nevertheless, considerable heterogeneity in study populations, experimental methodologies, and therapeutic protocols continues to limit the translation of these findings into routine clinical practice. Collectively, current evidence supports the MGBA as a valuable framework for understanding neurological diseases while underscoring the need for rigorously designed longitudinal studies and well-controlled clinical trials to define its therapeutic relevance better.}, }
@article {pmid42543118, year = {2026}, author = {Du, L and Yan, J}, title = {Lineage-calibrated peripheral monocyte-derived myeloid states in neurodegenerative disease: Recruitment, lesion decoding, and state persistence.}, journal = {Neurobiology of disease}, volume = {228}, number = {}, pages = {107556}, doi = {10.1016/j.nbd.2026.107556}, pmid = {42543118}, issn = {1095-953X}, abstract = {Peripheral monocytes and monocyte-derived macrophages are increasingly implicated in neurodegenerative disease, yet interpretation remains limited by phenotypic convergence with resident microglia, inconsistent lineage attribution, and strong dependence on experimental model and disease stage. We present a structured, lineage-calibrated framework that separates three linked processes: a recruitment gate controlling access to CNS borders and lesions; a lesion-decoding hub through which aggregate, lipid, cytokine, complement, antigenic, hypoxic, and danger-associated inputs are interpreted; and a state-persistence layer in which metabolic and epigenetic reinforcement stabilizes inflammatory, repair-supportive, or hybrid repair-restrictive programs. To make the framework operational, we first provide a cross-disease synthesis and then map representative models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis to their specific recruitment routes, lesion cues, lineage confidence, and functional outcomes. We also distinguish what single-cell or spatial data can infer from what only origin-resolving approaches can establish, and propose practical terminology for studies that cannot perform fate mapping or parabiosis. A worked therapeutic example illustrates why the same recruitment pathway may be harmful during lesion expansion but useful during debris clearance and recovery. The central question is therefore not whether monocytes are present, but which model, compartment, time point, evidentiary tier, and stabilized state justify a disease-modifying claim. This framework links mechanistic evidence to biomarkers, patient stratification, and stage-aware intervention while reducing over-attribution of peripheral origin.}, }
@article {pmid42543164, year = {2026}, author = {Wang, CY and Taylor, S and Pandya, VA and Clarke, BE and Pal, K and Shelkovnikova, TA and Wang, Y and Luisier, R and Patani, R}, title = {Intron retention in health and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {8}, pages = {2604-2618}, pmid = {42543164}, issn = {1460-2156}, support = {Patani/Dec22/957-793/MNDA_/Motor Neurone Disease Association/United Kingdom ; MN5DF/2022/003//My Name'5 Doddie Foundation/ ; BB-2024-c4-l4//Target ALS/ ; //Francis Crick Institute/ ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; FC010110//UK Medical Research Council/ ; FC010110/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.}, }
@article {pmid42544409, year = {2026}, author = {Tsang, LPM and Tan, MS and Foo, YY and Lee, CS}, title = {Professional identity formation of family medicine residents in Singapore: a qualitative study to identify influencing factors.}, journal = {Annals of medicine}, volume = {58}, number = {1}, pages = {2698271}, doi = {10.1080/07853890.2026.2698271}, pmid = {42544409}, issn = {1365-2060}, mesh = {Humans ; Singapore ; *Internship and Residency ; Qualitative Research ; *Social Identification ; Male ; *Family Practice/education ; Female ; *Burnout, Professional/psychology/prevention &amp; control ; Job Satisfaction ; *Physicians, Family/psychology ; Adult ; Community of Practice ; }, abstract = {BACKGROUND: Physician burnout and retention are critical challenges in Family Medicine (FM). Professional Identity Formation (PIF) in family physicians (FP) fosters resilience and job satisfaction but is often overlooked in residency training, particularly in predominantly hospital-based programs where residents are disconnected from the primary care community.<br><br>AIM AND METHODS: This qualitative study explored FP PIF in a predominantly hospital-based FM residency program in Singapore and identified factors influencing its development. Individual in-depth semi-structured interviews were conducted with FM residents and post-residency FPs selected through maximum variation purposive sampling. Data was collected and analysed iteratively using Braun and Clarke's reflexive thematic analysis. Cruess et&#xa0;al.'s conceptual model for PIF was used as a sensitising framework, alongside Lankveld et&#xa0;al.'s framework describing psychological processes underlying identity formation.<br><br>RESULTS: Thirteen participants were interviewed. Three themes were constructed. First, FP PIF wasunderpinned by four psychological 'senses' of competence, connectedness, appreciation, and career trajectory. Second, reflection and socialization drove development of these senses by enabling meaning-making, learning and belonging within the FM community of practice (CoP). Third, residency program features both enabled and/or constrained PIF; while some components scaffolded PIF, more intentional support was needed.<br><br>DISCUSSION AND CONCLUSION: PIF is a dynamic, context-dependent psychological process shaped by reflective practice, social participation, and program structure. Intentional support through curriculum design and faculty practices may strengthen PIF. These findings extend existing PIF frameworks and have implications for curriculum design, faculty development, program evaluation, and future research on fostering PIF in hospital-based residency training.}, }
@article {pmid42545188, year = {2026}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Moreschi, A and Frisco, F and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Cappa, SF and Calvo, A and Strong, MJ and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70706}, pmid = {42545188}, issn = {1468-1331}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; RF-2016-02362405//Ricerca Sanitaria Finalizzata - Ministero della Salute/ ; 2017SNW5MB//"Progetti di Rilevante Interesse Nazionale" programme of the Ministry of Education, University and Research/ ; 101017598//Horizon 2020/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Female ; *Cognitive Dysfunction/etiology/diagnosis/epidemiology/psychology ; Neuropsychological Tests ; Male ; Aged ; Middle Aged ; Phenotype ; Retrospective Studies ; }, abstract = {BACKGROUND: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks.<br><br>METHODS: We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures.<br><br>RESULTS: The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI).<br><br>CONCLUSIONS: This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.}, }
@article {pmid42546549, year = {2026}, author = {Silvagi, R and Rodriguez-Fohn, E and Reece, RJ and Cranford, JA and Alangaden, K and Byrd, M and Klausner, H and Pravin, R and Li, J and Conn, C and Dunne, R and O'Neil, BJ}, title = {Advanced vs basic life support outcomes in treatment of out-of-hospital-cardiac-arrest: A registry-based cohort study.}, journal = {The American journal of emergency medicine}, volume = {109}, number = {}, pages = {263-267}, doi = {10.1016/j.ajem.2026.07.021}, pmid = {42546549}, issn = {1532-8171}, abstract = {IMPORTANCE: The absolute effect on outcomes with Advanced, (ALS) as compared to Basic Life Support, (BLS) care in Out of Hospital Cardiac Arrest, (OHCA) remains unclear.<br><br>OBJECTIVE: To assess the association of ALS compared to BLS alone prehospital care on return of spontaneous circulation, (ROSC), survival to hospital discharge, and neurological outcome in OHCA in Detroit, MI.<br><br>METHODS: Retrospective analysis of 6746 patients from the Cardiac Arrest Registry to Enhance Survival database from January 2016 to December 2021 who had non-traumatic OHCA and received cardiopulmonary resuscitation. Cohorts were grouped by ALS v BLS care then initial rhythm and then compared by chi-squared, multivariable logistic, and multinomial regression analysis for outcomes of sustained ROSC, survival to hospital discharge and favorable neurological outcome at hospital discharge. The BLS cohort is defined by units that provided manual CPR, automated rhythm and defibrillation, airway management, but no endotracheal intubation or parenteral medications. ALS care was defined as manual rhythm interpretation, manual defibrillation, intravenous or intraosseous drug administration or endotracheal intubation.<br><br>RESULTS: Mean age was 62.6&#xa0;years (SD-16.7), with 56.3% male and 84.6% Black. Cohort breakdown: shockable ALS (S-ALS; n&#xa0;=&#xa0;330, 4.9%); shockable BLS (S-BLS; n&#xa0;=&#xa0;466, 6.9%); non-shockable ALS (NS-ALS; n&#xa0;=&#xa0;2793, 41.4%); non-shockable BLS (NS-BLS; n&#xa0;=&#xa0;3157, 46.8%). ROSC rates by cohort: S-ALS (37.9%); S-BLS (19.5%); NS-ALS (18.6%); NS-BLS (9.3%). ALS was associated with increased sustained ROSC for all initial rhythms (p&#xa0;<&#xa0;.001). S-ALS was associated with increased survival (p&#xa0;=&#xa0;.03), and neurologic outcome (p&#xa0;=&#xa0;.01) when compared to S-BLS.<br><br>CONCLUSION &amp; RELEVANCE: Advanced Life Support, relative to Basic Life Support alone, was associated with improved sustained return of spontaneous circulation across all initial rhythms, and improved survival to discharge and favorable neurologic outcome in shockable initial rhythms.}, }
@article {pmid42546822, year = {2026}, author = {Ghaderi, S and Mohammadi, S and Iturria-Medina, Y}, title = {Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.}, journal = {Magnetic resonance imaging}, volume = {}, number = {}, pages = {110765}, doi = {10.1016/j.mri.2026.110765}, pmid = {42546822}, issn = {1873-5894}, abstract = {Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.}, }
@article {pmid42547743, year = {2026}, author = {Tse, CS}, title = {Letter to the Editor Regarding Barkan et al.'s Article, "Randomized Trial of Intensive Nurse‑Led Follow‑up Versus Standard Care in Inflammatory Bowel Disease".}, journal = {Digestive diseases and sciences}, volume = {}, number = {}, pages = {}, pmid = {42547743}, issn = {1573-2568}, }
@article {pmid42534468, year = {2026}, author = {Luster, CB and Abdolmohammadi, B and Mastrodicasa, MJ and Nowinski, CJ and Feigel, ED and Finegan, B and White, AJ and Connors, EJ and Rovito, CA and Zafonte, RD and Alosco, ML and McKee, AC and Mez, J and Daneshvar, DH}, title = {Neurodegenerative mortality among National Football League Players.}, journal = {EClinicalMedicine}, volume = {97}, number = {}, pages = {104051}, pmid = {42534468}, issn = {2589-5370}, abstract = {BACKGROUND: Empirical research demonstrates elevated neurodegenerative mortality among individuals with repetitive head impact (RHI) exposure, including National Football League (NFL) players. This investigation addressed prior methodological limitations, including selection bias, subjective diagnoses, and retrospective reporting, by analyzing the relationship between RHI exposure and neurodegenerative mortality in a fully enumerated, 5.8-fold larger cohort of NFL players.<br><br>METHODS: A population-based retrospective cohort study was conducted comprising all current and former NFL athletes who debuted between 1960 and 2019 and played at least one regular or postseason NFL game, with National Death Index records (1979-2023) matched to Sports Reference, LLC data. Standardized mortality ratios (SMRs) were calculated from National Institute for Occupational Safety and Health data compared to an age-, sex-, race-, and calendar-year-standardized general population. Sensitivity analysis assessed whether the observed excess neurodegenerative mortality could be attributed to competing risks using a cause-specific hazard simulation.<br><br>FINDINGS: A total of 19,824 athletes had a cumulative 518,833 person-years (mean = 26.2 years, SD = 16.2), with 1994 decedents. NFL players exhibited lower all-cause mortality (SMR = 0.70; 95% CI: 0.67-0.74) but higher neurodegenerative mortality (SMR = 3.94; 95% CI: 3.38-4.56), including amyotrophic lateral sclerosis (SMR = 4.55; 95% CI = 3.13-6.38), all-cause dementia (SMR = 3.80; 95% CI = 3.11-4.60), and Parkinson's disease (SMR = 3.88; 95% CI: 2.76-5.30). Cause-specific hazard simulation indicated that competing risks alone would inflate the expected NDD SMR by a factor of 1.30, yielding a residual neurodegenerative SMR of 3.04 (95% CI: 2.63-3.50).<br><br>INTERPRETATION: Neurodegenerative mortality was nearly four times higher in NFL players compared to the general population and remained threefold higher after accounting for competing risks. Together, these findings strengthen the evidence for RHI exposure-related neurodegenerative mortality in NFL players that cannot be explained by differential survivorship.<br><br>FUNDING: The National Institute of Neurological Disorders and Stroke [U54NS115266; U01NS086659], the National Institute on Aging [P30AG13846; P30AG072978], and the Maloney/Carpenter Trauma-Related Neurodegenerative Disease Research Fund.}, }
@article {pmid42536230, year = {2026}, author = {Naktinytė, E and Vilimienė, R and Valančius, D and Baronas, K and Zagorskienė, I and Utkus, A and Klimašauskienė, A and Burnytė, B}, title = {Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42536230}, issn = {1364-6753}, mesh = {Humans ; *Motor Neuron Disease/genetics/epidemiology ; Female ; Retrospective Studies ; Lithuania/epidemiology ; Male ; Middle Aged ; *Genetic Variation ; C9orf72 Protein/genetics ; Aged ; Adult ; Phenotype ; Amyotrophic Lateral Sclerosis/genetics ; DNA Repeat Expansion ; }, abstract = {Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region.}, }
@article {pmid42537332, year = {2026}, author = {Silva Santos, M and Castro, J and de Carvalho, M}, title = {F-wave responses and recruitment at low intensities: Muscle-specific excitability profiles of intrinsic hand muscles.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {56}, number = {5}, pages = {103185}, doi = {10.1016/j.neucli.2026.103185}, pmid = {42537332}, issn = {1769-7131}, abstract = {OBJECTIVES: F-waves are late motor responses traditionally elicited via supramaximal stimulation. However, submaximal stimulation may offer a more sensitive probe for assessing spinal motoneuron excitability. This study characterizes F-wave recruitment curves using graded submaximal stimulation across various intrinsic hand muscles.<br><br>METHODS: F-waves were recorded from the abductor pollicis brevis (APB), abductor digiti minimi (ADM), and first dorsal interosseous (FDI) in 15 healthy subjects (ages 35-78). Four stimulus intensities were employed-10%, 20%, 30%, and 100% of the maximal compound muscle action potential (CMAP) amplitude-with 20 stimuli delivered per intensity. Analysis focused on F-wave frequency, amplitude, and matched F-wave/CMAP ratios (F-wave/CMAPm), where the F-wave and CMAP were recorded at identical stimulus intensities.<br><br>RESULTS: Most parameters correlated positively with stimulus intensity; however, F-wave/CMAPm consistently decreased as intensity increased. The ADM exhibited a distinct recruitment profile, with F-wave persistence rising steeply at low intensities and reaching near-saturation at 30%, while showing no significant amplitude differences between submaximal levels. In contrast, the APB and FDI displayed more linear recruitment patterns for both persistence and amplitude.<br><br>DISCUSSION: Submaximal stimulation reliably elicits F-waves and reveals muscle-specific excitability profiles. The ADM's high excitability suggests a more readily recruitable motoneuron pool. Furthermore, the inverse relationship between F-wave/CMAPm and stimulus intensity suggests the early recruitment of larger, highly excitable Type II motoneurons. This refined recruitment curve approach may provide valuable insights into the "split-hand" phenomenon observed in amyotrophic lateral sclerosis.}, }
@article {pmid42538529, year = {2026}, author = {Marcus, B}, title = {Invited Commentary on: Azizzadeh et al.'s "The Multilevel Facial Anatomic Classification System: A Comprehensive Framework for Contemporary Facelift and Neck Rejuvenation Surgery".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261466756}, doi = {10.1177/26893614261466756}, pmid = {42538529}, issn = {2689-3622}, }
@article {pmid42538750, year = {2026}, author = {Krutovs, V and Grosmane, A and Kažmere, RR and Roddate, M and Ķauķe, G and Grosa, DP and Šetlere, S and Dīriks, M and Karelis, G and Ķēniņa, V}, title = {Nationwide Epidemiology of Motor Neuron Diseases in Latvia (2020-2024): Incidence, Prevalence, and Clinical Characteristics.}, journal = {European journal of neurology}, volume = {33}, number = {8}, pages = {e70710}, pmid = {42538750}, issn = {1468-1331}, mesh = {Humans ; Latvia/epidemiology ; Prevalence ; Female ; Incidence ; *Motor Neuron Disease/epidemiology/physiopathology ; Male ; Retrospective Studies ; Adult ; Middle Aged ; Aged ; Muscular Atrophy, Spinal/epidemiology ; Adolescent ; Young Adult ; Child ; Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Aged, 80 and over ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well-studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population.<br><br>METHODS: A retrospective, hospital-based analysis was performed using records from Pauls Stradi&#x146;&#x161; Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD-10 codes. Incidence and prevalence rates were calculated per 100,000 population and age-standardized to the 2013 European Standard Population.<br><br>RESULTS: A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult-onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age-standardized incidence of ALS was 1.22 per 100,000 person-years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4&#x2009;months for ALS, 43.8&#x2009;months for PLS, 206.8&#x2009;months for SBMA and 17.3&#x2009;months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed.<br><br>CONCLUSION: This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized.}, }
@article {pmid42533374, year = {2026}, author = {Rotteau, L and Wong, BM and Mukerji, G and Moser, A and Feldman, S and Shojania, KG and Goldman, J}, title = {Qualitative study of the implementation of long-term care plus: An intervention-in-systems approach.}, journal = {Journal of health services research &amp; policy}, volume = {}, number = {}, pages = {13558196261470275}, doi = {10.1177/13558196261470275}, pmid = {42533374}, issn = {1758-1060}, abstract = {ObjectivesReducing resident transfers from long-term care (LTC) to emergency departments (ED) is a well-established quality target. LTC plus (LTC+) provides medical consultations, healthcare navigation, rapid diagnostics, and education to LTC home providers, based on the logic that providing enhanced medical care in LTC homes will decrease ED transfers. LTC+ was implemented across six hospital-hubs and 54 homes in Toronto, Canada. An evaluation demonstrated positive program satisfaction and impacts on care, however limited program uptake and impact on ED transfers. We examine LTC+ intervention components and their implementation and adaptations to understand these discrepancies and identify improvement opportunities.MethodsWe conducted 32 qualitative interviews with LTC home providers and administrators and consultant physicians, and three focus groups with residents and family members, at six LTC homes and three hospital-hubs. Analysis drew on Lennox et al.'s conceptualization of "intervention-in-systems" which outlines four spheres to categorize intervention components (accessibility of evidence base, process of enactment, dependent processes and sociocultural issues) and their interconnectedness and adaptations when implemented and spread in complex systems.ResultsLTC+ design and implementation was centered within the accessibility of evidence base (e.g., educating about LTC+) and process of enactment (e.g., identify residents being considered for ED transfer) spheres to support program goals. LTC+ use was aligned with original program logic, however, providers also accessed LTC+ in cases where an ED transfer was not being considered highlighting limitations of a logic focused solely on ED transfers. LTC+ design and implementation was less attentive to intervention components in the dependant processes and sociocultural issues spheres (e.g., staffing models, interprofessional interactions) impacting adoption.ConclusionThe "intervention-in-systems" analytic lens was useful in examining intervention components across the four spheres, including their gaps, adaptations and interconnections. Study findings informed revisions to program goals, intervention components, and evaluative approach, reinforcing program and financial sustainability.}, }
@article {pmid42533837, year = {2025}, author = {Edwards, CM}, title = {Response to Young et al.'s 'Letter to the Editor'.}, journal = {Journal of military, veteran and family health}, volume = {11}, number = {3}, pages = {198-201}, pmid = {42533837}, issn = {2368-7924}, }
@article {pmid42526365, year = {2026}, author = {Ahsan, A and Ou, JC and Majumder, P and Chiang, YH and Huang, JK and Huang, CS}, title = {A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.}, journal = {Journal of neuroimmunology}, volume = {420}, number = {}, pages = {579028}, doi = {10.1016/j.jneuroim.2026.579028}, pmid = {42526365}, issn = {1872-8421}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS.<br><br>METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I[2] statistic.<br><br>RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD&#xa0;=&#xa0;-0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD&#xa0;=&#xa0;-0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant.<br><br>CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder.<br><br>PROSPERO identifier CRD420251076035.}, }
@article {pmid42526625, year = {2026}, author = {Guth, MAS}, title = {Targeting TDP-43 in ALS: Regulatory hurdles, trial design deficiencies, and the causal evidence gap for CTx1000.}, journal = {Drug discovery today}, volume = {}, number = {}, pages = {104752}, doi = {10.1016/j.drudis.2026.104752}, pmid = {42526625}, issn = {1878-5832}, abstract = {The therapeutic landscape for amyotrophic lateral sclerosis (ALS) has been characterized by decades of clinical trial failures, often attributed to biological heterogeneity, end-point insensitivity, and a profound evidence gap regarding target engagement. With TAR DNA-binding protein 43 (TDP-43) aggregation emerging as a hallmark feature in the vast majority of ALS cases, new precision-medicine modalities - most notably the proteolysis-targeting chimera (PROTAC) CTx1000 - aim to address the underlying causal pathology through selective degradation of mislocalized TDP-43. This review critically evaluates the regulatory hurdles and trial design deficiencies that have historically undermined ALS clinical development, and incorporates the dual sequestration hypothesis as a framework to interpret the convergence of TDP-43 pathology across neurodegenerative diseases. It concludes that it is imperative that the field adopts more rigorous biomarker-led methodologies, and that although target-specific degraders offer a sophisticated technological leap, their success depends on addressing fundamental knowledge gaps in target engagement, age-dependent vector tropism, and trial design architecture.}, }
@article {pmid42528478, year = {2026}, author = {Palumbo, F and Iazzolino, B and Moglia, C and Manera, U and Matteoni, E and Cabras, S and Pellegrino, G and Minerva, E and Passidomo, V and Vasta, R and Mora, G and D'Ovidio, F and Canosa, A and Calvo, A and Chiò, A}, title = {Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78315}, pmid = {42528478}, issn = {1531-8249}, abstract = {OBJECTIVE: Behavioral impairment is common in amyotrophic lateral sclerosis (ALS) and strongly affects autonomy, caregiver burden, and outcomes, yet predictors of vulnerability remain unclear. We investigated whether premorbid regulatory traits and socio-educational exposures are associated with behavioral phenotypes in ALS within a behavioral reserve framework.<br><br>METHODS: We analyzed 965 consecutively assessed patients with ALS from a prospective tertiary-center cohort. Behavioral impairment was measured using the Frontal Systems Behavior Scale (FrSBe; family-rated before and after onset) and, in a subset (n&#x2009;=&#x2009;633), the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). Theory-driven hierarchical logistic regression models tested associations between behavioral outcomes and premorbid behavioral regulation, education, occupation, and a Social Interaction Index, including interaction effects. Prespecified sensitivity analyses addressed potential bias in premorbid estimates.<br><br>RESULTS: Premorbid behavioral regulation showed the strongest associations with behavioral impairment across all FrSBe models. Higher combined educational attainment and social exposure were associated with lower odds of impairment, with a significant interaction across multiple behavioral domains. These patterns persisted in restricted sensitivity analyses. Reserve proxies were not significantly associated with ECAS-CI total impairment, although domain-specific effects were observed.<br><br>INTERPRETATION: These findings provide empirical support for a behavioral reserve framework in ALS, in which premorbid regulatory traits and socio-educational exposures are associated with behavioral vulnerability. Although causal inference is limited, reserve-related factors may contribute to non-motor heterogeneity in ALS and may inform future approaches to early behavioral risk stratification. ANN NEUROL 2026.}, }
@article {pmid42528798, year = {2026}, author = {Gao, X and Chen, S and Mahabub, S and Cao, B and Deng, J and Ye, W and Yang, H and Zou, Z}, title = {A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1879866}, pmid = {42528798}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups.<br><br>METHODS: A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model.<br><br>RESULTS: Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2&#x202f;weeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI&#x202f;=&#x202f;4.58, 95% CI&#x202f;=&#x202f;1.31-16.07, HRMFI&#x202f;=&#x202f;4.59, 95% CI&#x202f;=&#x202f;2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696.<br><br>CONCLUSION: By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population.}, }
@article {pmid42529618, year = {2026}, author = {Fiskum, V and Winter-Hjelm, N and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Microscale dysfunction and mesoscale compensation in degenerating neuronal networks.}, journal = {Network neuroscience (Cambridge, Mass.)}, volume = {10}, number = {3}, pages = {594-612}, pmid = {42529618}, issn = {2472-1751}, abstract = {Progressive neurodegenerative diseases involve neuronal dysfunction across cellular, circuit, and whole-brain levels. Despite differences in anatomical origins, vulnerable neuronal subtypes, and specific misfolded proteins, these diseases share key features. In presymptomatic phases, neural networks engage compensatory processes to maintain function, including increased centralization and reliance on a rich-club of hub nodes. While such mechanisms have supporting evidence in some disorders, they remain less established in amyotrophic lateral sclerosis (ALS), limiting understanding of potential shared presymptomatic responses. To address this, we investigated structural and functional properties of ALS patient-derived motor neuron networks compared with healthy controls using longitudinal multielectrode array recordings and graph theory-based analysis. We observed microscale dysfunction marked by TAR DNA-binding protein 43 proteinopathy, hyperactivity, and reduced spike amplitude. Structurally, ALS networks exhibited neurite hypertrophy, suggesting attempts to form new connections. Mesoscale analyses revealed functional reconfigurations, including increased rich-club connectivity and network assortativity, indicating compensatory centralization. Our findings provide novel evidence that ALS network features can be recapitulated in in vitro models, and that these networks progressively become more centralized to preserve computational capacity, imposing growing demands on hub nodes and predisposing them to further damage. These results support models proposing common network reconfiguration mechanisms across neurodegenerative diseases.}, }
@article {pmid42529685, year = {2026}, author = {Cheung, N}, title = {Cellular Logistics and Synaptic Vesicle Vulnerability in Major Depressive Disorder and Amyotrophic Lateral Sclerosis Comorbidity: Insights From Nicotinamide Mononucleotide Rescue and Transcriptome-Wide Association Study Integration.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e113549}, pmid = {42529685}, issn = {2168-8184}, abstract = {BACKGROUND: Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are usually treated as unrelated, yet depressive symptoms occur in a substantial minority of people with ALS and may appear early. These symptoms are heterogeneous and may reflect syndromal MDD, psychological and functional burden, fatigue, apathy, pseudobulbar affect, frontotemporal involvement, sleep or respiratory disturbance, medication effects, or shared affective vulnerability. A proposed pruning-continuum model suggests both disorders may share vulnerability in microglia-mediated synaptic pruning, with ALS amplified by autophagy and protein-quality-control failure and MDD by RNA-processing, stress, and immune dysregulation. We performed an exploratory secondary transcriptome-wide association study (TWAS)/pathway-integration analysis to test whether predefined nicotinamide mononucleotide (NMN)-nominated pathways map onto this vulnerability.<br><br>METHODS: We integrated precomputed S-PrediXcan outputs for MDD and ALS across available brain-relevant tissues. Ten Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predefined from a prior re-analysis of NMN-associated transcriptional programs in aged mouse metabolic tissues. Mouse-derived candidates were represented by human ortholog symbols before the human TWAS screen. The analysis tested nominated pathways rather than the 35-gene NMN-robust list as a standalone set. Cross-tissue screening used Stouffer Z aggregation, tissue-level Wilcoxon testing, competitive permutation testing, percentile bootstrap intervals, pairwise disease statistics, Levene variance tests, concordance measures, and leave-one-out sensitivity analysis. No analysis was treated as confirmatory or evidence of causal mediation.<br><br>RESULTS: MDD showed the strongest Stouffer-based exploratory signal in the synaptic vesicle cycle pathway, with a meta-across-tissue Stouffer Z of 3.41 and a wide bootstrap 95% confidence interval of -0.46 to 7.40. This signal did not survive competitive permutation testing (p = 0.1222) or Wilcoxon testing (p = 0.1926). The strongest tissue-level result occurred in the amygdala (Z = 4.057; nominal Wilcoxon p = 0.0093), although tissue-level permutation testing was not performed in the multi-gene-set run. ALS showed no significant meta-across-tissue enrichment among the 10 nominated pathways but displayed candidate gene-level signals in autophagy, endosomal, and vesicle-related genes, including TBK1 and C9orf72. Exploratory Levene tests indicated variance heterogeneity in the regulation of the actin cytoskeleton, endocytosis, and neuroactive ligand-receptor interaction; the actin cytoskeleton and endocytosis remained significant in pooled global false discovery rate (FDR) analysis. Fourteen genes were influential in at least two focus pathways, including EGF, KNG1, FGF8, RAC1, PAK1, PAK2, RAF1, MAPK1, and FGFR1.<br><br>CONCLUSIONS: These findings are hypothesis-generating. MDD and ALS may stress overlapping cellular logistics processes while engaging largely different genes. MDD showed the strongest exploratory pathway-level signal in synaptic vesicle biology, whereas ALS showed candidate gene-level coherence in autophagy and endosomal processes without significant meta-pathway enrichment. NMN/NAD+ repletion is not established as a treatment for MDD, ALS, or their comorbidity. These findings generate hypotheses about NAD+-linked cellular stress pathways for future preclinical and clinical studies.}, }
@article {pmid42530312, year = {2026}, author = {Ndungo, E and Islam, D and Gonwong, S and Ruamsap, N and Milletich, PL and Agnememel, A and Demons, ST and Pasetti, MF}, title = {Protective immunity against Shigella sonnei in vaccinated and challenged adult Thai volunteers.}, journal = {mSphere}, volume = {}, number = {}, pages = {e0026926}, doi = {10.1128/msphere.00269-26}, pmid = {42530312}, issn = {2379-5042}, abstract = {A safe, effective, and affordable vaccine that can prevent Shigella-induced diarrhea could have a significant impact on reducing morbidity and mortality in populations at risk. WRSS1, a live attenuated Shigella sonnei vaccine candidate, was well tolerated and immunogenic in adult Thai volunteers, achieving 40% efficacy against wild-type (WT) S. sonnei. We performed an in-depth analysis of mucosal and systemic antibodies in these individuals following WRSS1 vaccination and S. sonnei challenge, including a broader analysis of antibody specificity, functional features, and associations with clinical protection. IgG and IgA against Shigella proteins IpaB, IpaC, IpaD, IpaH, VirG, and LPS from multiple strains, as well as complement-mediated bactericidal and opsonophagocytic killing activity, were assessed in serum, fecal extracts, and antibodies in lymphocyte supernatants. Shigella-specific serum and ALS IgG and IgA increased after WRSS1 vaccination and S. sonnei challenge, particularly in naïve individuals, and most robustly post-challenge. Shedding the vaccine or infecting strain was associated with ALS responses. Fecal IgA was broadly reactive to most antigens, while fecal IgG was specific for S. sonnei LPS. Functional antibodies were detected prominently in fecal extracts; the highest responders were naïve individuals post-challenge. Notably, higher protein-specific serum IgA titers before challenge were associated with clinical protection against disease. Our results highlight the nuanced immunity to Shigella in endemic regions and the importance of understanding the elements that mediate protection in these settings to inform effective vaccine implementation.IMPORTANCEUnderstanding the immune response in Shigella-endemic regions is critical for the design and implementation of vaccines for the target population. We characterized the breadth of systemic and mucosal antibody responses to WRSS1 vaccination and WT S. sonnei challenge in Thai adult volunteers. Antigen-specific IgG and IgA in ALS were elevated only in individuals who shed the vaccine or challenge strain, indicating exposure. Serum IgA responses to Shigella proteins were associated with clinical protection. Our findings underscore the value of serosurveillance in guiding public health interventions and support the concept of protein-based vaccines to prevent disease in high-burden settings.}, }
@article {pmid42530583, year = {2026}, author = {Graco, M and Russo, K and Grivell, N and Carey, K and Zaga, C and Saravanan, K and Sheers, NL and Berlowitz, DJ and , }, title = {A qualitative investigation of the factors influencing the uptake of noninvasive ventilation among Australians with motor neurone disease.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/09638288.2026.2704454}, pmid = {42530583}, issn = {1464-5165}, abstract = {PURPOSE: Non-invasive ventilation (NIV) improves quality of life and extends survival for people with motor neurone disease (pwMND); however, uptake in Australia remains modest. This study explored the factors that influence the uptake of NIV from the perspectives of pwMND, caregivers, and healthcare professionals.<br><br>METHODS: Thirty-nine semi-structured interviews were conducted with pwMND (n&#x2009;=&#x2009;8), family caregivers of pwMND (n&#x2009;=&#x2009;4), and healthcare professionals (n&#x2009;=&#x2009;27). A two-stage deductive-inductive analysis was performed to identify common themes that influence the uptake of NIV in MND.<br><br>RESULTS: Twenty-six key influencing factors were identified, relating to three major themes: influences on the pwMND's decision to trial NIV; healthcare professional knowledge, beliefs and behaviors; and inequity and lack of responsiveness in the healthcare system. Inductive analysis also identified a fourth theme, disparities in NIV uptake. Within this theme, women, older people, and First Nations Australians were acknowledged as demographic groups experiencing challenges to NIV uptake that warrant further investigation.<br><br>CONCLUSION: This research identified multiple modifiable factors influencing the uptake of NIV that can inform the design of targeted interventions to reduce inequitable access to NIV, increase uptake, and optimize quality of life for pwMND.}, }
@article {pmid42531420, year = {2026}, author = {Burke, KM and Brown, R and Calcagno, N and Gupta, AS and Gajos, KZ and Scheier, Z and Clark, A and Iyer, A and Higgins, MP and Keegan, M and Royse, TB and Remington, E and Connaghan, KP and Johnson, SA and Chew, S and Erb, MK and Berry, JD}, title = {Digital Remote Assessment of Motor and Speech Changes in Amyotrophic Lateral Sclerosis: Longitudinal Observational Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e85142}, pmid = {42531420}, issn = {2561-326X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Female ; Longitudinal Studies ; Male ; Middle Aged ; Aged ; Disease Progression ; Remote Patient Monitoring ; Digital Health ; *Speech/physiology ; Adult ; Reproducibility of Results ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an active trial landscape that relies on the sensitivity of selected clinical trial endpoints. Traditional clinical outcome assessments perform well in trials but lack strong psychometric properties and may not detect small but clinically meaningful disease progression. Digital health technologies offer a promising alternative for tracking ALS disease progression.<br><br>OBJECTIVE: This study assessed the feasibility of remote digital monitoring in ALS using a comprehensive battery of prescribed home-based assessments via a smartphone, a wearable device, and a computer-based mouse-clicking task.<br><br>METHODS: Participants completed weekly remote assessments, including motor and speech tasks via a smartphone app and a computer mouse-clicking task for 24 weeks. They also participated in 3 remote telephone visits in weeks 1, 13, and 25. Reliability, minimal detectable change, and correlations with self-reported ALS Functional Rating Scale-Revised subdomain scores were calculated for 8 features across the speech, fine motor, and gross motor smartphone app tasks and for all 32 features from the computer mouse-clicking task. Sensitivity to longitudinal change was assessed for the 8 smartphone-derived features and for a representative subset of 8 computer mouse-clicking features.<br><br>RESULTS: Forty-two participants (19 with ALS and 23 controls) completed 10,237 smartphone assessments and 459 computer mouse-clicking sessions. Baseline discriminative models differentiated ALS from controls with AUC values of 0.75-0.92. Digital measures correlated strongly with self-reported ALS Functional Rating Scale-Revised subdomain scores. Both participants with ALS and controls demonstrated improvement in fine motor and speech measures, with the exception of nondominant-hand pegboard performance, which declined in the ALS group. Improvements were smaller in participants with ALS, leading to increasing group differences over time, although only one feature showed a statistically significant separation over the 24 weeks. Gait and balance performance declined in both groups, with greater but nonsignificant separation observed for balance measures.<br><br>CONCLUSIONS: These findings support the feasibility of digital remote assessments in ALS, demonstrate the ability to discriminate between ALS and controls based on certain features collected from speech, fine, and gross motor tasks, and in some cases, quantify functional decline over time. Further research is necessary to explore the natural history of these features longitudinally in larger cohorts of participants with ALS over extended periods to enable their potential integration into clinical trials.}, }
@article {pmid42532824, year = {2026}, author = {Lin, YT and Yang, HL}, title = {[Applying Developmental Care Theory to the Improvement of Self-Regulation and Feeding Difficulties in a Late Preterm Infant Receiving Cardiac Surgery: A Nursing Experience].}, journal = {Hu li za zhi The journal of nursing}, volume = {73}, number = {4}, pages = {}, doi = {10.6224/JN.26413}, pmid = {42532824}, issn = {0047-262X}, mesh = {Humans ; Female ; Infant, Newborn ; *Infant, Premature ; *Self-Control ; *Cardiac Surgical Procedures ; *Feeding Behavior ; }, abstract = {When preterm infants present with organ anomalies that require immediate surgical intervention after birth, their immature nervous systems often limit their ability to cope with the stress of surgery and subsequent treatments. This often results in difficulties with self-regulation and related health issues. The case described in this study involves a late preterm female infant born at 36+4 weeks of gestation who underwent cardiac surgery on the fifth day after birth. Postoperatively, she exhibited neonatal neurodevelopmental disorganization, ineffective suck-swallow reflexes, and inadequate nutritional intake. The first author provided nursing care between April 22 to May 10, 2025, with a telephone follow-up on May 14. The provided interventions were guided by Als' Synactive Theory of Development and integrated the Seven Neuroprotective Core Measures of the Neonatal Integrative Developmental Care Model, encompassing environmental regulation, sleep and positioning support, stress and pain management, and family-centered care. Objective evaluation was conducted using the Preterm Infant Oral Feeding Readiness Assessment Scale (POFRAS). The results demonstrated improvements in both self-regulation and feeding difficulties. Notably, the incidence of crying episodes decreased, the infant was able to sustain a calm state for longer periods, coordination of suck-swallow-breathing improved, and oral intake increased. Consequently, the amount of supplemental gavage feeding was reduced, caregivers were able to provide effective care, and the POFRAS score rose from 21 to 32. The comprehensive care approach described in this study integrates theoretical frameworks with behavioral cue-based observations to effectively improve feeding difficulties and self-regulation in preterm infants undergoing invasive surgery while simultaneously enhancing caregiver competence and confidence.}, }
@article {pmid42533344, year = {2026}, author = {Bublitz, SK and Becker, B and Demleitner, AF and Dietz-Laukemann, P and Lingor, P and Littger, B and Lorenzl, S and Feddersen, B}, title = {Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42533344}, issn = {2524-3489}, abstract = {INTRODUCTION: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP).<br><br>METHODS: We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges.<br><br>RESULTS: Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences.<br><br>IMPLICATIONS: Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making.}, }
@article {pmid42523442, year = {2026}, author = {Jonk, SM and Nicol, A and Braun, A and Wang, W and Tribble, JR and Swoboda, P and Williams, PA}, title = {Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.07.08.737381}, pmid = {42523442}, issn = {2692-8205}, abstract = {Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans , we focused on pantothenate (vitamin B 5), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans , the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1 , encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans . Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.}, }
@article {pmid42523591, year = {2026}, author = {Balanis, T and Doulberis, M and Tutuian, R}, title = {EUS-guided transmural treatment of afferent loop syndrome: a systematic review and meta-analysis.}, journal = {Frontiers in gastroenterology (Lausanne, Switzerland)}, volume = {5}, number = {}, pages = {1853386}, pmid = {42523591}, issn = {2813-1169}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is an uncommon but clinically relevant complication after pancreaticobiliary or upper gastrointestinal reconstruction, most often in patients with recurrent malignant disease. Endoscopic ultrasound-guided creation of a transmural bypass, either as gastroenterostomy or enteroenterostomy, has emerged as a minimally invasive alternative to surgery or percutaneous drainage. We aimed to systematically review the available evidence and provide a pooled descriptive analysis of the efficacy and safety of EUS-guided treatment for ALS.<br><br>METHODS: A systematic review was performed in accordance with PRISMA principles. PubMed/MEDLINE, Embase and the Cochrane Library were searched up to 15 May 2025 for studies reporting EUS-guided gastroenterostomy or enteroenterostomy for ALS. Case reports, case series and observational studies with extractable outcome data were eligible. Data on study design, indication, stent type, technical success, clinical success, adverse events and follow-up were extracted and synthesized.<br><br>RESULTS: Twelve studies involving 134 patients were included. On crude analysis, technical success was achieved in 132/134 patients (98.5%), clinical success in 127/134 (94.8%), and adverse events were reported in 13/134 (9.7%). In the pooled random-effects analysis, the technical success rate was 93.5% (95% CI 87.1-96.8; I&#xb2;=0%), the clinical success rate was 91.0% (95% CI 84.5-94.9; I&#xb2;=0%), and the overall adverse-event rate was 14.6% (95% CI 9.1-22.5; I&#xb2;=0%). Adverse events were mainly procedure-related pain, fever, stent misdeployment, peritonitis or intra-abdominal infection. Electrocautery-enhanced lumen-apposing metal stents were used in most studies, whereas fully covered self-expandable metal stents were used in a smaller subset. Reported follow-up ranged from 1 to 15 months.<br><br>CONCLUSIONS: EUS-guided transmural bypass represents a promising, minimally invasive, and technically feasible alternative for the management of ALS. However, given the retrospective nature and small sample sizes of the available evidence, larger comparative trials are warranted to define its definitive role.}, }
@article {pmid42524305, year = {2026}, author = {Longo, UG and Merone, M and Schena, E and Bandini, B and Nicodemi, G and Zsidai, B and Hilkert, AS and Senorski, EH and Grassi, A and Ley, C and Herbst, E and Hirschmann, MT and Kopf, S and Seil, R and Tischer, T and Feldt, R and Samuelsson, K and Oettl, FC}, title = {A practical guide to the implementation of AI in orthopaedic research-Part 4: Prerequisites for a successful orthopedics AI-driven project in terms of interdisciplinary collaboration, data management, ethical approval and technology.}, journal = {Journal of experimental orthopaedics}, volume = {13}, number = {3}, pages = {e70863}, pmid = {42524305}, issn = {2197-1153}, abstract = {UNLABELLED: Translating artificial intelligence (AI) research in orthopedics from proof-of-concept studies into production-grade clinical systems requires the systematic satisfaction of four prerequisite domains: interdisciplinary team architecture, technical data management, ethical and regulatory governance and production-grade technology and deployment infrastructure. Despite a tenfold increase in orthopedic AI publications, fewer than 6% of studies reach routine clinical deployment, reflecting persistent gaps in each of these domains. This article provides a technically rigorous, evidence-based framework organized around these four pillars. The interdisciplinary team may be structured using a product-centric topology that decouples stream-aligned clinical teams from platform infrastructure teams, following Huffman et al.'s six-step AI project lifecycle: obtain/curate/label data; establish a reference standard; develop the model; evaluate performance; externally validate and iteratively reinforce until clinical implementation is viable. Data management requires data extraction protocols, integration for bulk exports and a multi-component de-identification pipeline. A multi-stage Institutional Review Board framework governs ethical oversight, scaling from Exempt review for retrospective de-identified studies to Full Board Review with prospective validation and mandatory human-override mechanisms for interventional deployment. Responsible clinical deployment requires a multi-layer Clinical Machine Learning Operations framework, implementing privacy-preserving deployment, clinical observability, compliance audit trails and human-in-the-loop governance. Model drift has to be monitored with a degradation threshold triggering mandatory human review.<br><br>LEVEL OF EVIDENCE: Level V.}, }
@article {pmid42524894, year = {2026}, author = {Guo, W and Cai, S and Li, Y and McGarry, BE and Caprio, TV and Temkin-Greener, H}, title = {User-Generated Google Maps Ratings, State Staffing and Training Regulations, and the Quality of Hospice Care in Assisted Living Communities.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70609}, pmid = {42524894}, issn = {1532-5415}, support = {Another Look 2020//Patrick and Catherine Weldon Donaghue Medical Research Foundation/ ; R01HS026893/HS/AHRQ HHS/United States ; }, abstract = {BACKGROUND: Hospice services are growing among Medicare beneficiaries, yet concerns remain about the hospice quality for residents in assisted living (AL) communities. Little is known about how AL characteristics and state regulations are associated with hospice care in these settings.<br><br>OBJECTIVES: To examine (1) whether AL user-generated google maps ratings (AL google maps ratings) and (2) state-level regulations on AL staffing are associated with hospice ratings: METHODS: We conducted a cross-sectional analysis of 15,947 AL communities. We included data on AL-specific direct care worker (DCW) state staffing and staff training regulations. Logistic regression models were used to assess associations, adjusting for AL, hospice, and market-level characteristics.<br><br>RESULTS: A one-star increase in an AL google maps rating was associated with 6% higher odds of being served by hospices with higher HIS scores (OR&#x2009;=&#x2009;1.06, p&#x2009;=&#x2009;0.032), but not with CAHPS scores. AL communities in states with higher regulatory specificity for DCW staffing had higher odds of being served by hospices with higher CAHPS (OR&#x2009;=&#x2009;1.46, p&#x2009;<&#x2009;0.001) and HIS scores (OR&#x2009;=&#x2009;1.35, p&#x2009;<&#x2009;0.001). ALs in states mandating more than 21&#x2009;h of DCW training, AL communities were more likely to be served by hospices with higher CAHPS scores (OR&#x2009;=&#x2009;1.33, p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: Higher AL google maps ratings were associated with higher hospice HIS performance. DCW staffing regulations were associated with both CAHPS and HIS, and DCW training regulations were associated with CAHPS only. These findings underscore the role of organizational quality and state regulatory policies in guiding end-of-life care in AL communities.}, }
@article {pmid42525902, year = {2026}, author = {Roberts, AL and Vilela Braga, AD and Tang, IW and Rotem, RS and Moo, LR and Miller, DR and Shirk, SD and Weisskopf, MG}, title = {Association of Military Branch and Rank With Amyotrophic Lateral Sclerosis Incidence Among United States Veterans.}, journal = {Neurology}, volume = {107}, number = {4}, pages = {e218303}, doi = {10.1212/WNL.0000000000218303}, pmid = {42525902}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Male ; United States/epidemiology ; *Veterans/statistics &amp; numerical data ; Female ; *Military Personnel/statistics &amp; numerical data ; Incidence ; Middle Aged ; Longitudinal Studies ; Adult ; Risk Factors ; Aged ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {BACKGROUND AND OBJECTIVES: Military service is one of the most consistent risk factors for the development of amyotrophic lateral sclerosis (ALS), but little is known about what aspects of military service matter. Understanding the distribution of ALS risk in military personnel may help identify key risk factors. We aimed to ascertain the association of United States (US) military branch and rank with incident ALS.<br><br>METHODS: We conducted a longitudinal cohort study including all veterans with a Veterans Health Administration encounter from January 1, 2000, through October 1, 2024, and more than 2 years of follow-up. Incident ALS was identified through medical records. Exposures included military branch (Army, Navy, Air Force, Marine Corps, Coast Guard, or multiple branches), military rank (officer, enlisted, or both), and length of service. Risk was estimated with Cox proportional hazards models, controlled for age, adjusted for race/ethnicity, and stratified by sex.<br><br>RESULTS: The analytic sample comprised 9,157,938 men (13,935 incident ALS cases, mean age = 56.9 years) and 784,941 women (484 cases, mean age = 42.4 at start of follow up). Among men, compared with service in the Army, service in the Air Force (hazard ratio [HR] = 1.29, 95% CI 1.23-1.35), Navy (HR = 1.15, 95% CI 1.10-1.20), and Coast Guard (HR = 1.26, 95% CI 1.06-1.50) was associated with higher rates of ALS and service in the Marines a lower rate (HR = 0.78, 95% CI 0.68-0.88). Officers had higher rates than enlisted personnel (men, HR = 1.64, 95% CI 1.53-1.74; women, HR = 1.72, 95% CI 1.31-2.27). Longer service was associated with lower rates of ALS. In age-stratified models, differences in hazard rates between Army veterans and Air Force, Navy, and Coast Guard veterans were greatest for the youngest men (17-61 years, HR range = 1.26 to 1.51) and smallest for the oldest (>75-104 years, HR range = 0.99 to 1.12).<br><br>DISCUSSION: ALS rates varied considerably by branch and rank in the US military, with larger differences among younger veterans. Officers and those serving in the Air Force, Navy, or Coast Guard may incur exposure to military environments that increase risk of ALS. It is imperative to identify relevant exposures to reduce harm to service members and, potentially, civilians with similar exposures.}, }
@article {pmid42525906, year = {2026}, author = {Hardiman, O}, title = {Amyotrophic Lateral Sclerosis in the Military: A Uniform Risk?.}, journal = {Neurology}, volume = {107}, number = {4}, pages = {e218481}, doi = {10.1212/WNL.0000000000218481}, pmid = {42525906}, issn = {1526-632X}, }
@article {pmid42526364, year = {2026}, author = {Stevenson, C and McNamara, N and John, R and Gallagher, S}, title = {Local community identification improves wellbeing by reducing loneliness: Longitudinal evidence from two studies.}, journal = {Social science &amp; medicine (1982)}, volume = {406}, number = {}, pages = {119543}, doi = {10.1016/j.socscimed.2026.119543}, pmid = {42526364}, issn = {1873-5347}, abstract = {Loneliness is a significant determinant of mental and physical health which has many root causes at local community level. Building on the Social Identity Approach to Health we test a longitudinal version of McNamara et al.'s (2021) neighbourhood identity model of wellbeing, which links local community identification to wellbeing via reduced loneliness. Study 1 was a two-wave survey of residents in mid-Nottinghamshire, UK (T1 N = 879; T2 N = 216). Mediation analyses showed that, over a one-year period, changes in community identification predicted increases in wellbeing via increases in perceived support and reductions in loneliness while controlling for a range of demographic factors. In Study 2, a secondary analysis of a large population-based UK study, i.e. Understanding Society (UKHLS; Waves 9 and 12; n = 38,056) showed that over a three-year period, increases in identification predicted improvements in GHQ-12 mental health and self-rated general health, again via increases in perceived support and reductions in loneliness. Across studies, the effect of neighbourhood identification on wellbeing occurred primarily through loneliness reduction. We discuss implications for reducing health inequalities through local community identity-building and social infrastructure, and outline priorities for policy and future research.}, }
@article {pmid42517609, year = {2026}, author = {Dillenburg, RF and Lopatina, A and Ruan, H and Scheidt, T and Mosna, S and Pekbilir, E and Bieber, J and Schäfer-Depoix, F and Landfester, K and Schmidt, C and Möckel, MM and Morsbach, S and Schmid, F and Dormann, D and Stelzl, L and Girard, M and Lemke, EA}, title = {A Phosphorylation-Induced Micellization Switch in the Low-Complexity Domain of TDP-43.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76625}, pmid = {42517609}, issn = {2198-3844}, support = {464588647//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; }, abstract = {Phase separation (PS) of the low-complexity domain (LCD) of TAR DNA-binding protein 43 kDa (TDP-43) is linked to pathogenic aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Here, we show that extensive phosphorylation of the LCD C-terminus redirects its self-assembly. Coarse-grained Monte Carlo simulations predicted that 12 Ser phosphorylations partition the 148-residue LCD into a hydrophobic N-terminal and highly charged C-terminal block, favouring finite-sized micellization over macroscopic PS. In vitro, LCD phosphorylated by casein kinase 1 delta (CK1δ; mean of 12 phosphorylations by native mass spectrometry) and phosphomimetic 12D/12DD mutants formed spherical nanoparticles (≈ 20-50 nm) above a low-micromolar critical micelle concentration, whereas the unphosphorylated LCD underwent reversible PS that matured into fibrils. Increasing ionic strength shifted the mutants toward anisotropic morphologies (wormlike 12D micelles and rigid 12DD nanocylinders). Turbidity assays and confocal imaging directly visualized the absence of PS in the phosphorylated form. Negative-stain and cryo-electron microscopy (cryo-EM) confirmed the spherical micellar architecture for the phosphorylated LCD and 12D/12DD mimics. Our data identify phosphorylation as a molecular switch tuning macrophase separation and fibril formation of TDP-43 LCD, providing a framework for an aggregation-protective role through microphase separation into size-limited micelles. Whether these assemblies are stable or kinetically trapped on pathological timescales remains unclear.}, }
@article {pmid42520183, year = {2026}, author = {Simão, S and Oliveira Santos, M and Gromicho, M and Martins, IP and de Carvalho, M}, title = {Evidence of stage-specific cognitive reserve effects on longitudinal cognition in amyotrophic lateral sclerosis.}, journal = {Journal of neuropsychology}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnp.70066}, pmid = {42520183}, issn = {1748-6653}, abstract = {About 50% of amyotrophic lateral sclerosis (ALS) patients develop cognitive-behavioural impairment, yet longitudinal studies diverge on onset and extent of decline. Cognitive reserve (CR) may modulate cognitive trajectories, although longitudinal evidence remains limited. We aim to characterize cognitive trajectories in ALS and healthy aging and to examine the role of CR proxies in shaping cognitive change over time. About 268 participants (169 patients, 99 controls) were evaluated twice over 6 to 18 months using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Mixed models were used to predict initial ECAS performance (ECAS1), and cognitive slope (ECAS2-ECAS1) using CR proxies (education, work and leisure), ECAS21-ECAS12 interval, demographics (age, sex, psychiatric medication) and clinical factors (disease duration, onset-region, respiratory capacity, functional decline, C9orf72 mutation and behavioural symptoms). In patients, education (p < .001) and leisure (p < .001) positively predicted ECAS1. However, longitudinally, education and leisure had negative main effects on cognition, protecting against decline through interactions with clinical variables. In controls, more education and leisure predicted better cognition through main effects and interactions. CR appears to exhibit a dynamic, phase-dependent influence in patients and controls, supporting initial cognitive performance and potentially offering subtle protection as disease progresses. The observed non-linear effects of all CR proxies and subgroup-specific effects highlight the importance of considering clinical context, time and initial cognition when evaluating CR's role in ALS.}, }
@article {pmid42520340, year = {2026}, author = {Morgan-Jack, BR and Katz, ML and Kick, GR and Johnson, GC and Delgado, K and Makinen, M and Coates, JR}, title = {Pathology of general proprioception in a canine disease model of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {489}, number = {}, pages = {126108}, doi = {10.1016/j.jns.2026.126108}, pmid = {42520340}, issn = {1878-5883}, abstract = {Some forms of amyotrophic lateral sclerosis (ALS) are associated with sequence variants in the superoxide dismutase 1 gene (SOD1). The mechanisms by which these variants contribute to ALS disease pathogenesis are poorly understood. Degenerative myelopathy (DM), a naturally occurring canine disease, shares similarities with some forms of SOD1-associated ALS, especially cases with sensory impairment. While motor pathway involvement in ALS has been extensively studied, sensory pathology has received comparatively less attention. To investigate whether pathology in the general proprioceptive pathway is associated with pelvic limb general proprioceptive ataxia, an early DM sign, we examined sensory system components of this pathway from Pembroke Welsh Corgis with early- and late-stage DM and age-matched controls. The disease was characterized by axonal pathology in the spinocerebellar tracts and the fasciculus gracilis, pronounced accumulation of SOD1-positive inclusions in nucleus thoracicus and dorsal root ganglia (DRG) neurons, and altered SOD1 immunolabeling in dorsal and ventral root axons and ensheathing myelin. Axonal pathology was also observed in a pelvic limb sensory nerve. These findings suggest that pathology in the proprioceptive sensory pathways may play a significant role in general proprioceptive ataxia in DM. Some dogs that were homozygous for the SOD1 risk allele did not develop clinical disease or the associated neuropathology, indicating that other factors in addition to the SOD1 mutation influence disease onset and progression.}, }
@article {pmid42521602, year = {2026}, author = {Pathapati, N and Nguyen, M and Ju, J and Maddukuri, M and Kiehl, J and Kvale, E and Thrift, AP and Berth, S and Grouls, A}, title = {Capturing Financial Burden Concerns in an ALS Multidisciplinary Clinic.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70364}, pmid = {42521602}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is associated with substantial financial burden. How financial concerns are documented or addressed in ALS multidisciplinary clinics (MDC) is unclear. We aimed to characterize financial concerns among people living with ALS (pALS) and how they are identified and documented by multidisciplinary clinic staff.<br><br>METHODS: We performed a retrospective electronic medical record (EMR) review for people living with ALS (pALS) attending at least two visits at the MDC, identifying documentation of financial concerns across all MDC notes throughout 2024. Semi-structured interviews with MDC staff explored experiences with financial concern discussions and documentation. Rapid qualitative analysis was used to analyze interview content.<br><br>RESULTS: Among 67 pALS with at least 2 MDC visits, 45 (67.2%) had &#x2265;&#x2009;1 documented financial concerns. Financial concerns were most documented in neurology physician notes and portal messages (both 77.8%) and included insurance denials, medication costs, disability/Medicare navigation, caregiving expenses, and home modifications. Social work and patient portal notes provided greater detail than other staff notes. Staff interviews highlighted insurance and equipment costs as frequent financial concerns. Four qualitative themes emerged: insurance challenges and reliance on non-insurance resources, financial barriers limiting care and quality of life, limited proactive conversations/documentation, and the central role of social work.<br><br>DISCUSSION: Financial concerns are common among pALS but are inconsistently discussed and documented in the EMR, often arising through asynchronous communication or social work. Integrating financial screening and promoting proactive multidisciplinary documentation may improve identification of financial concerns and support more equitable, person-centered ALS care.}, }
@article {pmid42521811, year = {2026}, author = {Willemse, SW and Demaegd, KC and Koole, W and van Eijk, RPA and van Rheenen, W and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42521811}, issn = {1476-5438}, support = {09150161810018//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; V0000319//ZonMw (Netherlands Organisation for Health Research and Development)/ ; }, abstract = {The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.}, }
@article {pmid42521895, year = {2026}, author = {Abidar, S and Nhiri, M and Bianchi, V}, title = {Suicide in neurodegenerative diseases: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42521895}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Suicide/psychology/statistics &amp; numerical data ; Amyotrophic Lateral Sclerosis/psychology ; Multiple Sclerosis/psychology ; }, abstract = {BACKGROUND AND OBJECTIVE: Suicide is a public health issue, which differs from suicidality, the continuum from suicidal ideation to the suicidal act, including suicide attempts and completed suicide. The main goal of the present study is to determine the relationship between Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with suicidality.<br><br>METHODS: This is a systematic review aiming to determine the relationship between AD, PD, ALS, and MS with suicidality following PRISMA 2020 guidelines by collecting cross-sectional, case-control, and cohort studies; case series; case reports; and retrospective and prospective studies from Google Scholar, PubMed, and Cochrane Library. The protocol of this systematic review was registered on PROSPERO; the registration number is CRD420261422354.<br><br>RESULTS: From 2247 records identified from electronic databases, only 24 articles were included: three studies focusing on AD, nine on PD, and six studies focusing on ALS and MS, respectively. These studies exhibited moderate to low risk of bias. Despite the broad differences regarding the neurochemistry, pathophysiology, diagnosis, symptoms, and treatments of the selected diseases, patients are at a higher risk of suicidality. Depression and low social connectivity are the most prevalent risk factors. Suicidality is mainly detected during the first years post-diagnosis in PD, ALS, and MS patients, while the results in AD are confusing.<br><br>CONCLUSIONS: Data about this topic is scarce and largely varying. Further research is required to elucidate this paradigmatic realm, fostering awareness, enhancing therapies, and providing explanations and interpretations of the mechanisms involved.}, }
@article {pmid42522587, year = {2026}, author = {Wood, P}, title = {Beyond procedural justice: Power, identity and the asymmetric architecture of public trust in security services.}, journal = {The British journal of social psychology}, volume = {65}, number = {4}, pages = {e70114}, pmid = {42522587}, issn = {2044-8309}, mesh = {*Trust/psychology ; Humans ; *Power, Psychological ; *Social Identification ; *Social Justice ; Social Group ; *Security Measures ; }, abstract = {Public trust in security services is a critical social-psychological phenomenon, yet existing theoretical accounts remain fragmented and insufficiently attentive to the structural power asymmetries characterising security-public relations. This article argues that the dominant paradigm, procedural justice theory, requires fundamental revision within intergroup and institutional power dynamics. Drawing upon procedural justice theory (Why people obey the law, 1990, Yale University Press; Why people obey the law, 2nd ed., 2006, Princeton University Press), social identity and self-categorisation theory (The social psychology of intergroup relations, 1979, 33, Brooks/Cole; Rediscovering the social group: A self-categorization theory, 1987, Blackwell), the integrative model of organisational trust (Academy of Management Review, 1995, 20, 709), intergroup contact theory (The nature of prejudice, 1954, Addison-Wesley), system justification theory (British Journal of Social Psychology, 1994, 33, 1), institutional betrayal theory (American Psychologist, 2014, 69, 575) and the political trust tradition (A systems analysis of political life, 1965, Wiley; Trust and trustworthiness, 2002, Russell Sage Foundation; Annual Review of Political Science, 2000, 3, 475), the article advances three propositions. First, trust formation is asymmetric: trust erodes faster than it accrues, with the asymmetry amplified for subordinate-status groups. Second, procedural justice effects are identity-contingent: perceived fairness operates differently depending on whether the authority is categorised as in-group protector or out-group enforcer. Third, trustworthiness appraisal under institutional betrayal requires reconceptualising Mayer et al.'s integrity dimension as epistemic credibility. A four-pathway model is proposed, with power asymmetry as a structural moderator and recursive feedback producing virtuous or vicious trust spirals.}, }
@article {pmid42522997, year = {2026}, author = {Stanley, LM and Scott, JA}, title = {Single-case design interventions for deaf disabled students: a systematic literature review.}, journal = {Journal of deaf studies and deaf education}, volume = {}, number = {}, pages = {}, doi = {10.1093/jdsade/enag045}, pmid = {42522997}, issn = {1465-7325}, abstract = {This systematic review examined single-case design (SCD) interventions for Deaf and Hard-of-Hearing students with co-occurring disabilities (i.e., who are Deaf Disabled). Ten peer-reviewed studies met the inclusion criteria, targeting communication, behavior, or academic outcomes. Behavioral interventions demonstrated more durable generalization, while academic gains often required continued reinforcement. Study quality evaluated using Horner et al.'s indicators revealed two high-quality studies, four acceptable, and four below minimum standards, indicating notable methodological limitations. Findings highlight a significant gap in rigorous, language-focused SCD research. Improved methodological quality is needed to better inform multidisciplinary teams in designing individualized, evidence-based supports, while also considering how normative assumptions shape definitions of "improvement" and influence interpretations of effectiveness.}, }
@article {pmid42523377, year = {2026}, author = {Breevoort, A and Ivanov, D and Horan-Portelance, L and Nana, A and Vatsavayai, S and Miravet, &#xc0;T and Wallace, JL and Ding, JW and Pereira, FL and Fernhoff, K and Gorno-Tempini, ML and Spina, S and Yokoyama, JS and Rosen, HJ and Grinberg, LT and Jacobs, FMJ and Miller, BL and Seeley, WW and Pollen, AA}, title = {Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42523377}, issn = {2692-8205}, abstract = {Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.}, }
@article {pmid42511680, year = {2026}, author = {Podshivalova, ES and Kutsev, SI and Shestopalov, AV}, title = {The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {14}, pages = {}, pmid = {42511680}, issn = {1422-0067}, mesh = {*Kynurenine/metabolism ; Humans ; Animals ; *Nervous System Diseases/metabolism/pathology ; Signal Transduction ; Metabolic Networks and Pathways ; Tryptophan/metabolism ; }, abstract = {The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent-and at times opposing-roles, attenuating dopaminergic neurotoxicity in Parkinson's disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms.}, }
@article {pmid42512084, year = {2026}, author = {Assialioui, A and Povedano, M and Senau, M and Ferrer, I and Arias, L}, title = {Retinal Thickness and Vascular Density Changes in Amyotrophic Lateral Sclerosis Assessed by Optical Coherence Tomography Angiography.}, journal = {Biomedicines}, volume = {14}, number = {7}, pages = {}, pmid = {42512084}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder involving neurovascular dysfunction. The retina allows in vivo assessment of neurovascular changes. This study evaluated retinal structural and microvascular alterations in ALS using optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A). Methods: This cross-sectional study included 46 participants with ALS and 19 healthy controls. Retinal thickness and vascular density in the superficial and deep retinal capillary plexuses and the choriocapillaris were quantified using OCT and OCT-A. Group comparisons and logistic regression analyses were performed to assess associations with ALS. Subgroup analyses were conducted according to clinical phenotype. Results: In total, 124 eyes were analyzed. ALS was associated with increased average retinal thickness (p = 0.023) and reduced vascular density in the superficial retinal capillary plexus (p = 0.005), deep retinal capillary plexus (p < 0.001), and choriocapillaris (p = 0.004). In logistic regression analyses, retinal thickness was positively associated with ALS status (OR = 1.42, p = 0.023), whereas higher vascular density in the superficial plexus, deep plexus, and choriocapillaris was associated with lower odds of ALS. No significant differences were observed between bulbar- and spinal-onset ALS phenotypes. Conclusions: ALS is associated with structural and microvascular retinal alterations detectable by OCT and OCT-A. These findings support the presence of systemic neurovascular dysfunction and highlight retinal imaging as a promising, non-invasive approach for investigating disease mechanisms and developing potential biomarkers.}, }
@article {pmid42512450, year = {2026}, author = {Yogi, S and Singh, A}, title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, pmid = {42512450}, issn = {2076-3425}, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.}, }
@article {pmid42512540, year = {2026}, author = {Manzo, J and Hernández-Aguilar, ME}, title = {Autism and Neurodegeneration: Distinct Disorders or a Shared Biological Continuum?.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, pmid = {42512540}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Autism spectrum disorder (ASD) is traditionally classified as a neurodevelopmental condition, whereas neurodegenerative diseases are defined by progressive neuronal decline in later life. This separation has shaped research and clinical practice, yet emerging evidence suggests potential biological overlap. This review aims to evaluate whether ASD and neurodegenerative disorders represent distinct entities or are linked through shared mechanisms operating across the lifespan.<br><br>METHODS: This narrative review synthesizes findings from genetic, molecular, cellular, circuit-level, and epidemiological studies examining ASD and major neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Emphasis is placed on identifying convergent pathways and evaluating evidence within a lifespan-oriented framework.<br><br>RESULTS: Across multiple levels of analysis, ASD and neurodegenerative diseases share partially overlapping biological mechanisms, including mitochondrial dysfunction, impaired proteostasis, neuroimmune alterations, and network-level instability. Genetic and molecular data reveal pleiotropic pathways influencing both early neurodevelopment and later neuronal resilience. Circuit-level studies highlight shared principles of network vulnerability, including cerebellar involvement and excitation-inhibition imbalance. Epidemiological data further indicate increased risk of dementia and parkinsonian features in autistic adults. These convergences suggest that early neurodevelopmental alterations may establish latent vulnerabilities that, under specific conditions, intersect with neurodegenerative processes later in life.<br><br>CONCLUSIONS: ASD and neurodegenerative diseases are best understood as distinct clinical conditions that share partially overlapping biological substrates. Rather than implying a deterministic progression, the evidence supports a model of lifespan convergence in which timing, context, and individual susceptibility shape outcomes. This framework highlights the need for integrated research and clinical approaches that consider brain health as a continuous process from development through aging.}, }
@article {pmid42513190, year = {2026}, author = {Funsueb, S and Thanavanich, C and Chudoung, C and Jomnong, P and Theanjumpol, P and Kittiwachana, S}, title = {Comprehensive and Non-Destructive Sweet Corn Shelf-Life Prediction Using Near-Infrared (NIR) Spectroscopy Coupled with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) Spectral Resolution.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {14}, pages = {}, doi = {10.3390/molecules31142512}, pmid = {42513190}, issn = {1420-3049}, support = {Proactive Researcher Program//Chiang Mai University/ ; }, mesh = {*Zea mays/chemistry ; Spectroscopy, Near-Infrared/methods ; Least-Squares Analysis ; *Food Storage ; Multivariate Analysis ; Temperature ; Kinetics ; }, abstract = {Accurate shelf-life prediction of perishable products remains challenging because quality deterioration involves multiple physicochemical changes that are not adequately captured by conventional univariate approaches. This study proposes a multivariate shelf-life prediction framework for sweet corn based on near-infrared (NIR) spectroscopy coupled with multivariate curve resolution-alternating least squares (MCR-ALS). NIR spectra were collected from sweet corn samples and analyzed using MCR-ALS to extract chemically interpretable concentration and spectral profiles. A total of 100 and 85 corn samples were used for model training and validation, respectively. The dominant MCR-ALS component showed strong correlations with total soluble solids, dry matter, and individual sugar contents (sucrose, glucose, and fructose), effectively describing the overall quality degradation process. Based on the zero-order kinetic model, the predicted shelf lives were 41.3, 11.0, and 8.9 days at 4, 13, and 25 °C, respectively. Arrhenius analysis of the MCR-ALS concentration profile yielded a temperature-dependent degradation rate with an activation energy of 54.05 kJ mol[-1] (R[2] = 0.8387). The practical applicability of the proposed framework was further examined using a separate harvest batch of sweet corn that underwent repeated non-destructive NIR measurements throughout storage. Overall, the proposed NIR-MCR-ALS framework provides a rapid, non-destructive, and chemically interpretable approach for shelf-life prediction and postharvest quality monitoring of perishable produce.}, }
@article {pmid42513312, year = {2026}, author = {Kordas, B}, title = {Multimodal Assessment of Consciousness with Brain-Computer Interfaces and Artificial Intelligence: From Acquired Brain Injury to Neurodegenerative Disease.}, journal = {Journal of clinical medicine}, volume = {15}, number = {14}, pages = {}, pmid = {42513312}, issn = {2077-0383}, support = {2023/49/N/NZ4/03958//National Science Centre/ ; }, abstract = {The assessment of consciousness has been shaped largely by research on acquired disorders of consciousness after acute or chronic brain injury, but similar problems of unreliable behavioral expression increasingly arise in neurodegenerative disease. This translational overlap is especially relevant when preserved cognition, awareness, or intentionality cannot be reliably expressed because of severe motor impairment, fluctuating arousal, cognitive decline, aphasia, apraxia, or impaired cooperation. In neurodegenerative disease, degeneration of arousal systems, large-scale brain networks, cognition, and motor pathways may similarly make observable behavior an unreliable measure of awareness. The challenge is not only to determine if a patient responds, but also to ask if residual awareness, intentionality, or covert cognition can still be detected through physiological signals. This review discusses how contemporary modalities reshape this assessment. Electroencephalography has moved from a descriptive measure of background activity to a bedside tool capable of probing event-related responses, network organization, and cortical complexity. Magnetic resonance methods reveal altered connectivity within thalamocortical and default mode network systems, while functional near-infrared spectroscopy adds a portable hemodynamic approach that may be repeated at the bedside and integrated with active paradigms. Brain-computer interfaces provide a translational step by converting neural responses into evidence of command following or, in selected patients, into communication, and artificial intelligence strengthens these approaches by extracting clinically meaningful patterns from complex neural and hemodynamic data. Additionally, autonomic measures, including heart rate variability and baroreflex indices, are considered as auxiliary physiological context for arousal and engagement, and not as direct markers of awareness. Because the most mature evidence for covert awareness and cognitive-motor dissociation comes from acquired disorders of consciousness, this review treats brain injury literature as a methodological foundation instead of as directly interchangeable evidence for neurodegenerative disease. It then examines how these approaches may be adapted to neurodegenerative contexts, especially ALS, severe dementia, Lewy body disease with fluctuating cognition, and conditions in which communication or motor output becomes unreliable.}, }
@article {pmid42514481, year = {2026}, author = {Xie, P and Wang, J and Tong, B and Di, C and Zhou, F and Wang, W}, title = {Genome-Wide Characterization of the HaALS Gene Family Reveals Its Potential Roles in Imazethapyr Tolerance in Sunflower (Helianthus annuus L.).}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {14}, pages = {}, doi = {10.3390/plants15142113}, pmid = {42514481}, issn = {2223-7747}, support = {CARS-14-1-06//Project of China Agriculture Research System/ ; CX25JC27//Heilongjiang Agricultural Science and Technology Innovation Leap Project/ ; }, abstract = {Acetolactate synthase (ALS; EC 2.2.1.6) catalyzes the first committed step in branched-chain amino acid (BCAA) biosynthesis and is the molecular target of multiple herbicide classes, including the imidazolinones. Here, we performed a genome-wide characterization of the HaALS gene family in sunflower (Helianthus annuus L.) and investigated genotype-dependent transcriptional responses to imazethapyr. A total of 11 HaALS genes were identified and classified into three phylogenetic clades (Groups A-C). All HaALS proteins contained the conserved TPP_enzyme domains (TPP_enzyme_N, TPP_enzyme_M, and TPP_enzyme_C), and purifying selection (Ka/Ks < 1) indicated strong evolutionary constraint on their core enzymatic function. Promoter analyses revealed abundant cis-regulatory elements associated with diverse stress and signaling inputs, supporting regulatory potential for herbicide-triggered transcriptional modulation. qRT-PCR analysis following imazethapyr application (0, 24, and 48 h) showed pronounced genotype-dependent expression reprogramming between the susceptible (S) and resistant (R) cultivars. In the R genotype, multiple HaALS members were strongly induced after treatment; specifically, HaALS4 reached a ~6-fold increase at 24 h and a >10-fold increase at 48 h, and HaALS11 increased to ~6-7-fold at 24 h while remaining above the baseline at 48 h; several additional paralogs exhibited intermediate induction (~3-8-fold by 48 h). In contrast, the S genotype showed limited changes (typically ~0.8-2-fold). Collectively, these findings define the evolutionary features of the sunflower HaALS family and identify herbicide-responsive paralogs that may contribute to imidazolinone tolerance, providing candidates for functional validation and molecular breeding.}, }
@article {pmid42514807, year = {2026}, author = {Cazacu, G and Pamfil, D and Chirilă, O and Totolin, M and Ciolacu, D and Ghilan, A and Niţă, L and Niţă, T and Vasile, C}, title = {Chemical Treatment of Some Lignosulfonates Under DBD Plasma Conditions-II: Characterization of the Modified Lignosulfonates Microparticles.}, journal = {Polymers}, volume = {18}, number = {14}, pages = {}, doi = {10.3390/polym18141756}, pmid = {42514807}, issn = {2073-4360}, abstract = {The chemically modified ammonium lignosulfonate (ALS) powders with carboxylic acids such as, oleic (OA) and lactic acid (LA) and γ-butyrolactone (BL) under dielectric barrier plasma discharge (DBD) have been characterized by average molecular weight and particle size determinations, morphology examination by optical and electronic microscopy (SEM), the study of the thermal properties by thermogravimetry (TG/DTG), differential scanning calorimetry (DSC), differential thermal analysis (DTA) and antioxidant activity tests by DPPH method. The thermal characterization of the modified lignosulfonates reveals their improved thermal stability comparatively with ALS. It has been established that the obtained microparticles are aggregates of particles, covered by modified polymer and exhibit a particular behavior depending on the chemical structure of the used modifier, leading to multifunctional active lignin-based products with better homogeneity. By surface modification, the antioxidant capacity of modified lignosulfonate powders has been maintained.}, }
@article {pmid42515387, year = {2026}, author = {Megalingam, RK and Kuttankulangara Manoharan, S and Cheriyan Manjooran, D and Kamble, D}, title = {Thrivaad: A Multilingual, Predictive Eye-Sign-Based AAC System Powered by Optimized Deep Learning.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {14}, pages = {}, doi = {10.3390/s26144503}, pmid = {42515387}, issn = {1424-8220}, mesh = {Humans ; *Deep Learning ; *Communication Devices for People with Disabilities ; *Eye Movements/physiology ; Brain-Computer Interfaces ; Multilingualism ; }, abstract = {Around 1.5% of the global population is suffering from speech impairments; the major causes for this are cerebral palsy and ALS, and the only way for these individuals to communicate is through Augmentative and Alternative Communication (AAC). These systems are either electronic or non-electronic. Based on new study developments, electronic methods, such as Brain-Computer Interaction (BCI) and eye-gaze-based communication, are assessed as the best choices, but they have their own limitations, incorporating limited adaptability to changing conditions, such as setup variations and user fatigue, which reduces the system's robustness. Our previous study, Netravad, shows potential for addressing these gaps, but it lacks multilingual support and will not yield the same results under changing lighting conditions. This study, Thrivaad, provides multilingual support and text prediction and integrates optimized deep learning to accurately capture eye movements even in varying environmental lighting conditions. Thrivaad uses eye movements as input from a webcam, and the Optuna-optimized YOLOv5 model is used to detect the eye direction accurately. Then communication is established in English, Malayalam, and Hindi. The text-prediction feature of this system improves communication by reducing the number of eye gestures required to form a message. This study included a total of 60 participants across three age groups with 35,263 eye-sign images collected. With this data, the YOLOv5 model is trained and then optimized by Optuna. The proposal system provides accurate eye direction, text prediction, multilingual support, and improved adaptability to changing conditions for eye-based AAC.}, }
@article {pmid42515735, year = {2026}, author = {Rosiak, N and Stojceski, F and Maroni, G and Piontek, B and Cielecka-Piontek, J}, title = {Integrative Network Pharmacology and Molecular Docking Analysis Reveals the Multitarget Mechanisms of Pterostilbene in Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {7}, pages = {}, doi = {10.3390/ph19071053}, pmid = {42515735}, issn = {1424-8247}, support = {UMO-2020/37/B/NZ7/03975//National Science Centre/ ; }, abstract = {Background: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein-protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR-disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub-bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation.}, }
@article {pmid42516233, year = {2026}, author = {Sancho-Castillo, S and Bargues-Navarro, G and Cárdenas Salazar, RG and Privado, J and Sanchis-Sanchis, E and Sancho-Cantus, D and Sanchis-Sanchis, CE and Cubero-Plazas, L and Cano Mateu, M and de la Rubia Ortí, JE}, title = {Influence of micronutrients on anxiety and depression in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1790327}, pmid = {42516233}, issn = {2296-861X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor function, with respiratory failure representing the leading cause of death. Beyond motor deterioration, ALS involves extramotor manifestations, including prominent anxiety and depression symptoms. The intake of certain micronutrients has been associated with these emotional symptoms, due to their role in monoaminergic and peptidic neurotransmitter synthesis pathways; furthermore, these emotional symptoms can severely reduce patients' quality of life. Therefore, this study aims to analyze the relationship between the intake of key micronutrients related to neurotransmitter activity and anxiety and depression symptoms in ALS patients.<br><br>METHODS: A cross-sectional study was conducted with 61 patients with bulbar- or spinal-onset ALS. Dietary micronutrient intake (iodine, magnesium, vitamin B6, vitamin B9, and vitamin C) was assessed using a seven-day dietary record and a Food Frequency Questionnaire. Depression was assessed using the ALS Depression Inventory-12 (ADI-12), while anxiety-related symptoms were assessed using the Beck Anxiety Inventory (BAI).<br><br>RESULTS: A path analysis was conducted to examine the statistical prediction of emotional measures from nutrient intake. The model showed a good fit to the data: NFI&#x202f;=&#x202f;1.000, GFI&#x202f;=&#x202f;1.000, and SRMR&#x202f;=&#x202f;0.001. Considering the magnitude of the effect of the regression weights (&#x3b2; &#x2265;&#x202f;0.14), depression scores exhibited exploratory associations with iodine (&#x3b2; =&#x202f;-0.21) and magnesium (&#x3b2; =&#x202f;0.22), while vitamin B9 (&#x3b2; =&#x202f;-0.32) emerged as an inferentially significant predictor (p <&#x202f;0.05). Anxiety-related symptom severity (BAI scores) showed exploratory associations with iodine (&#x3b2; =&#x202f;-0.31), vitamin B6 (&#x3b2; =&#x202f;0.24), and vitamin C (&#x3b2; =&#x202f;-0.15), whereas depression scores (&#x3b2; =&#x202f;0.51) were an inferentially significant predictor (p <&#x202f;0.05), with 41% of explained variance.<br><br>CONCLUSION: In this sample, lower vitamin B9 intake was statistically associated with depression scores in patients with ALS, while lower iodine and higher magnesium intake showed exploratory associations. Regarding anxiety-related symptoms assessed using the Beck Anxiety Inventory (BAI), higher scores were statistically associated with lower iodine and vitamin C intake, higher vitamin B6 intake, and elevated depression scores, and showed exploratory associations with lower iodine and vitamin C intake, and higher vitamin B6 intake.}, }
@article {pmid42502061, year = {2026}, author = {Mato, S and Fukaura, J and Miyamoto, M and Watanabe, I and Naoi, T and Nakagawa, H and Saito, K}, title = {Evaluation of the Reliability and Validity of the Japanese Version of the Voice Activity and Participation Profile (VAPP-J).}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.07.010}, pmid = {42502061}, issn = {1873-4588}, abstract = {OBJECTIVES: The aim of this study was to evaluate the reliability and validity of the Japanese version of the Voice Activity and Participation Profile (VAPP).<br><br>METHODS: A total of 100 patients with voice disorders (dysphonic group) and 52 students without voice disorders (non-dysphonic group) were enrolled between October 2024 and February 2026. The psychometric properties of the Japanese VAPP were assessed, including internal consistency, concurrent and discriminant validity, interrelationships among sections, comparisons between the Activity Limitation Score (ALS) and Participation Restriction Score (PRS), and responsiveness to voice therapy. Concurrent validity was evaluated by correlations with the Voice Handicap Index (VHI).<br><br>RESULTS: Cronbach's alpha for the total score was 0.98 and remained unchanged after item deletion, indicating excellent internal consistency. VAPP total scores showed a strong positive correlation with VHI scores (r = 0.93, P < 0.001). All VAPP scores (total, section scores, ALS, and PRS) were significantly higher in the dysphonic group than in the non-dysphonic group (P < 0.001). VAPP total scores improved significantly after voice therapy (P < 0.001). Correlations among sections ranged from 0.37 to 0.86 in the dysphonic group and from 0.36 to 0.82 in the non-dysphonic group. ALS scores were significantly higher than PRS scores in the dysphonic group (P < 0.05).<br><br>CONCLUSIONS: The Japanese version of the VAPP (VAPP-J) demonstrates high reliability and validity and could be a useful tool for clinical assessment of voice disorders in Japanese populations.}, }
@article {pmid42503607, year = {2026}, author = {Sanghai, N and Kelley, R and Lao, Y and Madlangsakay, MIR and Paul, P and Llanes-Cuesta, MA and Wang, JF and Zahedi, RP and Kong, J and Tranmer, GK}, title = {Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76432}, pmid = {42503607}, issn = {2198-3844}, support = {//Research Manitoba 2017 Health Research New Investigator Operating Grant/ ; //Natural Sciences and Engineering Research Council of Canada/ ; /CAPMC/CIHR/Canada ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered a highly complex, heterogeneous, fatal disease with a high unmet medical need that affects multiple pathophysiological pathways and has no known singular cause. Oxidative stress, however, is implicated as a central player in the progression of ALS and other neurodegenerative diseases. To date, only two FDA-approved drugs, Edaravone, an antioxidant, and Riluzole, an antiglutamatergic, have been widely used clinically, albeit with modest effects on the clinical course of ALS disease progression. Additionally, preclinical studies of both drugs in ALS mouse models have not shown any significant survival benefit, although some abatement in disease progression is observed and translated from preclinical animal models to clinical human studies.<br><br>METHODS: Using a trifunctional boron-based drug design strategy, we have synthesized a pyrazole small molecule called Borsantrazole (BSZ) and evaluated BSZ in cell-based experiments, acute and chronic toxicity models, and the SOD1-G37R ALS mouse model. We have also evaluated untargeted global proteomic and phosphoproteomic changes induced by BSZ.<br><br>RESULTS: Borsantrazole (a small molecule that can selectively target oxidative stress) with favorable CNS drug like properties (low ER values of 0.9 and 1.0 at 1 and 10&#xa0;&#xb5;m, respectively, suggesting lower Pgp efflux liability and the LogD at pH 7.4 was within the range of 1.2 to 3.1, suggesting BSZ is lipophilic at pH 7.4.) shows no signs of treatment associated toxicity (acute or chronic (120 days)), significantly increases survival (whole animals, 15.1 days (p&#xa0;=&#xa0;0.0326); males, 16.5 days; females, 13.7 days), rescued weight loss (27.1% control, 18.3% BSZ, p&#xa0;<&#xa0;0.0001), delays symptom onset (whole animals, 24.9 days (p&#xa0;=&#xa0;0.0011); males, 23.3 days; females, 26.4 days), delays disease onset (whole animals, 25.5 days (p&#xa0;=&#xa0;0.0001); males, 21.1 days; females, 29.8 days) and affects global proteomic changes in the SOD1-G37R mouse model of ALS. In total, 51 proteins were found to be significantly differentially expressed (p&#xa0;<&#xa0;0.05), including Ca3, Gan, Cplx2, Lrp4, Sqstm1, and 29 phosphorylation sites were differentially expressed and considered statistically significant, including T317 and T72 for neurofilaments light and heavy chain, respectively.<br><br>CONCLUSIONS: Herein, we report that BSZ has demonstrated a favorable safety profile and compelling proof-of-concept efficacy in a ALS mouse model and has the potential to become a disease-modifying ALS therapeutic following further clinical development. Within a broader perspective of treatments for neurodegenerative diseases, BSZ offers a new paradigm for trifunctional small molecule targeting of oxidative stress that can mitigate neuronal deterioration and serve as a potential treatment.}, }
@article {pmid42504602, year = {2026}, author = {Eisen, A and Durham, HD and Pioro, E}, title = {The aging brain that doesn't fail: how neural resilience masks neurodegeneration.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/21678421.2026.2705693}, pmid = {42504602}, issn = {2167-9223}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease are usually framed as consequences of aging-related pathogenic processes, including impaired proteostasis with protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Yet, most individuals, even into advanced age, do not develop clinically significant neurodegenerative disease. This discrepancy suggests that the nervous system possesses robust and redundant protective mechanisms that maintain neural integrity despite cumulative molecular and cellular stress. In this perspective, we propose that neurodegenerative diseases arise not simply from the presence of pathogenic processes, but when integrated resilience systems fail to maintain homeostasis or when reserve mechanisms no longer compensate for accumulated pathology. We have synthesized a threshold-based model of disease emergence based on evidence across proteostasis, mitochondrial function, neuroimmune regulation, glial biology, network-level compensation, and barrier integrity, while integrating genetic, environmental, developmental, and stochastic modifiers. We distinguish biological resilience, which actively limits or repairs pathology, from reserve, which permits function despite pathology. We further propose that clinical disease emerges only when age-related cumulative stress exceeds the combined capacity of resilience and reserve. Reframing neurodegeneration as a failure of preservation systems offers new directions for prevention and therapeutic development.}, }
@article {pmid42505224, year = {2026}, author = {Collaço, N and Kennington, A and Greenberg, N and Imber, T and Warne, D and Sodergren, S}, title = {Mapping Support-Seeking After Cancer Treatment: A Co-Designed Model of Triggers, Timing and Support Pathways in Young People with Lived Experience of Cancer.}, journal = {Current oncology (Toronto, Ont.)}, volume = {33}, number = {7}, pages = {}, doi = {10.3390/curroncol33070422}, pmid = {42505224}, issn = {1718-7729}, mesh = {Humans ; *Neoplasms/psychology/therapy ; *Social Support ; Female ; Male ; Young Adult ; Adolescent ; *Help-Seeking Behavior ; Adult ; }, abstract = {Post cancer treatment, many young people often live with ongoing emotional, social, and physical difficulties, but support is not always accessed when it is needed. This study aimed to co-produce a conceptual model of support-seeking after cancer treatment with young people with lived experience of cancer, to better understand the triggers, timing, and pathways influencing engagement with support. This co-design work, informed by Bird et al.'s generative framework for co-production, built upon a prior study involving interviews and co-design workshops with young people and healthcare/allied health professionals, and informed a preliminary model of support-seeking. The current work involved two further co-production stages through an online survey and workshop to refine this model. Data were analysed using a thematic approach to support conceptual model development. Four interconnected themes shaped support-seeking: (1) readiness to engage: recognition, emotional readiness, and relational safety; (2) access and appraisal of support: visibility, fit, feasibility, and burden; (3) pathways to support: multi-modal, layered, and non-linear engagement; and (4) support trajectory: changing needs and recurrent engagement. Engagement in support-seeking depended on the alignment of readiness, recognition of need, and relational safety. This model offers a framework to improve how post-treatment support is designed and delivered in practice.}, }
@article {pmid42505342, year = {2026}, author = {Yang, CS and Ma, Y and Xie, JL and Lou, XY and Lv, YT and Wu, TX and Xu, HF and Zou, SM and Wu, ZY and Li, HF}, title = {Pathogenicity Classification of TARDBP Variants of Uncertain Significance: An Integrative Clinical Characterization and Functional Validation.}, journal = {Cells}, volume = {15}, number = {14}, pages = {}, doi = {10.3390/cells15141232}, pmid = {42505342}, issn = {2073-4409}, support = {2025ZD1802600//Innovative Drug Research and Development National Science and Technology Major Project/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Mutation/genetics ; Female ; Genetic Variation ; }, abstract = {TAR DNA binding protein (TARDBP) is one of the major causative genes of amyotrophic lateral sclerosis (ALS), which drives disease progression through both gain-of-toxicity (GOT) and loss-of-function (LOF) mechanisms. The mutant TDP-43 exhibits aberrant nucleocytoplasmic distribution and forms cytotoxic hyperphosphorylated aggregates, a process that can be robustly recapitulated in vitro. Thus, functional assays in cell lines serve as a reliable metric for the pathogenicity classification of TARDBP variants. In this study, we performed in vitro experiments to classify the pathogenicity of 28 TARDBP variants of uncertain significance (VUS) among the 172 previously reported TARDBP variants. 22 of these VUS were determined to be functionally abnormal, of which 12 could be further classified as likely pathogenic (LP) variants according to American College of Medical Genetics (ACMG) and the ClinGen Sequence Variant Interpretation (SVI) Working Group guidelines. We also summarized the clinical characteristics of 35 ALS patients carrying 12 variants in the TARDBP gene. Pathogenic missense variants were predominantly clustered in the C-terminal domain (CTD) of TARDBP. Variants in TARDBP exon 6 may lead to an earlier age at onset. ALS caused by TARDBP mutations exhibits marked phenotypic heterogeneity, along with incomplete penetrance in carriers. Patient-derived primary skin fibroblasts serve as a feasible cellular model for the functional assessment of variant pathogenicity. Our findings expand the TARDBP mutation spectrum, and provides a preliminary basis for preclinical research on TARDBP-targeted therapies for ALS.}, }
@article {pmid42505348, year = {2026}, author = {Liu, B and Zhang, L and Lv, B and Xu, C and Han, L and Yan, Q and Wang, X}, title = {Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.}, journal = {Cells}, volume = {15}, number = {14}, pages = {}, doi = {10.3390/cells15141238}, pmid = {42505348}, issn = {2073-4409}, mesh = {Humans ; *Copper/metabolism ; *Cuproptosis ; *Homeostasis ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Mitochondria/metabolism ; Proteotoxic Stress ; }, abstract = {Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.}, }
@article {pmid42506061, year = {2026}, author = {Zeng, CW}, title = {Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.}, journal = {Neurology international}, volume = {18}, number = {7}, pages = {}, doi = {10.3390/neurolint18070139}, pmid = {42506061}, issn = {2035-8385}, abstract = {Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research.}, }
@article {pmid42506583, year = {2026}, author = {Remus, S and Donelle, L and Bauer, M and Nagle, L}, title = {A Nursing Homecare Data Science Investigation Using "Persons with ALS" (PALS) Electronic Health Records (EHRs).}, journal = {The Canadian journal of nursing research = Revue canadienne de recherche en sciences infirmieres}, volume = {}, number = {}, pages = {8445621261469904}, doi = {10.1177/08445621261469904}, pmid = {42506583}, issn = {1705-7051}, abstract = {BackgroundData science, rooted in computer science, statistics, and information science is advancing healthcare research by unlocking "insights" from big data to discover knowledge about patient experiences and answer previously unanswerable questions. The comparatively limited engagement of Canadian nurse researchers in this field, relative to counterparts in other jurisdictions (e.g., United States) served as a key impetus for initiating this data science study.PurposeTo investigate homecare electronic health records (EHRs) of "persons with ALS" (PALS) disease and identify care-related factors that influence their preferences and ability to be safely supported at home.MethodGuided by a nursing informatics' data, information, knowledge, wisdom (DIKW) framework and the knowledge discovery in databases (KDD) methodology, a retrospective, secondary analysis of an integrated dataset (1159 clinical assessments and administrative data) documenting 240 PALS's homecare encounters (April 1, 2009 - July 31, 2019) was conducted. EHR data was analyzed using correlations and logistic regression to model institutionalization risk factors of PALS.ResultsFive significant models were generated that accurately distinguished PALS institutionalization status (at home/not home) while offering comparable predictive performance. The final model featuring six factors offers homecare providers real-time insights into PALS clinical status at the point of care. Four relate to ALS clinical manifestations of disease decline and two assessment outcome measures (MAPLe and CHESS), strongly predicting institutionalization and caregiver burden.ConclusionBig data science offers nurse researchers a transformative way to advance knowledge development that supports high-quality, sustainable healthcare delivery while fulfilling an intended benefit of EHRs.}, }
@article {pmid42507931, year = {2026}, author = {Ozguney, B and Puterbaugh, RZ and Viswanathan, R and Shenoy, J and Mohanty, P and Mittal, J and Fawzi, NL}, title = {Methionine oxidation alters both helical assembly and disordered contacts in human TDP-43 C-terminal domain phase separation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {31}, pages = {e2537431123}, doi = {10.1073/pnas.2537431123}, pmid = {42507931}, issn = {1091-6490}, support = {R01NS116176//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; not applicable//Radala Foundation/ ; }, abstract = {TAR DNA binding protein 43 (TDP-43), a key protein linked to ALS pathology, undergoes phase separation and forms functional assemblies via condensation within cells. The conserved region (CR) within its C-terminal domain (CTD) mediates self-assembly through helix-helix interactions, while the flanking intrinsically disordered regions (IDRs) contribute to phase separation through transient interactions involving aromatic and hydrophobic residues. The CTD contains ten methionine residues distributed equally between these regions, making it particularly susceptible to oxidative modifications. While methionine oxidation is known to impair TDP-43 phase separation, neither the precise mechanism nor the specific contribution of methionines in the CR compared to the IDRs has been determined. Here, we combine NMR spectroscopy and molecular dynamics (MD) simulations to reveal if and how methionine oxidation in each region differentially affects CTD structure and phase separation. To assess the change of secondary structure caused by oxidation, we measured NMR random coil chemical shift values for methionine sulfoxide. Oxidation of CR methionines disrupts helical structure and directly impairs intermolecular helical association, while oxidation of IDR methionines disrupts long-range contacts. Hence, oxidation of methionines in both regions contributes to impaired phase separation, albeit through different mechanisms. These findings establish methionines as critical redox-sensitive modulators in TDP-43 phase behavior and provide molecular insights into how oxidative stress may contribute to TDP-43 dysregulation in neurodegenerative diseases.}, }
@article {pmid42508294, year = {2026}, author = {Liu, X and Fu, W and Cui, X and Feng, Y and Wen, B and Shan, L and Xu, X and Yang, J and Zhang, J and He, L and Zang, Y and Zhao, S and Yao, X and Liu, Y and Ma, M and Du, B and Dang, J and Zou, Z and Feng, H and Lu, Z and Zhang, Y and Wu, Z and Shang, H and Yin, P and Fan, D}, title = {Huoling Shengji granule in amyotrophic lateral sclerosis: A multicenter, randomized, double-blind, riluzole-controlled trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00953}, doi = {10.1016/j.neurot.2026.e00953}, pmid = {42508294}, issn = {1878-7479}, abstract = {Currently, no curative therapies exist for Amyotrophic Lateral Sclerosis (ALS). This study aimed to evaluate the efficacy and safety of Huoling Shengji granules (HLSJ), a traditional Chinese medicine (TCM), compared to the standard treatment riluzole. A multicenter, randomized, double-blind, double-dummy, active-controlled Phase II clinical trial was conducted across 11 centers in China. A total of 140 ALS patients were randomly assigned (1:1) to receive either HLSJ or riluzole for 48 weeks. The primary endpoint, analyzed in the full analysis set (FAS), was the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from baseline to Week 48. Safety profiles were comparable between groups, with no significant difference in adverse events (80.28% vs. 80.56%, P = 0.9671). Analysis using the pre-specified Last Observation Carried Forward (LOCF) method showed a numerical advantage for HLSJ (1.07 points) but lacked statistical superiority. However, a more scientific analysis using the Mixed Model for Repeated Measures (MMRM), recommended for progressive diseases, indicated that HLSJ was significantly superior to riluzole in slowing ALSFRS-R score decline (Least Squares Mean Difference [LSMD]: 2.29 points; 95% confidence interval [CI]: 0.52 to 4.06; P = 0.0114). While the LOCF model showed no statistical difference, the MMRM analysis confirmed that HLSJ demonstrated significant efficacy superior to riluzole with a favorable safety profile. These findings provide a critical basis for conducting pivotal Phase III confirmatory trials of HLSJ for ALS treatment.}, }
@article {pmid42508356, year = {2026}, author = {Wu, W and Lalli, GS and Wu, H}, title = {Linking Big Five personality traits to L2 willingness to communicate with GenAI chatbots: A mixed-methods study of the mediating role of regulatory focus.}, journal = {Acta psychologica}, volume = {269}, number = {}, pages = {107516}, doi = {10.1016/j.actpsy.2026.107516}, pmid = {42508356}, issn = {1873-6297}, abstract = {Generative artificial intelligence (GenAI) chatbots are increasingly used for second language (L2) speaking practice, yet learners' willingness to communicate (WTC) with them remains insufficiently understood. Building on MacIntyre et al.'s (1998) Pyramid Model, this study examined how the Big Five personality traits and regulatory focus jointly shape L2 WTC in GenAI-mediated interaction. Survey data from 426 Chinese university learners were analyzed using Partial Least Squares Structural Equation Modeling, complemented by qualitative thematic analysis. Openness emerged as the only trait directly predicting WTC and was positively associated with both promotion and prevention focus. Agreeableness positively predicted prevention focus, whereas Extraversion showed a negative association; Conscientiousness and Neuroticism were unrelated to regulatory focus. Prevention focus, but not promotion focus, significantly predicted WTC. Indirect effects indicated that Openness and Agreeableness enhanced WTC through prevention focus, while Extraversion exerted a negative indirect effect. Qualitative analysis identified four themes, with psychological safety and controllability explaining why prevention-focused learners favored GenAI. Together, the findings suggest that GenAI's de-socialized, low-risk interaction environment reshapes how personality and motivational dispositions translate into L2 WTC, offering implications for both L2 pedagogy and the design of GenAI-supported speaking tools.}, }
@article {pmid42508391, year = {2026}, author = {Gao, W and Lee, HY and Min, KJ}, title = {Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2026.0366}, pmid = {42508391}, issn = {2152-5250}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are increasingly recognized as manifestations of aging-associated systemic dysfunction, rather than isolated brain disorders. Central to this dysfunction is the interplay among metaflammation, mitochondrial breakdown, and chronic neuroinflammation. Metaflammation, driven by peripheral metabolic stress, may prime the brain's immune environment through cytokine signaling and blood-brain barrier compromise. This metabolic-inflammatory crosstalk is thought to impair mitochondrial integrity in neurons and glial cells, promoting oxidative stress and the release of pro-inflammatory mitochondrial components. These mitochondrial signals, in turn, may activate microglial and astrocytic innate immune responses, creating a potentially self-reinforcing cycle of neuroinflammation and energy failure that may contribute to neuronal loss. This review outlines a proposed framework linking metaflammation to neurodegeneration, emphasizing shared mechanisms across AD, PD, and ALS. We further examine preclinical and clinical advances in therapeutic strategies that target this axis including anti-inflammatory agents, caloric restriction, mitophagy enhancers, mitochondrial antioxidants, and senescence-targeted therapies. Together, these interventions reflect a shift from symptom management to systemic metabolic and immune modulation, offering a unified framework for understanding and potentially influencing age-related neurodegeneration.}, }
@article {pmid42508540, year = {2026}, author = {Sun, R and Duan, X and Wang, X and Liu, J and Li, Z and Wang, Y}, title = {R-loops: Biological Functions, Regulatory Mechanisms, and Therapeutic Implications in Brain Diseases-A Review.}, journal = {Molecular and cellular probes}, volume = {}, number = {}, pages = {102081}, doi = {10.1016/j.mcp.2026.102081}, pmid = {42508540}, issn = {1096-1194}, abstract = {BACKGROUND: R-loops are three-stranded nucleic acid structures formed by a DNA-RNA hybrid and a displaced single-stranded DNA. They regulate transcription, replication, and DNA repair, but their dysregulation causes genomic instability and inflammation, contributing to brain diseases. The nervous system exhibits selective vulnerability to R-loop stress due to ultra-long gene transcription, post-mitotic longevity, and high metabolic demands.<br><br>METHODS: This review synthesizes current literature from PubMed, Scopus, Web of Science, and Embase (2010-2026) on R-loop biology, with a focus on brain-specific mechanisms, regulatory factors (SETX, ZPR1, METTL3, TDP-43/FUS), and disease models.<br><br>RESULTS: In neurodegeneration, R-loop accumulation drives repeat expansion disorders (Fragile X, Huntington's disease) and loss-of-function SETX mutations (AOA2), whereas gain-of-function SETX (L389S) causes pathological R-loop depletion in ALS4, disrupting TGF-&#x3b2; signaling. TDP-43/FUS and SMN are integral to R-loop resolution, unifying ALS/FTD and SMA. In brain cancers, METTL3-mediated m[6]A modification of TERRA stabilizes telomeric R-loops in ALT-positive neuroblastoma, creating a therapeutic vulnerability to METTL3 inhibitors (STM2457, STC-15). Glioma stem cells rely on m[6]A-modified circPOLR2B to regulate R-loop formation and malignancy. Clinical-stage agents (EP102, TUG1ASO, ATX-559) and R-loop-derived prognostic signatures (RLPI) are emerging, but translation is hindered by a lack of non-invasive biomarkers and the dual physiological/pathological roles of R-loops.<br><br>CONCLUSIONS: R-loops are central to brain disease pathogenesis, offering promising therapeutic targets. Future research should prioritize precision R-loop modulators, non-invasive biomarkers, and combinatorial strategies.}, }
@article {pmid42508631, year = {2026}, author = {Alanazi, SM and Al-Kuraishy, HM and Alexiou, A and Papadakis, M and Faheem, SA and Batiha, GE}, title = {Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {149}, number = {}, pages = {111834}, doi = {10.1016/j.pnpbp.2026.111834}, pmid = {42508631}, issn = {1878-4216}, abstract = {Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.}, }
@article {pmid42508735, year = {2026}, author = {Piccolo, LL and Panto, C and Yeewa, R and Yubolphan, R and Poound, P and Potikanond, S and Jantrapirom, S}, title = {Context-dependent YEATS-domain inhibition enhances neuronal resilience and improves ALS phenotypes.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107549}, doi = {10.1016/j.nbd.2026.107549}, pmid = {42508735}, issn = {1095-953X}, abstract = {Neuronal loss in neurodegenerative disease is driven in part by maladaptive stress signaling and impaired adaptation to proteotoxic challenges. ENL and AF9 are YEATS-domain acyl-lysine reader proteins best characterized in leukemia, but their functions in neurons remains unclear. Here, we defined the role of the ENL/AF9 YEATS domain using complementary chemical and genetic perturbations. We applied the selective YEATS inhibitor SR-0813 in differentiated human neurons and modulated ENL/AF9 activity in Drosophila using either SR-0813 or ENL/AF9 knockdown. In flies, SR-0813 phenocopied ENL/AF9 knockdown by extending lifespan and enhancing stress tolerance. To test disease-context specificity, we performed a Drosophila genetic modifier screen across neurodegeneration models. ENL/AF9 reduction was beneficial in UBQLN2[P497H] and SOD1[G94A] but showed reduced efficacy or became detrimental in chronic aggregation or mitochondrial stress models such as (GGGGCC)49 and polyQ disease. In human neurons, SR-0813 improved survival across multiple stress conditions, with the strongest protection during endoplasmic reticulum stress. Mechanistically, ENL/AF9 YEATS inhibition dampened PERK-dependent integrated stress response signaling and reduced apoptotic commitment without broadly enhancing proteostasis capacity. Together, these findings identified ENL/AF9 as modulators of neuronal stress-response dynamics and established ENL/AF9 YEATS-domain inhibition as a context-dependent strategy to enhance neuronal resilience with relevance to ALS and related proteotoxic disorders.}, }
@article {pmid42509371, year = {2026}, author = {Ran, X and Wuu, J and Qin, ZS and McDermott, MP and Cooper-Knock, J and Li, Y and Granit, V and Grignon, AL and Lin, E and Fernandez, MC and Colato, D and Carberry, N and Lill, CM and Piazza, P and Malaspina, A and Benatar, M}, title = {Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {42509371}, issn = {1546-170X}, support = {R01 NS105479, U54 NS092091//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 NS105479, U54 NS092091//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; R01 NS105479, U54 NS092091//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 4365, 172123//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 4365, 172123//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 4365, 172123//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 2015, 16-TACL-242//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; 2015, 16-TACL-242//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; 2015, 16-TACL-242//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, abstract = {The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6 years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.}, }
@article {pmid42509459, year = {2026}, author = {Sellin, J and Öijerstedt, L and von der Gablentz, J and Chamoun, S and Kläppe, U and Press, R and Samuelsson, K and Grosskreutz, J and Ingre, C}, title = {Plasma cardiac troponin T complements neurofilament light chain by reflecting disease phase and phenotypic variation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42509459}, issn = {1432-1459}, support = {GR 1578/6-1//Deutsche Forschungsgemeinschaft/ ; GR 1578/9-1//Deutsche Forschungsgemeinschaft/ ; EXC 2167/2 - 390884018//Germany`s Excellence Strategy/ ; }, abstract = {BACKGROUND: Neurofilament light chain (NfL) is an established marker of neuronal injury and disease aggressiveness in amyotrophic lateral sclerosis (ALS). In contrast, the clinical and biological significance of cardiac troponin T (cTnT) in ALS is not fully understood. We aimed to evaluate the relationship between plasma cTnT and disease aggressiveness, progression stage, and clinical phenotype in comparison with NfL.<br><br>METHODS: Plasma cTnT and cerebrospinal fluid (CSF) NfL were analysed at diagnosis in a population-based cohort of 526 patients with ALS. Disease aggressiveness was modelled using the D50 framework, which quantifies the time taken to lose 50% of functional capacity (ALSFRS-R) and normalises individual disease trajectories. Biomarker associations with disease aggressiveness, phase, and clinical variables were assessed through group comparisons, logistic and linear regression, and receiver operating characteristic analyses.<br><br>RESULTS: Neurofilament light chain in CSF was strongly associated with disease aggressiveness, with higher levels in patients with more aggressive disease. In contrast, plasma hs-cTnT did not correlate with D50. Across disease phases, CSF NfL remained relatively stable, whereas plasma hs-cTnT increased with advancing rD50, suggesting accumulation with disease progression. Plasma hs-cTnT levels were higher in patients with spinal compared to bulbar onset. Combined biomarker models improved sensitivity and negative predictive value for identifying less aggressive disease.<br><br>CONCLUSION: Plasma hs-cTnT and CSF NfL capture distinct but complementary dimensions of ALS pathology. While NfL reflects disease aggressiveness, hs-cTnT aligns with disease phase and clinical phenotype, supporting its use as a complementary biomarker for ALS characterisation and monitoring.}, }
@article {pmid42510076, year = {2026}, author = {Uzun, E and İçöz, D and Apaydın, BK and Orhan, K}, title = {Investigation of the Use of Artificial Intelligence in Anterior Loop Detection: A Panoramic Radiography Study.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {14}, pages = {}, doi = {10.3390/diagnostics16142213}, pmid = {42510076}, issn = {2075-4418}, support = {2024HZDP003//Pamukkale University/ ; }, abstract = {Background/Objectives: The accurate detection of the anterior loop (AL) of the inferior alveolar nerve is critical to avoid neurosensory complications during surgical procedures in the interforaminal region, and panoramic radiography continues to be widely used in routine dental diagnostics due to its accessibility and cost-effectiveness. This study aimed to evaluate the performance of a deep learning approach in automatic detection of the AL in panoramic radiographs. Methods: A total of 305 anonymised panoramic radiographs containing 413 annotated ALs were used to train a YOLOv8x-based model for automatic AL detection. The dataset was divided into training, validation, and test sets consisting of 245 images (332 AL annotations), 30 images (40 AL annotations), and 30 images (41 AL annotations). Labelling was carried out by using the polygonal annotation method. The model's performance in identifying the AL region was measured using precision, recall, F1 score, and mean average precision (mAP@0.5). Results: The model achieved a precision of 0.75, a recall of 0.6585, and a F1 score of 0.7013. The average precision at an intersection over union (IoU) threshold of 0.5 (mAP@0.5) was 0.739. Conclusions: This study demonstrates the feasibility of using a YOLOv8x-based detection model to detect ALs in panoramic radiographs. Although further improvements are needed to enhance model sensitivity and generalisability, the findings demonstrate the potential to support clinical decision-making.}, }
@article {pmid42510722, year = {2026}, author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C}, title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.}, journal = {Biology}, volume = {15}, number = {14}, pages = {}, doi = {10.3390/biology15141176}, pmid = {42510722}, issn = {2079-7737}, abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.}, }
@article {pmid42511587, year = {2026}, author = {Korošec, T and Rogelj, B and Župunski, V}, title = {LINE-1 Retrotransposons and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {14}, pages = {}, doi = {10.3390/ijms27146244}, pmid = {42511587}, issn = {1422-0067}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. While monogenic causes account for a minority of cases, in most cases, ALS is sporadic and likely arises from multilayer interactions of genetic architecture, aging-associated loss of genome regulation, and inflammatory stress. Long interspersed nuclear element-1 (LINE-1) retrotransposons are endogenous mobile elements that are tightly controlled through various cellular mechanisms under normal conditions. When abnormally active, they are involved in gene inactivation, expression regulation, and genomic instability, leading to cellular processes such as innate immunity and cell death. Here, we present mechanistic links between LINE-1 and ALS. These include evidence that the burden of retrotransposition-competent LINE-1s (RC-L1s) is increased in ALS genomes, positioning RC-L1 load as a candidate contributor to missing heritability in sporadic disease. We also integrate emerging data showing that LINE-1 RNA can be intrinsically toxic independently of new insertions, as it promotes chromatin opening and transcriptional epigenetic noise, particularly when nuclear RNA surveillance pathways fail in TDP-43 pathology. Finally, we review how LINE-1-derived DNA/RNA intermediates can engage innate immune sensors, highlighting the cGAS-STING axis as a plausible route from LINE-1 de-repression to neuroinflammation. Together, these concepts support a model in which genetic RC-L1 load and age-/pathology-driven LINE-1 de-repression converge on nuclear dysfunction and inflammatory amplification, suggesting concrete molecular nodes for therapeutic intervention.}, }
@article {pmid42492571, year = {2026}, author = {Tavares de Sousa, M and Crispi, F and Gomez, O and Hergert, B and Hecher, K}, title = {The carotid-subclavian artery index (CSAI) in the fetal aortic arch with classical branching and brachiobicephalic trunk in a midtrimester low risk population.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2922-1435}, pmid = {42492571}, issn = {1438-8782}, abstract = {Purpose The carotid-subclavian artery index (CSAI) has shown high sensitivity and specificity for diagnosing coarctation of the aorta (CoA) in fetuses and neonates. We investigated whether variations in aortic arch (AA) branching without CoA affect CSAI by comparing fetuses with the classical pattern to those with a brachiobicephalic trunk (BBCT), the most frequent variant. Material and Methods In this prospective cohort study of 335 low-risk singleton pregnancies (19 - 22 weeks of gestation), standardized fetal echocardiography was used to assess AA branching in a sagittal view. Two blinded observers classified branching patterns and calculated CSAI. Results Adequate image quality was obtained in 262/335 (78.2%). 194/262 (74%) fetuses showed a classical pattern and 66 (25.2%) a branching variant. Furthermore, two fetuses (0.8%) due to disagreement on branching pattern. 50/66 (76.8%) fetuses with isolated BBCT were compared with 194 cases with classical AA branching pattern. 16 other variants were excluded. Interobserver agreement showed an intraclass correlation coefficient (ICC) of 0.87 (95%CI: 0.89-0.95). Mean CSAI was significantly lower in BBCT (0.71 ± 0.14) than in classical branching (1.46 ± 0.37; P < 0.001). None required cardiac intervention within two years. Conclusions Targeted fetal echocardiography showed a lower CSAI in cases with BBCT than in classical branching pattern. Future studies are warranted to assess the diagnostic impact of our findings in the setting of suspected CoA. Zielsetzung: Der Carotis-Subclavian-Artery-Index (CSAI) wird in der Diagnostik der Aortenisthmusstenose (CoA) eingesetzt. Wir untersuchten, ob der CSAI bei Feten mit Varianten der Aortenabgänge eine Rolle spielt und verglichen diesen mit Werten bei Aortenbögen mit klassischen Abgängen. Material und Methoden: In dieser prospektiven Kohortenstudie wurden 335 Einlingsschwangerschaften mit niedrigem Risiko zwischen der 19. und 22. Schwangerschaftswoche mittels standardisierter fetaler Echokardiografie untersucht. Der Aortenbogen wurde in sagittaler Ebene dargestellt. Zwei voneinander unabhängige Untersuchende beurteilten verblindet das Abgangsmuster und berechneten den CSAIErgebnisse: Eine ausreichende Bildqualität konnte bei 262 von 335 Fällen (78,2 %) erzielt werden. 194/262 (74 %) Feten zeigten ein klassisches Abgangsmuster, 66 (25,2 %) eine Variante. Bei zwei Feten (0,8 %) bestand Uneinigkeit über das Abgangsmuster. 50/66 (76,8 %) Feten mit isoliertem BBCT wurden mit den 194 Fällen mit klassischem Abgang verglichen; 16 weitere Varianten wurden ausgeschlossen. Die Interobserver-Übereinstimmung zeigte einen Intraklassen-Korrelationskoeffizienten (ICC) von 0,87 (95 %-KI: 0,89-0,95). Der mittlere CSAI war bei BBCT signifikant niedriger (0,71 ± 0,14) als bei klassischem Abgang (1,46 ± 0,37; p < 0,001). Kein Kind benötigte innerhalb von zwei Jahren eine kardiale Intervention. Schlussfolgerung: Die gezielte fetale Echokardiografie zeigte einen signifikant niedrigeren CSAI bei Feten mit BBCT im Vergleich zu Feten mit klassischem Aortenbogenabgang. Weitere Studien sind erforderlich, um die diagnostische Bedeutung dieser Befunde im Kontext eines Verdachts auf Aortenisthmusstenose zu klären.}, }
@article {pmid42493042, year = {2026}, author = {Shen, J and Gu, Q and Huang, Q and Chu, S and Li, R}, title = {Identification of resistance to multiple herbicides and metabolic resistance to penoxsulam in barnyardgrass (Echinochloa crus-galli).}, journal = {Pesticide biochemistry and physiology}, volume = {222}, number = {}, pages = {107231}, doi = {10.1016/j.pestbp.2026.107231}, pmid = {42493042}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Echinochloa/drug effects/genetics/metabolism ; *Sulfonamides/pharmacology ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Uridine/analogs &amp; derivatives ; }, abstract = {Barnyardgrass (Echinochloa crus-galli) is a problematic weed in rice production, and resistance to multiple herbicides threatens sustainable management. The resistant (R) population JZWD lacks ALS target-site mutations for penoxsulam, indicating metabolic resistance. Whole-plant assays revealed that JZWD exhibited moderate resistance to penoxsulam, glufosinate ammonium and haloxyfop-P, and low resistance to quinclorac, glyphosate and halauxifen-methyl, while it was susceptible to quizalofop-p-ethyl. The synergistic effects of malathion confirmed the involvement of P450 in penoxsulam resistance. Transcriptome sequencing (RNA-Seq) of untreated and penoxsulam-treated resistant and susceptible plants revealed 25 candidate genes belonging to major detoxification enzyme families (12 cytochrome P450 monooxygenases, 3 glutathione S-transferases, 3 uridine diphosphate-dependent glycos-yltransferases, 3 ATP-binding cassette transporters and 4 peroxidase). Four core genes (CYP72A616-like, UGT83A1, CYP97B2 and PODSPC4-1) were significantly upregulated in at least two resistance-related comparisons. KEGG enrichment revealed primary metabolism pathways enriched among the upregulated genes. Technical qRT-PCR validation of the same RNA samples confirmed the RNA-Seq results for most genes. Independent biological samples revealed that CYP72A616-like was constitutively overexpressed (35.87-fold) in the R population, whereas UGT83A1, CYP97B2 and PODSPC4-1 were strongly induced by penoxsulam (8.75 to 334.92-fold). Two additional P450s (CYP71C42 and CYP734A1) were also upregulated. Among the three additional resistant populations, four representative P450 genes showed variable upregulation patterns under untreated conditions (14.79 to 160.19-fold), and all three populations were strongly induced by penoxsulam (16.25 to 945.07-fold). These results suggest that metabolic resistance mediated by P450s and other detoxification enzymes underlies multiple herbicide resistance in E. crus-galli, providing targets for resistance monitoring and sustainable weed management.}, }
@article {pmid42493742, year = {2026}, author = {Criss, S and Abim-Karmon, RS and Teel, J and Rodríguez, V and Bennon, A and Wills, S and Gonzales, S and Nayreau, DD and Bharadwaj, V and Kim, HG and Woollery, J and Fair, ML}, title = {Trust, Participation, and Power: Community Perspectives from the Equity in Public Health Initiative.}, journal = {Journal of community health}, volume = {}, number = {}, pages = {}, pmid = {42493742}, issn = {1573-3610}, abstract = {Health disparities arise from unequal power relations shaping resource allocation, governance, and community agency. Community power is a key mechanism for addressing disparities. This study examines how visible, hidden, and invisible power operate within a U.S. county to inform inclusive governance. We conducted seven focus groups with Black and Hispanic residents (n = 68) and sixteen semi-structured interviews with elected officials, government staff, and advocacy leaders in Greenville County, South Carolina. Data were collected between March and December 2024. Transcripts were collaboratively coded in NVivo and analyzed using thematic analysis guided by Heller et al.'s Three Faces of Power framework. Visible power appeared through inequitable resource distribution, limited transparency, and barriers to civic participation. Hidden power functioned through faith based organizations, schools, nonprofits, and social media, connecting residents with decision makers. Invisible power reflected how socioeconomic status, race and ethnicity, immigration, and language shaped perceptions of agency and trust. Participants called for participatory structures that move beyond consultation toward shared authority and sustained engagement. Strengthening community power through structural reforms, inclusive governance practices, and targeted civic engagement may improve health outcomes and reduce disparities. Future research should examine scalable co-governance models.}, }
@article {pmid42493871, year = {2026}, author = {Torabi, SJ and Tollefson, TT}, title = {Invited Commentary on: Fincher et al.'s "Biochemical, Mechanical, and Warping Behavior of Fresh Frozen Costal Cartilage Allograft": A Look into Rib Grafts to Be Used for Rhinoplasty from Human Donors.}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261472664}, doi = {10.1177/26893614261472664}, pmid = {42493871}, issn = {2689-3622}, }
@article {pmid42494173, year = {2026}, author = {Sellin, J and Waldorf, S and von der Gablentz, J and Grehl, T and Nazlican, H and Meyer, T and Grosskreutz, J and Weydt, P and Bernsen, S}, title = {Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, pmid = {42494173}, issn = {2328-9503}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS.<br><br>METHODS: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n&#x2009;=&#x2009;433) and an independent replication cohort (Bonn, n&#x2009;=&#x2009;185).<br><br>RESULTS: TnT levels were strongly associated with rD50-defined disease phases in the discovery cohort (p&#x2009;<&#x2009;0.001). While not all subgroup-specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50-derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p&#x2009;<&#x2009;0.001). Associations between TnT levels and D50-defined disease aggressiveness were generally weaker and less consistent.<br><br>INTERPRETATION: TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials.}, }
@article {pmid42494493, year = {2026}, author = {Kennedy, J and Al Khleifat, A and King, A and Al-Sarraj, S and Al-Chalabi, A and Mitchell, JC and Troakes, C}, title = {Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag272}, pmid = {42494493}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, η 2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, η 2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality.}, }
@article {pmid42495327, year = {2026}, author = {Zhan, K and Wang, Y and Lin, J and Chen, F and Fan, X and Hu, P and Wen, J and Gong, F and Zhang, N}, title = {From Simplified Pretreatment to Sensitive Analysis: An Immobilization-Free Cathodic Photoelectrochemical Assay for Sulfonylurea Herbicide Residue and Its Accumulation.}, journal = {ACS omega}, volume = {11}, number = {28}, pages = {42504-42514}, pmid = {42495327}, issn = {2470-1343}, abstract = {Sensitive and selective detection of agricultural chemicals in complex matrices necessitates streamlined workflows without performance loss. By combining the inherent high sensitivity of photoelectrochemical (PEC) analysis with the high selectivity of enzymatic recognition, an immobilization-free PEC assay for the sulfonylurea herbicide chlorsulfuron (Chs) was developed, with purification steps omitted and analytical procedure simplified. Specifically, BiOI nanoflakes (NFs)/NiO heterojunction was fabricated as a sensing platform, generating strong and stable cathodic photocurrent in the presence of dissolved O2. The catalytic reaction of acetolactate synthase (ALS) consumed O2, quenching the photocurrent response. Conversely, upon addition of the model target Chs, a representative sulfonylurea herbicide and effective inhibitor of ALS, the signal was recovered. By monitoring the photocurrent change before and after the enzymatic reaction, Chs was quantified over a linear range of 0.25-100 μg/L, with a limit of detection (LOD) of 0.16 μg/L. The assay avoids laborious probe-immobilization steps by directly adding the enzyme into the electrolyte, significantly simplifying the detection protocol. Furthermore, by omitting traditional purification procedures, the overall workflow was further optimized. The method was successfully applied to detect Chs residues in wheat powder and to evaluate its accumulation in wheat seedlings, with accuracy and reliability validated by high-performance liquid chromatography (HPLC). This work achieves highly sensitive and immobilization-free PEC analysis of Chs and offers a feasible approach for sulfonylurea herbicide detection in selected agricultural samples, with streamlined pretreatment process and enhanced analytical efficiency.}, }
@article {pmid42495582, year = {2026}, author = {Yu, Z and Ross, JP and Rochefort, D and Li, B and Bornais, K and Chum, M and Farhan, SMK and Dion, PA and Rouleau, GA}, title = {Erratum: Consequences of the Novel ALS-Associated KIF5A Variant c.2993-6C&gt;A for Exon 27 Splicing and Axonal Transport of SFPQ.}, journal = {Neurology. Genetics}, volume = {12}, number = {4}, pages = {e200410}, pmid = {42495582}, issn = {2376-7839}, abstract = {[This corrects the article DOI: 10.1212/NXG.0000000000200362.].}, }
@article {pmid42497114, year = {2026}, author = {Yasuda, K}, title = {Functional constraint, not evolutionary domain expansion, is a stronger correlate of pathogenic variant burden in human RNA-binding proteins.}, journal = {Human molecular genetics}, volume = {35}, number = {15}, pages = {}, doi = {10.1093/hmg/ddag067}, pmid = {42497114}, issn = {1460-2083}, support = {23 K05147//JSPS/ ; }, mesh = {Humans ; Evolution, Molecular ; *RNA-Binding Proteins/genetics/chemistry/metabolism ; Animals ; Protein Domains/genetics ; Genetic Variation ; Amyotrophic Lateral Sclerosis/genetics ; Ribonuclease, Pancreatic/genetics ; }, abstract = {Whether evolutionary innovation predisposes genes to pathogenic variation is a fundamental question in evolutionary medicine. RBP domain family diversity correlates with neural complexity across metazoans via vertebrate-specific domain expansions. Here, we tested whether such expanded RBP domains harbor elevated pathogenic variant burden relative to evolutionarily conserved domains. We classified 2961 human RBP-encoding genes into expanded (n = 25 genes, 8 Pfam domains; vertebrate/invertebrate gene count ratio ≥ 3.0) and non-expanded control (n = 231 genes, 89 Pfam domains) groups, and integrated ClinVar pathogenic variants with gnomAD v4.1 constraint metrics. Contrary to our hypothesis, expanded domains showed lower median pathogenic variant density than non-expanded domains (P = .140, rank-biserial r = 0.180, 95% CI [-0.089, 0.444]), consistent across sensitivity analyses and count-based models. In multivariable analysis, functional constraint (pLI) was a stronger predictor of variant density than evolutionary expansion status. At the family level, no expanded domain showed significantly elevated burden; instead, the most prominent outliers were conserved non-expanded domains associated with established neurodegenerative diseases (SMN, Nop). The RNaseA family, despite 26-fold vertebrate expansion, harbored ClinVar pathogenic variants in only 1 of 15 members-fewer than expected by chance (binomial P = 0.030). The sole exception, ANG (Angiogenin), concentrates all seven ALS9-associated variants at its catalytic triad and nuclear localization signal, reflecting functional specialization rather than expansion per se. These findings indicate that evolutionary domain expansion does not confer generalized disease vulnerability in RBPs, and that pathogenic variant burden is more closely linked to functional constraint and lineage-specific subfunctionalization than to evolutionary novelty.}, }
@article {pmid42497626, year = {2026}, author = {Lee, JY and Hong, S and Kim, E}, title = {Soft skills education and training across the nursing continuum: A scoping review.}, journal = {Nurse education today}, volume = {166}, number = {}, pages = {107287}, doi = {10.1016/j.nedt.2026.107287}, pmid = {42497626}, issn = {1532-2793}, abstract = {AIMS: Soft skills are essential for safe and effective nursing practice, supporting communication, collaboration, and professional judgment in complex care settings. Despite their importance, new graduate nurses often struggle with core soft skills, highlighting a persistent gap between education and clinical demands. This scoping review maps current evidence on soft skills education and training for nursing students and nurses, focusing on core concepts, teaching approaches, and evaluation methods.<br><br>DESIGN: This scoping review was conducted following the PRISMA Scoping Review guidelines.<br><br>DATA SOURCES: Five databases-MEDLINE, CINAHL, Embase, Cochrane Library, and PsycINFO-were searched for studies published 2015-2025.<br><br>REVIEW METHODS: Eligible studies used experimental designs to deliver soft skill-focused education or training to nursing students or nurses. Data extraction followed the TIDieR checklist, and soft skills were classified using an adapted version of Song et al.'s framework.<br><br>RESULTS: Twenty-four studies met the inclusion criteria; most involved nursing students and quasi-experimental designs. Effective Interaction and Professionalism were the most frequently addressed skill domains. Student-focused programs emphasized interpersonal and cognitive skills, whereas nurse programs concentrated on preparedness, work management, and teamwork. Traditional lectures predominated, while participatory and emerging approaches such as virtual reality, escape rooms, and game-based learning were less common. Nurse training was typically single-session, whereas student programs were more longitudinal. Most studies relied on self-report measures and included limited follow-up.<br><br>CONCLUSIONS: A distinctive pattern emerged between students and nurses, suggesting that student-focused programs tend to emphasize foundational interpersonal skills while nurse-focused interventions are more likely to address clinically integrated competencies. This gap underscores the need to better align nursing curricula with real-world competency requirements. Educational programs on soft skills should incorporate active, learner-centered teaching strategies, rigorous evaluation methods with long-term follow-up, and validated assessment tools to better prepare nurses for contemporary healthcare demands.}, }
@article {pmid42498430, year = {2026}, author = {Desai, KM and Thakkar, MD and Somaiya, TS and Thomas, DC}, title = {Neurodegenerative Diseases and Sleep Disorders: The Bidirectional Relationship.}, journal = {The Medical clinics of North America}, volume = {110}, number = {5}, pages = {889-905}, doi = {10.1016/j.mcna.2025.12.001}, pmid = {42498430}, issn = {1557-9859}, mesh = {Humans ; *Sleep Wake Disorders/diagnosis/complications/etiology/therapy/physiopathology ; *Neurodegenerative Diseases/complications/diagnosis/physiopathology ; Parkinson Disease/complications ; }, abstract = {Neurodegeneration is mostly irreversible and progressive. Neurodegenerative diseases (NDDs) represent a large group of disorders that have varied clinical and pathologic representations. These include Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis, among others. A common factor in all these NDDs is sleep disorders (SDs). NDDs and SDs are bidirectional. Screening for SDs should be an integral part of a workup of NDDs. Management of one can improve the prognosis of the other.}, }
@article {pmid42498658, year = {2026}, author = {Palm, A and Ekström, M and Einarsson, J and Ersson, K and Ingre, C and Kläppe, U and Lindberg, E and Ljunggren, M and Nygren, I and Sundh, J and Grote, L}, title = {Home mechanical ventilation for amyotrophic lateral sclerosis-a national study of survival and treatment trends across 27 years.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/annalsats/aaoag219}, pmid = {42498658}, issn = {2325-6621}, abstract = {RATIONALE: Home mechanical ventilation (HMV) improves survival in Amyotrophic lateral sclerosis (ALS) and may be provided non-invasively (NIV) or invasively (IV). While NIV is guideline-recommended, the role of IV remains controversial, and data on long-term outcomes and NIV-to-IV transitions are limited.<br><br>OBJECTIVES: To examine survival across HMV strategies in people with ALS (pwALS) in Sweden over 27 years, factors associated with IV initiation, temporal trends in IV use and survival, and regional variation in IV utilisation.<br><br>METHODS: A longitudinal cohort study of pwALS in the Swedish National Registry of Ventilatory Failure (Swedevox) 1996-2022, cross-linked with national registries. Factors associated with mortality and treatment patterns were assessed using multivariable regression models.<br><br>RESULTS: Among 1,360 pwALS, initial NIV was most common (92%), followed by IV (5%) and NIV-to-IV transitions (3%). Most IV initiations were non-elective (77% vs. 18% NIV, p&#x2009;<&#x2009;0.001). NIV-to-IV transitions occurred mainly in metropolitan areas (OR 5.11; 95% CI 2.30-11.4). Median survival differed across observed treatment pathways (p&#x2009;<&#x2009;0.001): 1.7 years with NIV, 4.9 years with IV, and 6.5 years with NIV-to-IV. Mortality was associated with higher age (aHR 1.33 per decade; 95% CI 1.26-1.41), female sex (aHR 1.15; 95% CI 1.02-1.29), and acute initiation (aHR 1.26; 95% CI 1.08-1.47). Longer time from diagnosis to NIV initiation was associated with reduced mortality risk (aHR 0.58 per year; 95% CI 0.55-0.62). Over time, patients initiated HMV at older age with better lung function and lower PaCO2 values among those with available measurements, whereas overall survival remained unchanged.<br><br>CONCLUSION: Patients receiving IV had longer observed survival, likely reflecting the benefits of a secured airway as well as patient selection and underlying disease trajectory. Most IV initiations were unplanned. Over three decades, HMV was initiated in older patients at an earlier stage of respiratory decline, but overall survival remained unchanged. IV use increased with marked regional variation.}, }
@article {pmid42499995, year = {2026}, author = {Nassour, J and Berberich, N and Utpadel-Fischler, D and Wächter, T and Cheng, G}, title = {A dexterous soft hand exoskeleton restores intentional grasping in individuals with severe hand impairment.}, journal = {Nature machine intelligence}, volume = {8}, number = {7}, pages = {1100-1114}, pmid = {42499995}, issn = {2522-5839}, abstract = {Soft hand exoskeletons have emerged as promising assistive devices for individuals with impaired hand function. However, most existing systems provide limited dexterity and primarily target users with moderate hand ability, leaving individuals with severe hand paralysis without effective solutions for reliable grasping of diverse objects. Here we report the translational development of a lightweight, textile-based soft robotic exoskeleton glove with wrist dorsiflexion and an active opposable and abductable thumb, designed to restore hand function in a patient with severe right-hand impairment due to amyotrophic lateral sclerosis. We followed a co-creation approach, enhancing dexterity by increasing hand articulations based on patient needs. Furthermore, to enhance the patient's sense of control, a non-invasive surface electromyography-based grasp predictor (97% sensitivity) was combined with motion data and machine learning-based error correction to compensate for weak, noisy muscle signals, compared with healthy controls (n = 15). The exoskeleton enabled the patient to grasp objects, achieve a Box-and-Blocks Test score of 5 and perform meaningful tasks, including feeding himself. We further validated the exoskeleton in patients with stroke (n = 6). While exoskeleton assistance on average reduced Action Research Arm Test scores of moderately impaired patients by 9, severely impaired patients scored 17 points higher when using the exoskeleton. These results indicate that the dexterous soft hand exoskeleton is particularly effective for individuals with severe to near-complete hand paralysis, while its utility for patients with moderate residual function is limited and task dependent.}, }
@article {pmid42500961, year = {2026}, author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Ding, F and Ba, L and Liu, M and Zhang, M}, title = {Cardiac autonomic dysfunction is associated with advanced stage, fast progression and poor survival in amyotrophic lateral sclerosis.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602261472982}, doi = {10.1177/22143602261472982}, pmid = {42500961}, issn = {2214-3602}, abstract = {ObjectiveTo investigate the association of cardiac autonomic dysfunction with clinical staging and disease progression rate upon diagnosis of amyotrophic lateral sclerosis (ALS), and its impact on survival.Methods24-hour Holter was performed in 95 ALS patients at diagnosis and 39 controls. Patients were grouped by King's Clinical Staging and progression rate (ΔFS, median cut-off 0.67). Heart rate variability parameters were compared across groups. A survival-based cut-point optimization approach was used to determine the cut-off value of standard deviation of all normal-to-normal intervals (SDNN). Kaplan-Meier estimator and multivariable Cox regression analysis were used to evaluate of the effect of SDNN on survival during a median follow-up of 21.5 months.ResultsΔFS in ALS patients in King's Stage 4 upon diagnosis was faster (P=0.007) compared to that of those diagnosed in earlier stages, featuring a higher incidence of respiratory (P<0.001) and bulbar symptoms (P<0.001). In addition, ALS patients in King's Stage 4 exhibited elevated HR-min (P=0.007) and decreased RR intervals (RRI) (P=0.032), SDNN (P=0.004), and standard deviation of the averages of NN intervals in all 5-min segments (SDANN) values (P=0.020) compared to controls. Patients in the ΔFS-fast group had a higher HR-min than those in the ΔFS-slow group (P=0.013) and controls (P=0.003) and lower SDNN (P=0.018) than controls. Both Kaplan-Meier estimator (P=0.03) and multivariable Cox regression analysis (P=0.019) showed that lower SDNN (cut-off value: 111 ms) was associated with poor survival in ALS patients.ConclusionUpon diagnosis, ALS patients in King's Stage 4 and with faster disease progression demonstrated significantly diminished cardiac autonomic control. Lower SDNN was associated with poor survival in ALS.}, }
@article {pmid42501325, year = {2026}, author = {Jia, Y and Cui, B and Liang, Y and Zhang, M and Wang, S and Wang, Y and Chen, H}, title = {Focal epilepsy expands the phenotype of FUS-associated amyotrophic lateral sclerosis.}, journal = {Epilepsia}, volume = {}, number = {}, pages = {}, doi = {10.1002/epi.70409}, pmid = {42501325}, issn = {1528-1167}, support = {82401705//National Natural Science Foundation of China/ ; 82371461//National Natural Science Foundation of China/ ; 2022YFC2503802//National Key Research and Development Program of China/ ; }, abstract = {Epileptic seizures are an exceedingly rare manifestation in classic amyotrophic lateral sclerosis (ALS). Emerging case reports suggest a potential link between ALS associated with FUS gene mutations (FUS-ALS) and seizures, expanding the disease's phenotypic spectrum. A 25-year-old man presented with a 5-month history of rapidly progressive limb weakness, atrophy, and both upper and lower motor neuron signs, consistent with ALS. Notably, he developed two types of epileptic seizures during the disease course, including focal motor seizures and focal seizures evolving to bilateral tonic-clonic seizures. Electroencephalography revealed epileptiform discharges over the right frontotemporal region. Brain [18]F-fluorodeoxyglucose positron emission tomography-computed tomography showed focal hypometabolism in the right frontal cortex. Genetic testing identified a de novo pathogenic FUS variant (c.1574C>T, p.Pro525Leu). The patient was diagnosed with FUS-ALS with comorbid focal epilepsy. Treatment with levetiracetam partially controlled the seizures, but motor function continued to deteriorate. This case highlights focal epilepsy as a comorbid feature in FUS-ALS, broadening the recognized phenotypic spectrum. Genetic testing for FUS mutations should be considered in young-onset ALS patients presenting with seizures.}, }
@article {pmid42492371, year = {2026}, author = {Majumder, M and Borucki, DM and Chowdhury, N and Mallah, K and Tomlinson, S}, title = {Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00969}, doi = {10.1016/j.neurot.2026.e00969}, pmid = {42492371}, issn = {1878-7479}, abstract = {Complement activation contributes to amyotrophic lateral sclerosis (ALS) neuropathology, but whether motor neuron degeneration is driven by proximal or terminal activation products remains unresolved. Failed trials of C5 inhibition - ravulizumab (CHAMPION-ALS) and zilucoplan (ATHLEET/HEALEY ALS Trial), and of systemic C3 inhibition (pegcetacoplan, MERIDIAN) underscore this mechanistic gap. We compared two pharmacologically distinct inhibitors in hSOD1[G93A] mice. CR2Crry blocks complement at C3 and localizes to sites of active deposition. BB5.1, functionally equivalent to ravulizumab, selectively blocks C5a generation and membrane attack complex (MAC) assembly. Treatment began at symptom onset and continued to humane endpoint. Both agents achieved robust target engagement across spinal cord, sciatic nerve, and neuromuscular junction (NMJ). Only CR2Crry extended survival, preserved motor function, and attenuated weight loss. CR2Crry reduced microglial activation and C3 opsonization in the ventral horn, diminished macrophage infiltration, preserved sciatic nerve axonal integrity, and maintained NMJ innervation. BB5.1 failed to modify any functional or neurodegenerative pathology despite confirmed MAC suppression. Proximal C3 activation products, not C5a or MAC, are the dominant drivers of complement-mediated neurodegeneration in the hSOD1[G93A] model of ALS. Site-targeted C3 inhibition may address the mechanistic limitation underlying recent clinical trial failures and represents a translationally justified therapeutic strategy.}, }
@article {pmid42489267, year = {2026}, author = {Xie, Q and Zhu, Y and Jiang, W and Xie, H and Li, Y and Hu, M and Li, K and Yu, H and Pan, Y and Jiang, C and Song, X and Fan, D and Deng, B}, title = {A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76778}, pmid = {42489267}, issn = {2198-3844}, support = {ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; 2025L-C7//Hebei Key Laboratory of Neurology/ ; }, abstract = {Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1[G93A] mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.}, }
@article {pmid42489904, year = {2026}, author = {Jellinger, KA}, title = {Psychiatric disorders in amyotrophic lateral sclerosis: a short note.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42489904}, issn = {1435-1463}, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) has been defined as a rapidly progressive neurodegenerative disorder that affects the large motor neurons of the brain and spinal cord. The assumption that ALS is a pure motor disorder has been increasingly challenged by accumulating evidence about an association between ALS and psychiatric disorders. They often precede the onset of motor symptoms or psychoses; hallucinations and schizophrenia may occur as concomitant changes. These non-motor disorders have a close relationship with disease onset or may be related to a larger framework of neuronal network disruptions in motor neuron disorders. The link between ALS and schizophrenia was supported by substantial genetic correlations associating the C9orf72 gene expansion with psychiatric disorders. The genetic correlation between ALS and schizophrenia was estimated to be 14.3% with frequent polygenic risk scores. Increased psychotic symptoms in C9orf72 carriers correlate with atrophy in a distributed cortical and subcortical network that includes multiple cerebral regions. ALS kindreds often present higher rates of psychiatric illnesses, and early schizophrenia is significantly associated with the development of ALS. Further studies should attempt to delineate the risk of psychiatric disorders in C9orf72 kindreds to aid in clinical decision making and genetic counseling, through collaborations between neurology and psychiatry.}, }
@article {pmid42491041, year = {2026}, author = {Wei, Z and Bai, L and Liu, X and Zhou, Y and Zheng, L and Zhang, B and Wang, L and Zou, W}, title = {Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1820758}, pmid = {42491041}, issn = {1662-5099}, abstract = {Histone lactylation is an emerging epigenetic modification that covalently links the glycolytic metabolite lactate to histones, thereby establishing a direct link between cellular metabolic status and gene transcription programs. Recent studies have shown that this modification plays a key role in regulating cellular sensitivity to ferroptosis, forming a novel regulatory axis of "glycolysis-lactylation-ferroptosis." This article systematically reviews the biological functions of histone lactylation in the nervous system, with a focus on elucidating how it participates in the pathological processes of various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral stroke, and amyotrophic lateral sclerosis (ALS), by regulating the expression of ferroptosis-related genes. The article integrates the latest research on molecular mechanisms, explores the value of this regulatory axis as a potential biomarker for disease diagnosis and a therapeutic target, and provides an outlook on future research directions in this field.}, }
@article {pmid42492205, year = {2026}, author = {Alizadeh, I and Darvishpour, A}, title = {Medical students' metaphors of English for Medical Purposes (EMP) teachers: Insights into educational philosophies in the Iranian context.}, journal = {Acta psychologica}, volume = {269}, number = {}, pages = {107472}, doi = {10.1016/j.actpsy.2026.107472}, pmid = {42492205}, issn = {1873-6297}, abstract = {Understanding learners' beliefs about teachers is critical for shaping English for Specific Purposes (ESP), particularly English for Medical Purposes (EMP), teaching practices in discipline-specific contexts. This qualitative descriptive study examines Iranian medical students' metaphorical conceptualizations of EMP teachers to explore how the students perceive teaching roles, authority, support, and participation in medical English classrooms. Data were collected from 144 undergraduate medical students at an Iranian medical sciences university through a sentence-completion task, in which the participants generated metaphors describing their EMP teachers. The data were analyzed using Cameron and Low's (1999) metaphor analysis framework and interpreted through Oxford et al.'s (1998) four educational philosophies of social Order, cultural transmission, learner-centered growth, and social reform. Analysis of 152 metaphors revealed that students' beliefs were predominantly aligned with learner-centered growth and cultural transmission philosophies, with the fewer reflecting the social order philosophy. No metaphors corresponded to the social reform philosophy of the teacher as a learning partner or an acceptor. While many metaphors depicted EMP teachers as supportive facilitators, they also reflected hierarchical expectations and limited learner agency. These findings offer insights into how teaching roles are constructed in EMP classrooms and provide practical implications for teachers seeking to balance disciplinary requirements with participatory teaching approaches.}, }
@article {pmid42484509, year = {2026}, author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I}, title = {An investigation of factors associated with speech intelligibility in patients with amyotrophic lateral sclerosis: Integrating acoustic and lingual motor measures.}, journal = {Clinical linguistics &amp; phonetics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/02699206.2026.2704600}, pmid = {42484509}, issn = {1464-5076}, abstract = {Speech intelligibility in amyotrophic lateral sclerosis (ALS) progressively declines, but contributing clinical factors may vary according to disease presentation and extent of bulbar involvement. This study examined factors associated with intelligibility in three ALS groups: spinal-onset, spinal-onset with bulbar involvement (spinal + bulbar), and bulbar-onset. Speech intelligibility (visual analogue scale), hypernasality, maximum tongue pressure, respiratory function (%VC and FEV1/FVC), and second formant (F2) transition measures (transition duration and excursion) were evaluated. Exploratory two- and three-dimensional visualisations were used to examine interrelationships among variables, and regression analyses were conducted in groups with sufficient sample size. In spinal-onset ALS, only hypernasality was associated with intelligibility. In bulbar-onset ALS, both tongue pressure and hypernasality were significantly associated with intelligibility, while preserved F2 excursion showed an additional trend towards better intelligibility. In the spinal + bulbar group, descriptive findings suggested that reduced tongue pressure and increased hypernasality were associated with lower intelligibility. These findings suggest that speech intelligibility in ALS is influenced by different combinations of bulbar-related impairments depending on clinical presentation and extent of bulbar involvement. In particular, tongue strength, velopharyngeal function, and residual tongue mobility may be relevant to intelligibility outcomes with bulbar involvement. Combined evaluation of these measures may help inform individualised clinical assessment and management.}, }
@article {pmid42484672, year = {2026}, author = {Shen, Z and Yu, Q}, title = {Protein arginine methyltransferases as regulators of phase separation: implications in cancer and neurodegenerative diseases.}, journal = {European biophysics journal : EBJ}, volume = {}, number = {}, pages = {}, pmid = {42484672}, issn = {1432-1017}, abstract = {Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, a key post-translational modification (PTM) regulating chromatin organization, RNA metabolism, and signaling. Recent studies reveal that PRMT-mediated methylation also modulates liquid-liquid phase separation (LLPS), which organizes membraneless condensates controlling transcription, stress response, and genome stability. Dysregulated PRMT activity disrupts condensate dynamics, contributing to cancer and neurodegenerative diseases. In cancer, PRMT1, PRMT5, and PRMT6 promote tumor progression via methylation-dependent condensates that enhance oncogenic transcription and stress resistance. In the nervous system, PRMT1, PRMT4, PRMT5, PRMT6, and PRMT8 regulate LLPS of proteins, linking aberrant methylation to ALS and Huntington's disease. This review highlights PRMTs as key modulators of phase separation and potential therapeutic targets in both oncology and neurodegeneration.}, }
@article {pmid42484778, year = {2026}, author = {Lill, CM and Homann, J and Ohlei, O and Smith-Byrne, K and Viallon, V and Huerta, JM and Artaud, F and Zhao, Y and Britten, A and Deecke, L and Dobricic, V and Mokoroa, O and Guevara, M and Petrova, D and Trupp, M and Sabin, J and Gröninger, M and Colorado-Yohar, SM and Alonso-Martin, S and Cabrera-Castro, N and Groppa, S and Robinson, O and Hansen, J and Eriksson, S and Sieri, S and Jimenez, A and Tong, TYN and Kaaks, R and Severi, G and Travis, R and Wareham, N and Benedet, AL and Zetterberg, H and Franke, A and Elbaz, A and Bertram, L and Vermeulen, R and Middleton, L and Masala, G and Sacerdote, C and Peters, S and Katzke, V and Ferrari, P and Gunter, MJ and Riboli, E}, title = {EPIC4ND-European Prospective Investigation into Cancer and Nutrition follow-up for neurodegenerative diseases.}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {42484778}, issn = {1573-7284}, support = {#008994//Michael J Fox Foundation/ ; JPND2021-650-289//EU Joint Programme - Neurodegenerative Disease Research/ ; LI 2654/3-1//Deutsche Forschungsgemeinschaft/ ; LI 2654/4-1 (Heisenberg)//Deutsche Forschungsgemeinschaft/ ; INTRAIBS-2020-06//Instituto de Investigaci&#xf3;n Biosanitaria ibs.GRANADA/ ; }, abstract = {The 'European Prospective Investigation into Cancer and Nutrition' cohort (EPIC) is a prospective study including ~ 520,000 participants recruited across Europe (1991-2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6415 initially non-diseased participants (aged 35-80 years, mean age at baseline: 54 ± 9, 64% women) including 1899 incident cases with up to 30 years of follow-up and data on at least one omics domain available from pre-disease blood samples. EPIC4ND includes 4604 subcohort members (4441 non-cases and 163 incident cases) and 1811 additional incident cases ascertained from the broader EPIC cohort. Among the incident cases, there are 1190 dementia cases (818 AD), 610 PD cases, and 199 ALS cases. Additionally, 72 prevalent PD cases and 118 incident Parkinsonism cases are available for comparison. Molecular data generated encompass proteomics, genome-wide DNA methylation, and SNP genotyping with 4127 EPIC4ND participants (including 1635 incident cases) having data on all three domains. Smaller studies include data on metals, metabolites, and environmental chemicals, while ongoing efforts focus on ultrasensitive targeted biomarker measurements and small RNA sequencing. Genome-wide association studies and analyses of epidemiological risk factors validate the dataset by confirming many known risk factors. Leveraging these extensive pre-disease multi-layered omics data offers a unique opportunity to identify biomarker signatures predicting neurodegenerative diseases and to explore their interplay with epidemiological risk factors.}, }
@article {pmid42485154, year = {2026}, author = {Cohn, B and Theoryn, T and Sommerland, O and Murali, P and Yu, JH and Anderson, K and McWalter, K and Johnson, B and Doherty, D and Bamshad, MJ and MacDuffie, KE}, title = {Capturing Perceived Utility from Qualitative Studies of Genomic Sequencing: Translating a Conceptual Model into a Working Codebook.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/23294515.2026.2691711}, pmid = {42485154}, issn = {2329-4523}, abstract = {INTRODUCTION: As genomic sequencing (GS) is integrated into clinical medicine, understanding how patients and families perceive its utility is critical. Conceptual models for perceived utility have been developed, however, direct application of such models to independently-collected qualitative data remains rare. To fill this gap, we translated a comprehensive model of perceived utility (Smith et al. 2022) into a codebook and revised it via application to a qualitative dataset capturing parent-reported utility of GS.<br><br>METHODS: Using the domains and subdomains from Smith et&#xa0;al.'s conceptual model, we developed an initial codebook. We tested the derived codebook on data from 40 interviews with parents of children enrolled in SeqFirst, a research study offering GS for critically ill newborns in the neonatal intensive care unit and young children (<3&#x2009;years) with unexplained developmental differences. Four coders independently applied the codebook. We addressed ambiguities through memoing and refined definitions via study team consensus.<br><br>RESULTS: The resulting codebook includes all five of Smith et&#xa0;al.'s (2022) domains: clinical, emotional, behavioral, cognitive, and social utility. We renamed and relocated several subdomains to add additional clarity in coding decisions, and developed definitions for all subdomain codes. The final codebook is included as a resource for future research.<br><br>CONCLUSIONS: This study translates a conceptual framework of perceived utility of GS into a practical codebook for qualitative research. Our intent is to facilitate conceptually-grounded, replicable coding across studies and settings, supporting both inductive and deductive analyses. Applying this codebook can enhance comparability of qualitative findings, inform refinement of conceptual models, and guide the further development of patient-centered measures of GS utility.}, }
@article {pmid42485353, year = {2026}, author = {Vanunu, M and Zecharia, N and Dror, O and Omer, Y and Brukental, H and Harel-Beja, R and Hatib, K and Azoulay-Shemer, T and Holland, D and Shtienberg, D and Bahar, O}, title = {Identification of an Almond Cultivar Resistant to Xylella fastidiosa subsp. fastidiosa and Insights into Host-Specific Bacterial Behavior.}, journal = {Plant disease}, volume = {}, number = {}, pages = {}, doi = {10.1094/PDIS-02-26-0369-RE}, pmid = {42485353}, issn = {0191-2917}, abstract = {Xylella fastidiosa (Xf) is a xylem-limited bacterial pathogen causing disease in a variety of important agricultural crops, including almonds. Almond leaf scorch (ALS) disease was first identified in Israel in 2017 and is associated with the subspecies X. fastidiosa subsp. fastidiosa (Xff) sequence type 1. Currently, there is no effective means to cure infected almond trees, and ALS management relies primarily on uprooting infected trees and reducing vector populations, yet these methods are only moderately effective. Thus, identifying resistant almond genotypes is a critical goal for developing durable ALS management strategies. In this study, we utilized three complementary methods to evaluate resistance among various almond genotypes: 1) grafting onto Xff-infected trees; (2) mechanically inoculating young trees' stems; and (3) mechanically inoculating individual leaves. In a field-based grafting experiment involving seven genotypes, 'Lauranne' exhibited strong resistance to Xff infection compared to the other tested cultivars. In subsequent two experiments, we monitored Xff migration and colonization in 'Lauranne', a susceptible almond cultivar ('Um ElFahem'), and a non-host plant, plum. Although Xff was able to migrate and replicate within 'Lauranne', it did so at significantly lower levels and with slower progression rate. Histological analysis at the leaf level further confirmed that the number of Xff-colonized xylem vessels was substantially reduced in 'Lauranne' relative to the susceptible cultivar. These findings highlight 'Lauranne' as a promising resistant cultivar and underscore the importance of identifying resistance mechanisms in almonds. Incorporating resistant genotypes (such as 'Lauranne') into breeding programs may offer a durable and sustainable solution to manage ALS in the future.}, }
@article {pmid42487057, year = {2026}, author = {Adams, J}, title = {"Hermeneutic burden" and clinical responsibility: a response to Sparrow et al. on explanation and machine learning.}, journal = {Monash bioethics review}, volume = {}, number = {}, pages = {}, pmid = {42487057}, issn = {1836-6716}, abstract = {This paper critically reviews Sparrow et al.'s notion of the "hermeneutic burden" placed upon clinicians by the demand for explainable artificial intelligence (XAI) in the context of adaptive machine learning (ML) systems. While Sparrow et al. highlight important additional labour that may be required of clinicians, this response argues that framing explanation primarily in terms of such a burden obscures its overall ethical significance. This paper therefore offers a supplementary account of the interpretive work associated with XAI in medicine that places it within existing models of the patient-clinician relationship. In particular, Emanuel and Emanuel's influential typology consisting of four models of the patient-physician relationship is used to extract possible justifications for the responsibility to grasp and explain not only patients' values and conditions but also ML outputs. This allows us to distinguish between 'hermeneutic burden' and 'hermeneutic responsibility' and emphasise that explanation in medicine is not an incidental task but part of a clinician's professional role, particularly on 'interpretive' and 'deliberative' models. The paper thus argues that viewing explanation as a hermeneutic responsibility linked to patient autonomy clarifies the ethical significance of XAI in terms of both the grounds and scope of clinicians' responsibilities. At its core, the ethical challenge raised by XAI in clinical practice concerns not only the burdens it may impose on clinicians but also the evolution of clinicians' traditional interpretive duties in the novel context of ML-mediated care.}, }
@article {pmid42487076, year = {2026}, author = {Picchiarelli, G and Wienand, A and Megat, S and Hutten, S and Aly, A and Been, M and Weber, I and Bonanno, A and Mishra, N and Sternburg, E and Cauchy, P and Dieterle, S and Catinozzi, M and Lobo-Mancheno, J and Walgrave, H and Demais, V and Hener, P and Kessler, P and Tzeplaeff, L and Huebers, A and Zeuschner, D and Rosenbohm, A and Ludolph, AC and Boutillier, AL and Boeckers, T and Dormann, D and Demestre, M and Sellier, C and Lagier-Tourenne, C and Storkebaum, E and Dupuis, L}, title = {FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5.}, journal = {The EMBO journal}, volume = {}, number = {}, pages = {}, pmid = {42487076}, issn = {1460-2075}, support = {ANR-16-CE92-0031,ANR-19-CE17-0016,ANR-20-CE17-0008,ANR-21-CE17-0039//Agence Nationale de la Recherche (ANR)/ ; ANR-10-IDEX-0002//Agence Nationale de la Recherche (ANR)/ ; ANR-20-SFRI-0012//Agence Nationale de la Recherche (ANR)/ ; ANR-24-INBS-0005 FBI BIOGEN//Agence Nationale de la Recherche (ANR)/ ; #23646 #18280//French Muscular Dystrophy Association (AFM)/ ; Coup d'&#xe9;lan 2019//Fondation Bettencourt Schueller (Bettencourt Schueller Foundation)/ ; DEQ20180339179//Fondation pour la Recherche M&#xe9;dicale (FRM)/ ; rare disease award 2019//AXA Research Fund (FONDS AXA POUR LA RECHERCHE)/ ; 2016,2021//Association pour la Recherche sur la Scl&#xe9;rose Lat&#xe9;rale Amyotrophique et autres Maladies du Motoneurone (ARSLA)/ ; 2235//ALS Association (ALSA)/ ; 946876//Muscular Dystrophy Association (MDA)/ ; Open Competition ENW-M//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ ; 442698351//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ ; 497669232//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ ; ERC-2017-COG 770244//EC | European Research Council (ERC)/ ; ClueDol//region grand est/ ; 84012490//EC | ERDF | Interreg/ ; }, abstract = {FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionarily conserved cell-autonomous function of FUS in muscle development. Mechanistically, FUS is required for the transcription of MEF2 target genes, binds to the promoter of genes bound by ETS transcription factors, in particular ETV5, and co-activates the transcription of MEF2-dependent genes with ETV5. FUS phase-separates with ETV5 and MEF2A, and stimulation of MEF2-dependent transcription by FUS is dependent upon its phase separation properties. Finally, Etv5 haploinsufficiency exacerbates muscle weakness and atrophy in Fus knock-in mice. Our findings establish a key role for FUS in skeletal muscle differentiation through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.}, }
@article {pmid42487414, year = {2026}, author = {Bruce, AJ and Menapace, DC}, title = {Invited Commentary on: Gaebe et al's "Effectiveness and Safety of Extracellular Vesicle-Based Therapies for Non-Surgical Facial Rejuvenation: A Systematic Review": Extracellular Vesicles in Aesthetic Medicine: Promise Requires Proof.}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261466120}, doi = {10.1177/26893614261466120}, pmid = {42487414}, issn = {2689-3622}, }
@article {pmid42479532, year = {2026}, author = {Khan, JS and Mohammadi, M and Ammitzboll, AL and Hagen, EM and Blicher, J and Obai, I and Cardoso, ASS and Kirtas, O and Kaeseler, RL and Rasmussen, J and Struijk, LNSA}, title = {A Tendon-Driven Wrist Abduction-Adduction Joint Improves Performance of a 5 DoF Upper Limb Exoskeleton - Implementation and Experimental Evaluation.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2026.3715599}, pmid = {42479532}, issn = {1558-2531}, abstract = {OBJECTIVE: Wrist function is essential in performing activities of daily living (ADLs). However, there is limited experimental evidence on the functional impact of wrist Abduction-Adduction (Ab-Ad) joint assistance in upper limb exoskeletons (ULEs) during ADLs. This study provides the first implementation and demonstration of a clock spring-based wrist Ab-Ad joint into a five degree of freedom (DoF) ULE, EXOTIC2 exoskeleton and evaluates its effect, to support individuals with severe motor impairments.<br><br>METHODS: A compact, lightweight wrist module with tendon-driven abduction and spring-driven adduction was integrated into the EXOTIC exoskeleton. Eight adults with no motor disabilities completed drinking and scratching tasks under randomized wrist-enabled and wrist-locked conditions along with a preliminary feasibility test in one individual with Amyotrophic lateral sclerosis (ALS). Kinematic and task performance metrics including wrist range of motion, task completion time, spillage and leveling metrics were assessed.<br><br>RESULTS: Implementing the wrist Ab-Ad DoF improved task success metrics. Spill incidence during the drinking task decreased from 56% to 3%, and leveling success for scratching task improved from 28% to 75%.<br><br>CONCLUSION: Integrating wrist Ab-Ad assistance improved key functional task outcomes without increasing execution time.<br><br>SIGNIFICANCE: The study provides the experimental evidence that active wrist Ab-Ad control enhances task-level performance in exoskeleton-assisted ADLs and supports the inclusion of wrist deviation in future assistive exoskeletons.}, }
@article {pmid42479906, year = {2026}, author = {Tahedl, M and Siah, WF and Lope, J and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Tan, EL and Toomey, A and Kleinerova, J and Bede, P}, title = {Neurotransmitter-Defined Degeneration Patterns in Sporadic and C9orf72-Associated Amyotrophic Lateral Sclerosis: Predilection to GABAergic, Serotonergic, Opioid, Glutamatergic, Endocannabinoid, and Microglial Systems-Implications for Therapy Development.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78316}, pmid = {42479906}, issn = {1531-8249}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a markedly distinctive clinical and neuroradiological signature, with the preferential involvement of specific brain networks and the apparent sparing of others. The molecular underpinnings of the strikingly selective anatomical vulnerability have not been fully elucidated to date despite the potential therapeutic relevance of characterizing neurotransmitter receptor-defined susceptibility to degeneration.<br><br>METHODS: A large neuroimaging study was undertaken with 258 participants to systematically evaluate topological associations between neurodegeneration and neurotransmitter expression distributions. Patients were stratified based on their genetic profile into sporadic and C90rf72 hexanucleotide repeat expansion carriers. Anatomical associations were evaluated between patterns of atrophy and topological neurotransmitter receptor distributions. Cross-sectional and longitudinal trends were comprehensively evaluated over 4 consecutive timepoints.<br><br>RESULTS: Our analyses reveal topological associations between neurodegeneration in sporadic ALS and GABA-A receptor &#x3b1;5-selective component (GABAa5), serotonin 1a receptor, and kappa opioid receptor expression maps. In addition to these networks, neuronal loss in patients with GGGGCC hexanucleotide repeat expansions exhibit predilection to glutamatergic, endocannabinoid, and microglial systems. Our multi-timepoint longitudinal analyses reveal dynamic temporal associations between focal volume loss and neurotransmitter expression with increasing spatial associations with noradrenaline transporter and GABAa5, but high attrition rates preclude definite longitudinal inferences.<br><br>INTERPRETATION: Our data suggest the preferential vulnerability of GABAergic, serotonergic, kappa opioid mediated networks in sporadic ALS. In C9orf72-assocaited ALS, glutamatergic, endocannabinoid circuits are also susceptible and microglia-mediated neuroinflammation is also implicated. The comprehensive evaluation of neurotransmitter-receptor associations not only offer academic insights regarding pathophysiological processes in ALS, but may inform targeted therapy development strategies. ANN NEUROL 2026.}, }
@article {pmid42480869, year = {2026}, author = {Petro, TM and Pattee, GL and Esmael, A and Agarkova, IV and Dunigan, DD and Chiodo, F and De Castro, C and Van Etten, JL}, title = {Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.}, journal = {Antiviral research}, volume = {253}, number = {}, pages = {106491}, doi = {10.1016/j.antiviral.2026.106491}, pmid = {42480869}, issn = {1872-9096}, abstract = {Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.}, }
@article {pmid42481428, year = {2026}, author = {Fukumoto, T and Osaki, Y and Hanada, K and Fujita, K and Kaji, R and Izumi, Y}, title = {The Anterior Belly of the Digastric Muscle as a Novel Target for Needle Electromyography in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70354}, pmid = {42481428}, issn = {1097-4598}, support = {JPMH23FC1008//Ministry of Health, Labour and Welfare, Japan, through the Research Program on Rare and Intractable Diseases/ ; }, abstract = {INTRODUCTION/AIMS: Needle electromyography (EMG) in the bulbar region aids in the diagnosis of amyotrophic lateral sclerosis (ALS) but remains technically challenging. The genioglossus muscle (GM) is commonly examined; however, pain and poor relaxation may limit its evaluation. The trapezius is an alternative target but is innervated by the spinal accessory nerve. We investigated the utility of the anterior belly of the digastric muscle (ABDM), innervated by the trigeminal nerve, for bulbar EMG evaluation.<br><br>METHODS: In this unblinded, prospective observational study, consecutive patients with suspected ALS underwent needle EMG of the ABDM, GM, masseter muscle (MM), and trapezius. Relaxation levels, EMG abnormalities, and pain (100-mm visual analog scale [VAS]) were assessed.<br><br>RESULTS: Twenty-seven clinically diagnosed ALS patients were analyzed. Relaxation was better in the ABDM than in the GM (p&#x2009;<&#x2009;0.001) and comparable to that in the MM and trapezius. Fasciculation potentials were detected more often in the ABDM (52%) than in the GM (0%) and MM (22%; p&#x2009;=&#x2009;0.039) and were comparable to the trapezius (59%). Chronic denervation occurred at similar frequencies across muscles (33%-59%). The combination of abnormal spontaneous activity and chronic denervation was most frequent in the ABDM (37%). Pain was lower with the ABDM (median VAS score of 21) than with the GM (28; p&#x2009;=&#x2009;0.0052) and MM (32; p&#x2009;<&#x2009;0.001) and was similar to the trapezius (23).<br><br>DISCUSSION: The ABDM may be a practical additional target for bulbar EMG in ALS, with favorable relaxation, lower pain, and potentially improved electrodiagnostic yield.}, }
@article {pmid42481875, year = {2026}, author = {Sahin, U and Firat-Karalar, EN}, title = {The centrosome-cilium-centriolar satellite axis in neurodegenerative diseases.}, journal = {EMBO reports}, volume = {}, number = {}, pages = {}, pmid = {42481875}, issn = {1469-3178}, support = {101078097//EC | H2020 | PRIORITY 'Excellent science' | H2020 European Research Council (ERC)/ ; 3336//European Molecular Biology Organization (EMBO)/ ; 3622//European Molecular Biology Organization (EMBO)/ ; YIP//European Molecular Biology Organization (EMBO)/ ; (SU PREG)//Sabanci University President's Research/ ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and hereditary ataxias, remain major global health challenges with limited therapeutic options. Although clinically and genetically diverse, these diseases share extensively studied cellular and molecular hallmarks, including protein aggregation, impaired proteostasis, cytoskeletal abnormalities, altered energy metabolism, nucleic acid damage, and chronic inflammation. Emerging evidence indicates that dysfunction of the centrosome-cilium-satellite axis intersects with these established pathways in disease- and cell type-specific contexts. This axis, composed of centrosomes, primary cilia, and centriolar satellites, coordinates cytoskeletal organization, ciliary signaling, trafficking, proteostasis, and stress responses and acquires specialized functions in neurons that support polarity, connectivity, and long-term maintenance. In this review, we outline the structure, function, and neuronal specializations of the centrosome-cilium-satellite axis, then examine how its dysfunction has been reported in neurodegenerative disease models. We also discuss centriolar satellites as regulators of centrosome and cilium biology whose disease-specific roles in classical NDDs remain comparatively underexplored, with insights from Huntington's disease and schizophrenia. Finally, we discuss therapeutic strategies aimed at restoring axis structure and dynamics, modulating ciliary signaling, and correcting disease-linked genetic or transcript-level defects, emphasizing mechanism-based approaches that require validation in disease-relevant models. Together, the centrosome-cilium-satellite axis provides an emerging framework for understanding context-dependent organelle dysfunction in neuronal vulnerability and neurodegeneration.}, }
@article {pmid42482399, year = {2026}, author = {Merrill, K and Giesel, BP and Barclay, JS}, title = {Assessing Involvement and Training of Academic Palliative Care Programs in the Care of Patients with Sickle Cell Disease: A Nationwide Survey.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {10966218261472552}, doi = {10.1177/10966218261472552}, pmid = {42482399}, issn = {1557-7740}, abstract = {BACKGROUND: Despite high symptom burden and limited lifespan associated with sickle cell disease (SCD), specialty palliative care (PC) services remain underutilized in this marginalized population.[1,2] The extent of routine involvement, barriers to care, and training in the care of SCD patients at academic PC programs in the United States has not been quantified.<br><br>OBJECTIVE: To assess PC involvement and training in SCD care, identify barriers to access, and inform integration strategies.<br><br>DESIGN/SETTING: An anonymous Qualtrics survey, developed through literature review and expert panel, was emailed to 180 palliative medicine fellowship program directors or surrogates (June 18-July 25, 2025) in the United States. The survey included demographics, program practices regarding SCD and other chronic conditions (cystic fibrosis, amyotrophic lateral sclerosis, and chronic nonmalignant pain), frequency of routine SCD education, and perceived barriers to providing care to these patients.<br><br>RESULTS: Fifty-one responses were received (28.3% response rate). Only 37% of programs routinely care for SCD patients (31.5% inpatient only, 10.5% outpatient, 58% both). Among these, 68% regularly prescribed opioids. Programs not routinely involved reported exceptions for patients with limited prognosis, comorbidities such as active cancer, or imminent end-of-life needs. The most common reported barriers to seeing patients with SCD were lack of outpatient resources (46%) and staffing constraints (44%). Free-text responses cited limited referrals, competing specialty ownership (hematology), institutional restrictions, and scope-of-practice limitations. Only 38% of programs included SCD in their fellowship curriculum, and 20% offered routine training for all PC team members.<br><br>CONCLUSIONS: Fewer than half of academic PC programs routinely care for SCD patients, and most programs lack formal SCD training. Institutional and systemic barriers limit access, highlighting the need for resources and education to expand PC integration into SCD care. There is a need for consensus guidelines stratifying PC involvement in SCD patients.}, }
@article {pmid42482414, year = {2026}, author = {Topsøe-Jensen, SK and Wingren, CJ and Villa, C}, title = {Forensic bruise documentation with alternate light sources: Preliminary observation on deceased individuals in a routine illuminated autopsy setting.}, journal = {Journal of forensic sciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/1556-4029.70404}, pmid = {42482414}, issn = {1556-4029}, abstract = {Alternate light sources (ALS) have been suggested to improve bruise visibility for medicolegal evaluations. Previous studies have recommended darkened conditions; however, this does not reflect real-life autopsy settings, where multiple examinations are conducted simultaneously and turning off the lights is neither practical nor safe. This study evaluated the use of ALS for documenting bruises under normal lighting conditions without altering the autopsy setup. We photographed 161 bruises (99 recent, 62 non-recent) using CrimeLite® AUTO (Foster+Freeman) under common white light (CWL), violet ALS with 415 nm long-pass (VLP), violet ALS with 415 nm band-pass (VBP), and blue ALS with 445 nm long-pass (BLP). Bruises were classified as recent or non-recent based on the presence of yellow coloration. Visibility was scored using a "modified" Bruise Visibility Scale (BVS), and surface area was measured. Observer variability was assessed using Cohen's kappa (κ) and intraclass correlation coefficients (ICC); logistic and Cox regression analyses were performed to evaluate BVS and size across lighting sources. We found that ALS did not enhance bruise visibility compared to CWL. VBP and BLP reduced visibility, while VLP showed occasional improvements but without statistical significance. Surface area measurements indicated that VLP visualizes bruises with larger dimensions than under CWL, whereas BLP and VBP did not. Observer agreement for the four BVS categories yielded κ values ranging from moderate to substantial, while ICCs showed excellent agreement for surface-area measurements for most light sources. Despite its limitations, the study suggests that ALS, particularly VLP, may have potential utility for bruise documentation under normal lighting conditions.}, }
@article {pmid42482658, year = {2026}, author = {Wang, J and Wang, Y and Yang, T and Yan, X and Luo, J and Wu, S and Tong, J and Zhao, M and Yang, G}, title = {Sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in amyotrophic lateral sclerosis: a retrospective cross-sectional study.}, journal = {Annals of medicine}, volume = {58}, number = {1}, pages = {2703317}, doi = {10.1080/07853890.2026.2703317}, pmid = {42482658}, issn = {1365-2060}, mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/physiopathology ; Middle Aged ; Biomarkers/blood ; Ultrasonography ; Aged ; Sex Factors ; Disease Progression ; Blood Sedimentation ; *Inflammation/blood ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with substantial clinical heterogeneity. Systemic inflammatory markers and neuromuscular ultrasound measurements have both been studied in ALS, but their sex-associated differences within ALS cohorts remain incompletely characterized.<br><br>OBJECTIVE: To examine sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in patients with ALS, and to determine whether these differences persisted after adjustment for available clinical and anthropometric variables.<br><br>METHODS: In this retrospective cross-sectional study, 135 patients with ALS were included. Routine inflammatory markers, including neutrophils, monocytes, lymphocytes, platelets, and erythrocyte sedimentation rate (ESR), were analyzed alongside quantitative neuromuscular ultrasound measurements. Between-sex comparisons were performed, and false discovery rate correction was applied to account for multiple testing. Multivariable linear regression analyses were performed with adjustment for age, disease duration, body mass index (BMI), ALSFRS-R total score, FVC% predicted, smoking status, hypertension, and diabetes.<br><br>RESULTS: Female patients showed lower ALSFRS-R total scores and higher estimated progression rates in unadjusted comparisons, whereas pulmonary function variables did not differ significantly between sexes. After FDR correction, estimated progression rate, neutrophil count, monocyte count, ESR, and masseter muscle thickness remained significantly different between sexes, while the ALSFRS-R difference was borderline significant. In fully adjusted models, female sex was associated with lower neutrophil count, monocyte count, and median nerve cross-sectional area; biceps brachii thickness showed a less stable association after sensitivity analysis. An exploratory secondary analysis showed lower rectus femoris cross-sectional area during thigh-lift in female patients after full adjustment. In the spline sensitivity analysis, this association remained statistically significant but was interpreted cautiously because it was not present in the earlier adjustment models.<br><br>CONCLUSIONS: Selected routine inflammatory markers and neuromuscular ultrasound measurements differed between male and female patients within this ALS cohort. These findings support consideration of sex and anthropometric context, including body size, when interpreting inflammatory markers and ultrasound-based structural measurements. In the absence of healthy controls, the observed ultrasound differences cannot be attributed specifically to ALS-related biology. Studies with healthy controls, longitudinal functional outcomes, body-composition assessment, and independent multicenter cohorts are needed to clarify the disease-specific and prognostic relevance of these observations.}, }
@article {pmid42483382, year = {2026}, author = {Joy, B}, title = {Is the stroke-COVID link solid? A critical analysis of Aghamiri et al.'s research methodology and findings.}, journal = {Journal of family medicine and primary care}, volume = {15}, number = {5}, pages = {2177-2178}, pmid = {42483382}, issn = {2249-4863}, }
@article {pmid42484074, year = {2026}, author = {Carberry, N and Wuu, J and Benatar, M}, title = {SOD1-lowering therapy for patients with wildtype SOD1-ALS: a case report.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2705142}, pmid = {42484074}, issn = {2167-9223}, abstract = {Background and Objectives: To describe clinical and biomarker experience using an SOD1 antisense oligonucleotide (ASO) in a patient with non-SOD1 amyotrophic lateral sclerosis (ALS). Methods: Case report. Results: In a 72-year-old male with non-SOD1 ALS, rapid decline on the ALS functional rating scale revised (ALSFRS-R) and a rise in serum neurofilament light chain (NfL) concentration were observed following 3 loading doses of an SOD1 ASO before the patient succumbed to disease. The time from symptom onset to death was 9 months. Discussion: While treatment was initiated relatively late (∼7 months) after symptom onset and follow-up duration was short, the observed increase (as opposed to a reduction) in serum NfL and accompanying rapid functional decline, suggest the lack of a therapeutic effect in someone with fast progressing non-SOD1 ALS.}, }
@article {pmid42471754, year = {2026}, author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK}, title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71675}, pmid = {42471754}, issn = {1552-5279}, support = {//Johnson &amp; Johnson/ ; }, mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; }, abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.<br><br>METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.<br><br>RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd&#xa0;=&#xa0;7.1&#xa0;nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.<br><br>DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.}, }
@article {pmid42472717, year = {2026}, author = {Fowler, C and Kaelber, DC and Bliwise, DL and Greer, MK}, title = {Rapid Eye Movement Sleep Suppressing Antidepressant Prescription is Associated with Improved Survival in Amyotrophic Lateral Sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42472717}, issn = {1590-3478}, support = {UM1TR004528//Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/drug therapy ; Female ; Male ; *Antidepressive Agents/therapeutic use/pharmacology ; *Riluzole/therapeutic use ; Middle Aged ; *Sleep, REM/drug effects ; Aged ; }, abstract = {INTRODUCTION: Rapid eye movement (REM) sleep is a period of physiological vulnerability for patients with neuromuscular disease, owing to a generalized loss of muscle tone that spares only the diaphragm. Several antidepressants have been observed to reduce REM sleep fraction on polysomnography. We investigated whether prescription of REM-suppressing antidepressants (RSAs) versus non-REM-suppressing antidepressants (NRSAs) is associated with differential survival in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Using the U.S. Collaborative Network of the TriNetX Analytics platform, we compared 1-year mortality in ALS patients prescribed RSAs or NRSAs within 3 months of diagnosis, identified by ICD-10-CM-coded encounter diagnoses with riluzole prescription between May 2014 and May 2024. We used Cox proportional hazards models, Kaplan-Meier analysis, and risk difference analysis, with and without propensity score matching (PSM).<br><br>RESULTS: Among 14,441 patients with ALS and riluzole prescription, 5,057 were prescribed either RSAs (N = 4,177) or NRSAs (N = 880). The NRSA cohort had a higher risk of death (HR 1.28, 95% CI 1.11 - 1.46), with 1-year survival of 60.73% versus 68.61% for RSAs (log-rank p<0.001). After PSM, the difference narrowed and was borderline by log-rank test (60.97% vs 65.92%, p=0.035), while the risk-difference analysis was no longer significant (RR 1.07, 95% CI 0.92 - 1.25), indicating an attenuated and statistically fragile association.<br><br>CONCLUSIONS: RSA prescription was associated with modestly better survival, but this association weakened markedly after matching and cannot establish causation; residual confounding, particularly by indication, cannot be excluded. These findings are hypothesis-generating, and prospective studies incorporating polysomnography and ALS-specific prognostic factors are needed.}, }
@article {pmid42473037, year = {2026}, author = {Ban, Y and Wang, T and Zhang, Z and Yuan, WQ and Zhang, M and Shi, K and Li, C and Feng, Z}, title = {Tribenuron-methyl resistance in catchweed bedstraw (Galium aparine): status and MIRA-based rapid detection of ALS D376E mutation.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71132}, pmid = {42473037}, issn = {1526-4998}, support = {2023YFD1400500//National Key Research and Development Program of China/ ; 32372567//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Catchweed bedstraw (Galium aparine) is a highly competitive malignant broadleaf weed that significantly reduces the yield and quality in wheat and rapeseed cropping systems. The prolonged and exclusive use of tribenuron-methyl has led to widespread resistance development, posing a significant threat to the sustainability of weed management practices. To enable timely intervention and support evidence-based decision-making, systematic monitoring of resistance status and the development of a rapid, reliable detection method are urgently required.<br><br>RESULTS: We collected 113 populations of G. aparine from major wheat-growing regions across China, among which 83 populations were found to be resistant to tribenuron-methyl. The sequencing of the ALS gene revealed six distinct mutation patterns at sites P197, D376 and W574 within resistant populations, among which D376E was the most frequently observed. To enable rapid field resistance monitoring, the multienzyme isothermal rapid amplification (MIRA) assay was developed for detecting the D376E mutation. This new detection system can assess target-site resistance within 80&#x2009;min at a constant temperature of 39&#x2009;&#xb0;C.<br><br>CONCLUSION: This study investigated tribenuron-methyl resistance in 113 G. aparine populations from various provinces of China and generated a comprehensive resistance distribution map. The MIRA-based method for rapidly detecting the ALS D376E substitution in G. aparine was developed. Collectively, our study provides valuable knowledge and a practical tool for the management of G. aparine. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid42473039, year = {2026}, author = {Koppisetti, RK and Barthélemy, NR and Horie, K and Ly, CV and Roberts, KF and Koutarapu, S and Perrin, RJ and Franklin, EE and Pedicone, C and Orrick, J and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Goate, AM and Karch, CM and Bateman, RJ and Mukherjee, S}, title = {Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78300}, pmid = {42473039}, issn = {1531-8249}, support = {UL1TR004419/TR/NCATS NIH HHS/United States ; 1U54NS123746-01/NS/NINDS NIH HHS/United States ; R01NS095773/NS/NINDS NIH HHS/United States ; R01NS110890/NS/NINDS NIH HHS/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; P41GM103422/GM/NIGMS NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; P01AG03991/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.<br><br>METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.<br><br>RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.<br><br>INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.}, }
@article {pmid42473218, year = {2026}, author = {Keskin, A and Mogulkoc, R and Baltaci, AK}, title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575484348260702044851}, pmid = {42473218}, issn = {1875-5607}, abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).}, }
@article {pmid42473814, year = {2026}, author = {Shao, D and Wen, X and Xu, X and Liu, X and Guo, B and Li, B and Wang, G and Liu, X and Men, S}, title = {Cyprosulfamide mitigates nicosulfuron phytotoxicity in maize through activation of GST-associated phase II detoxification involving ZmGST24.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71142}, pmid = {42473814}, issn = {1526-4998}, support = {32370271//National Natural Science Foundation of China/ ; 2026KJCXZX-LYS-14//HAAFS Agriculture Science and Technology Innovation Project/ ; 254Z6303G//Project of Central Guidance for Local Science and Technology Development Funds/ ; 23JCYBJC01180//Natural Science Foundation of Tianjin/ ; 24YFXTHZ00050//Key Research and Development Program of Tianjin/ ; }, abstract = {BACKGROUND: Nicosulfuron is an acetolactate synthase (ALS)-inhibiting herbicide widely used in maize production. However, under unfavorable environmental conditions, its phytotoxicity to maize remains a practical concern. Cyprosulfamide (CSA) is an effective safener for maize, yet the contribution of glutathione S-transferases (GST)-associated phase II detoxification to CSA-conferred protection against nicosulfuron injury remains poorly understood.<br><br>RESULTS: CSA markedly alleviated nicosulfuron-induced growth inhibition in maize seedlings and effectively reduced herbicide injury under field conditions. Inhibitor assays showed that both cytochrome P450-mediated phase I metabolism and GST-associated phase II detoxification contribute to maize tolerance to nicosulfuron. Proteomic analysis further revealed that, relative to nicosulfuron treatment alone, co-application of nicosulfuron and CSA significantly enriched the glutathione metabolism pathway in maize leaves. Among the induced GST candidate genes, ZmGST24 showed the strongest transcriptional response. Phylogenetic and conserved motif analyses supported its functional similarity to previously reported GSTs involved in herbicide detoxification. Molecular docking suggested favorable binding of ZmGST24 to nicosulfuron, and heterologous expression in yeast demonstrated that ZmGST24 not only enhanced tolerance to nicosulfuron, but also increased tolerance to several herbicides commonly used in maize fields.<br><br>CONCLUSION: These findings indicate that the protective effect of CSA against nicosulfuron phytotoxicity in maize is associated with activation of GST-associated phase II detoxification. The pronounced response of the glutathione metabolism pathway, together with the functional characterization of ZmGST24, identifies this gene as a promising candidate involved in CSA-induced herbicide tolerance and as a potential target for improving herbicide safety in maize. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid42474734, year = {2026}, author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N}, title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42474734}, issn = {1432-1459}, mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.<br><br>METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.<br><br>RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.<br><br>CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.}, }
@article {pmid42475136, year = {2026}, author = {Evans, NG}, title = {Mapping the Scientific Mesolevel: Where Are We Aiming?.}, journal = {The Hastings Center report}, volume = {56}, number = {4}, pages = {48-50}, pmid = {42475136}, issn = {1552-146X}, support = {OT2OD032644/NH/NIH HHS/United States ; }, mesh = {Humans ; *Ethics, Research ; *Science/ethics/organization &amp; administration ; }, abstract = {Susan Wolf et al.'s article "Filling the Network Gap in Research Ethics: Analyzing Ethical Issues at Scale in Big Team Science" aims to provide analysis of ethics at the level of scientific teams. But is the emphasis on formal teams the appropriate target? In this commentary, I argue that we ought to take a much broader view, looking at the "interstitial spaces" of scientific research, including the informal networks of power and esteem that shape scientific careers, the formation and function of large teams, receipt of funding, and publication. I claim that these informal networks do as much, if not more than, formal organizing efforts in structuring scientific inquiry and norms. I conclude that an ethics of team science will be richer, more rigorous, and more effective if it treats the culture of science as a central object of study and then asks which kinds of formal organizing principles best promote and protect our ethical commitments.}, }
@article {pmid42475592, year = {2026}, author = {Haim, G and Hornstein, E}, title = {The dual face of miR-146a in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {30}, pages = {e2617170123}, doi = {10.1073/pnas.2617170123}, pmid = {42475592}, issn = {1091-6490}, }
@article {pmid42476327, year = {2026}, author = {Pattnaik, PP and Prusty, SK and Pati, S and Jew, KA and Bora, AK and Sahoo, J and Sahu, PK}, title = {Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.}, journal = {Gene}, volume = {1010}, number = {}, pages = {150318}, doi = {10.1016/j.gene.2026.150318}, pmid = {42476327}, issn = {1879-0038}, abstract = {Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.}, }
@article {pmid42476836, year = {2026}, author = {Mathis, S and Le Masson, G}, title = {When algorithms speak first: The public health risk of consumer AI in ALS diagnosis.}, journal = {Journal of the neurological sciences}, volume = {}, number = {}, pages = {126098}, doi = {10.1016/j.jns.2026.126098}, pmid = {42476836}, issn = {1878-5883}, abstract = {BACKGROUND: Consumer AI platforms are increasingly used by patients to interpret medical reports, including ENMG results for ALS. While AI shows promise in controlled clinical settings (e.g., stroke imaging, melanoma detection), consumer-facing tools often provide overconfident, context-free diagnostic assertions (e.g., 'definitive evidence of ALS'), leading to premature and potentially harmful life-altering decisions.<br><br>OBJECTIVE: To highlight the clinical, ethical, and regulatory risks of unregulated AI in ALS diagnosis and propose actionable solutions.<br><br>DISCUSSION: We present a case of AI-mediated misdiagnosis, analyze the limitations of consumer-facing AI (lack of clinical context, longitudinal data, and specialist oversight), and discuss the "authority paradox" (patients trusting AI outputs over clinicians' nuanced assessments). We propose a structured 4-step clinical approach for managing AI-mediated self-diagnoses and urge regulators to classify such tools as high-risk under the EU AI Act.<br><br>CONCLUSION: The uncritical adoption of consumer AI in ALS diagnosis represents a public health risk. Clinicians, regulators, and developers must collaborate to ensure AI serves patients safely and ethically.}, }
@article {pmid42477767, year = {2026}, author = {Zhang, H and Li, C and Yu, J and Liang, Y and Wu, Y and Cao, F}, title = {Unraveling the role of lipid metabolism in ALS risk: a Mendelian randomization analysis using GWAS data.}, journal = {Orphanet journal of rare diseases}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13023-026-04503-2}, pmid = {42477767}, issn = {1750-1172}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Lipid metabolism is closely related to neuronal function and energy homeostasis, but the genetic association between specific lipid species and ALS risk remains unclear.<br><br>OBJECTIVE: This study aimed to investigate the potential causal associations between genetically predicted lipid species and ALS risk using a two-sample Mendelian randomization (MR) approach.<br><br>METHODS: Summary-level GWAS data for 179 lipid species were obtained from 7,174 Finnish participants in the GeneRISK cohort. ALS GWAS data included 29,612 ALS cases and 122,656 controls. The inverse variance weighted (IVW) method was used as the primary MR approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses. False discovery rate (FDR) correction was applied across all lipid traits based on IVW P values. Sensitivity analyses were conducted to assess heterogeneity, horizontal pleiotropy, and robustness.<br><br>RESULTS: After FDR correction, genetically predicted higher levels of diacylglycerol (DAG) (18:1_18:1), phosphatidylcholine (PC) (16:1_18:1), PC (18:0_18:1), phosphatidylethanolamine (PE) (O-16:1_18:2), and several triacylglycerol (TAG) species were associated with increased ALS risk. Phosphatidylinositol (PI) (16:0_18:1) showed only a nominal protective association and did not remain significant after FDR correction. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy.<br><br>CONCLUSION: This MR study provides genetic evidence supporting potential associations between specific lipid species and ALS risk. These findings highlight lipid metabolism as a relevant pathway in ALS susceptibility.}, }
@article {pmid42477825, year = {2026}, author = {Brenner, D and Ponomarenko, A and Petrut, I and Beyrle, S and Contardo, M and Loss, I and Radke, C and Frank, J and Zimmer, E and Schlesner, M and Achenbach, P and Scheveneels, W and Aly, A and Nazlican, H and Hesebeck-Brinkmann, J and Oeckl, P and Müller, K and Siebert, R and Böckers, T and van Eijk, K and Veldink, J and Kleger, A and Mulaw, M and Andersen, PM and Forsberg, K and Weishaupt, JH and Loghmani, SB and Grehl, T and van Damme, P and Weis, J and Catanese, A}, title = {Correction: A rare missense variant impacting NEK1 kinase function is associated with ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42477825}, issn = {2051-5960}, }
@article {pmid42470084, year = {2026}, author = {Morgado Linares, RY and Rojas-Marcos, &#xcd; and Mesa, M and Martínez, E and Cabrera-Serrano, M and Paradas, C}, title = {Impact of Sexuality in Patients With Motor Neuron Disease.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70348}, pmid = {42470084}, issn = {1097-4598}, abstract = {INTRODUCTION: Sexuality is a relevant yet understudied aspect in people living with motor neuron disease (MND). This study aimed to assess whether sexuality in people with MND is influenced by motor, cognitive, behavioral, or mood disturbances, and to explore whether being sexually active impacts caregiver burden.<br><br>METHODS: We conducted a cross-sectional observational study involving participants with MND and their primary caregivers from three ALS multidisciplinary units in Seville, Spain. Data were collected between October 2018 and July 2021. Functional, cognitive, behavioral, and mood assessments were conducted. Sexuality was evaluated through sex-specific questionnaires. Caregiver burden was assessed using the Zarit Burden Interview.<br><br>RESULTS: Among 66 participants who completed the sexuality assessment, 42.9% reported sexual activity in the previous month. Of these, 70% had no sexual dysfunction, while 26.7% had moderate and 3.3% severe dysfunction. No correlation was found between sexual activity and motor function. Sexual activity was less frequent in participants with apathy (p&#x2009;=&#x2009;0.026), depression (p&#x2009;=&#x2009;0.021), and frontotemporal dementia (p&#x2009;=&#x2009;0.013). Among sexually active patients, those with cognitive impairment-particularly memory dysfunction-had higher rates of orgasm difficulties (p&#x2009;=&#x2009;0.019). No other clinical parameters were related to sexuality. Sexuality of participants with MND did not influence caregiver burden.<br><br>DISCUSSION: Sexuality in MND is more associated with cognitive and mood factors than with motor disability. Addressing sexuality in clinical practice may contribute to improving quality of life and should be integrated into the multidisciplinary care of MND patients.}, }
@article {pmid42471032, year = {2026}, author = {Barrera-Chamorro, L and Gonzalez-de la Rosa, T and Arzalluz-Luque, J and Torrecillas-Lopez, M and Marquez-Paradas, E and Claro-Cala, CM and Navarro-Hortal, MD and Eichau, S and Garcia-Sanchez, MI and Montserrat-de la Paz, S}, title = {Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/10408398.2026.2703335}, pmid = {42471032}, issn = {1549-7852}, abstract = {Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are increasingly associated with disruption of the microbiota-gut-brain axis. Common alterations include reduced beneficial microbial taxa, impaired short-chain fatty acid production, intestinal and blood-brain barrier dysfunction, and sustained inflammatory responses. These findings support the development of microbiota-targeted dietary interventions. This review summarizes current evidence on polyphenols, bioactive peptides, and pectin-derived oligosaccharides (POS) as prebiotic or prebiotic-like compounds with potential activity through the microbiota-gut-brain axis. Particular attention is given to structure-function relationships, host-microbe interactions, and the sustainable recovery of these compounds from food by-products. Preclinical studies suggest that these bioactives may reduce microglial activation, improve mitochondrial function, strengthen intestinal and blood-brain barrier integrity, and enhance cognitive or motor performance. Early clinical studies also indicate possible benefits on mood, selected cognitive outcomes, metabolic regulation, and inflammatory biomarkers, although evidence remains limited. Microbiota-derived metabolites from polyphenols, such as urolithins, together with glycomacropeptide and POS, appear to be key mediators. However, clinical validation in major neurodegenerative diseases remains fragmented. Standardized formulations, mechanistic trials, harmonized endpoints, and precision-nutrition strategies are required to confirm their therapeutic potential.}, }
@article {pmid42471133, year = {2026}, author = {Rojano-Delgado, A and Sohrabi, S and Gherekhloo, J and Domínguez-Valenzuela, JA and Palma-Bautista, C and Alcántara-de la Cruz, R and De Prado, R}, title = {Evolution of multiple resistance under long-term herbicide exposure reshapes Mediterranean perennial agroecosystems.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {}, number = {}, pages = {128781}, doi = {10.1016/j.envpol.2026.128781}, pmid = {42471133}, issn = {1873-6424}, abstract = {Decades of intensive herbicide use in perennial cropping systems have imposed substantial environmental pressures and accelerated the evolution of herbicide-resistant weed populations. In Andalusia (southern Spain), citrus and olive orchards rely heavily on glyphosate and other herbicide modes of action, resulting in chronic ecosystem exposure, declining herbicide efficacy, and increasing chemical inputs. We surveyed ten dominant weed species across eleven orchards to characterize resistance patterns and investigate underlying physiological mechanisms relevant to environmental persistence and contaminant cycling. Rapid screening assays using six widely applied herbicides (atrazine, 2,4-D, glyphosate, oxyfluorfen, quizalofop-ethyl, and tribenuron-methyl) revealed widespread multiple and cross-resistance in both dicots and monocots. Amaranthus albus, A. viridis, Conyza bonariensis, and Solanum nigrum displayed resistance to atrazine, glyphosate, and tribenuron-methyl, while Lolium rigidum and Sorghum halepense showed broad-spectrum resistance involving target-site alterations and enhanced metabolic detoxification, partially reversed by the cytochrome P450 inhibitor malathion. Complementary biochemical assays targeting PSII, ALS, ACCase, and EPSPS, together with diagnostic tests for PPO- and auxin-related herbicides, indicated diverse non-target-site resistance pathways, suggesting increased herbicide transformation and altered degradation dynamics in soil-plant systems. The emergence of complex resistance mechanisms reflects prolonged selection pressure from intensive herbicide regimes and implies elevated risks of environmental accumulation, off-target effects, and reduced sustainability of chemical-based weed control. These findings highlight the need to reduce herbicide dependence and adopt integrated weed management strategies that minimize pollutant loads in Mediterranean agroecosystems.}, }
@article {pmid42471678, year = {2026}, author = {Ekowa, JL and Onyekwelu, AI and Fatai, KE}, title = {Physiotherapy and rehabilitation for survivors of female genital mutilation/cutting: a scoping review.}, journal = {BMC women's health}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12905-026-04708-4}, pmid = {42471678}, issn = {1472-6874}, abstract = {BACKGROUND: Female genital mutilation/cutting (FGM/C) affects more than 230 million girls and women worldwide and is associated with chronic pelvic pain, pelvic floor dysfunction, lower urinary tract symptoms, psychosexual dysfunction, and reduced quality of life. Although physiotherapy and rehabilitation may contribute to multidisciplinary care, the available evidence has not been comprehensively synthesised.<br><br>OBJECTIVE: To map the existing evidence on physiotherapy and rehabilitation for women living with FGM/C and identify evidence gaps relevant to clinical practice and future research.<br><br>METHODS: A scoping review was conducted following the Arksey and O'Malley framework, Levac et al.'s methodological enhancements, and PRISMA-ScR guidelines. Electronic databases and grey literature were searched from inception to January 2026. Eligible studies included adolescent (&#x2265;&#x2009;15 years) and adult women living with FGM/C, together with rehabilitation-relevant studies involving healthcare professionals. Data were charted and synthesised narratively.<br><br>RESULTS: Of 872 records identified, 21 studies met the inclusion criteria. Most evidence was observational or descriptive, with only one randomized controlled trial and one rehabilitation-focused case report directly evaluating rehabilitation interventions. Frequently reported rehabilitation-related impairments included psychosexual dysfunction, chronic pelvic pain, pelvic floor dysfunction, lower urinary tract symptoms, dyspareunia, and reduced quality of life. Reported rehabilitation approaches included pelvic floor rehabilitation, bladder retraining, biofeedback, psychosexual rehabilitation, and multidisciplinary care. Only one study included adolescents, and none specifically evaluated rehabilitation interventions for this population.<br><br>CONCLUSION: Women living with FGM/C experience substantial rehabilitation needs affecting physical, psychosexual, urinary, and psychosocial health. Although physiotherapy and rehabilitation are increasingly recognised as important components of multidisciplinary care, direct evidence evaluating rehabilitation interventions remains limited. Future research should prioritise rehabilitation-focused intervention studies, implementation research, and standardised outcome measures to strengthen the evidence base and inform comprehensive, survivor-centred care.}, }
@article {pmid42467293, year = {2026}, author = {Hassan, MA and Al Amin, M and Sweilam, SH and Abohassan, M and Krishnan, K and Gupta, JK and Jahnavi, P and Vodeti, R and Radha, R and Gupta, PS and Reddy, KTK}, title = {Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42467293}, issn = {1568-5608}, abstract = {Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.}, }
@article {pmid42467750, year = {2026}, author = {Deressa, JD and Behaksra, SW and Molla, E and Letebo, A and Shumie, G and Adnew, B and Alemayehu, DH and Kassa, FA and Seyoum, T and Tafa, EB and Woldekidan, K and Ejigu, LA and Huwe, T and Keffale, M and Bayissa, GA and Koepfli, C and Chala, B and Asmamaw, Y and Tadesse, FG and Gadisa, E}, title = {Therapeutic efficacy of artemether-lumefantrine plus single low dose primaquine for the treatment of uncomplicated Plasmodium falciparum malaria in a high transmission setting, Western Ethiopia.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0335833}, pmid = {42467750}, issn = {1932-6203}, mesh = {Humans ; *Primaquine/therapeutic use/administration &amp; dosage ; *Artemether, Lumefantrine Drug Combination/therapeutic use/administration &amp; dosage ; *Malaria, Falciparum/drug therapy/transmission/epidemiology/parasitology ; *Antimalarials/therapeutic use/administration &amp; dosage ; Female ; Male ; Ethiopia/epidemiology ; Plasmodium falciparum/drug effects/genetics ; Child, Preschool ; Adolescent ; Treatment Outcome ; Child ; Adult ; Drug Therapy, Combination ; Young Adult ; }, abstract = {BACKGROUND: The development and spread of drug-resistant parasites continue to threaten progress toward malaria elimination. Therapeutic efficacy and molecular resistance marker studies are needed to guide national control programs. In African settings, evidence of partial resistance to artemisinin-based combination therapies (ACTs) associated with Pfkelch13 mutations is accumulating, and World Health Organization (WHO) recommends regular monitoring of first line antimalarial drugs for early detection of resistant parasites. In this study, we evaluated the efficacy of artemether-lumefantrine (AL) combined with a single low dose of primaquine (PQ) for treating uncomplicated Plasmodium falciparum malaria in a co-endemic area where P. falciparum predominates.<br><br>METHODS AND FINDINGS: One hundred twenty-three patients with P. falciparum mono-infection were enrolled between November 2020 to March 2021 and treated with artemether-lumefantrine (AL) plus a single low dose of primaquine (PQ) as per the national malaria treatment guideline and followed up for 28 days. Ethical approval was obtained from the AHRI/ALERT ethics committee (Po/23/19), and the study was registered at Pan-African clinical trials registry (PACTR) with unique identification number of PACTR202509595696440. Pfmsp2 capillary electrophoresis (CE) genotyping was used to differentiate recrudescence from new infections. More than half (56.1%) of the participants had high parasitemia (>10,000 parasites/&#x3bc;L) at enrollment. On day 3, 16.9% (20/118) remained parasitemic, and of the 10 individuals with detectable gametocytes at enrollment, only 3.4% remained gametocytemic on day 3, and 100% parasite clearance was observed on day 7, respectively. Multiplicity of infection was 3.8 at enrollment and 1.7 at the time of recurrence. The adequate clinical and parasitological responses at 28-day (ACPR) of per protocol analysis (PPA) was 73.7% for PCR-uncorrected and 91.3% for PCR-corrected, respectively and while, the intention-to-treat analysis (ITA), the Kaplan-Meier estimated treatment success at day 28 was 93.2% (95% CI: 88.5-98.2) after PCR correction, compared with 78.3% (95% CI: 71.0-86.4) in the PCR-uncorrected analysis. In our study assessment, no cases of severe malaria or serious adverse events occurred.<br><br>CONCLUSIONS: The efficacy observed in this study, although remaining above the WHO policy change threshold after PCR correction, may indicate a potential decline in AL's effectiveness in this high transmission setting. However, because antimalarial drug concentrations were not measured and evening doses were not fully directly observed, reduced drug exposure or imperfect adherence cannot be excluded as possible contributors to the observed treatment outcomes Therefore, we suggest regular therapeutic efficacy monitoring and further investigation using advanced molecular techniques, such as next-generation sequencing (NGS), to enable early detection of resistance-associated parasite variants that may compromise treatment efficacy.}, }
@article {pmid42468019, year = {2026}, author = {Gou, CY and Smith, SE}, title = {Interventional Procedures for Musculoskeletal Pain in ALS Patients: A Case Series.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {105}, number = {8}, pages = {e117-e120}, doi = {10.1097/PHM.0000000000002964}, pmid = {42468019}, issn = {1537-7385}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications ; Female ; *Musculoskeletal Pain/etiology/therapy/drug therapy ; Retrospective Studies ; *Pain Management/methods ; Aged ; Adult ; }, abstract = {Many patients with amyotrophic lateral sclerosis (ALS) experience musculoskeletal pain, yet data on the safety and efficacy of interventional procedures for pain relief in this population are limited. This study aims to describe the characteristics, outcomes, and procedural considerations of pain interventions performed for musculoskeletal pain in ALS patients. A retrospective chart review was conducted of ALS patients referred for interventional pain management by a neuromuscular physiatrist at a single academic institution's interdisciplinary ALS Center between February 2021 and February 2025. Eleven patients (mean age: 57 y, 64% male) underwent 14 procedures. Shoulder pain was the most common indication (43%), followed by spine (29%) and hip (14%) pain. Procedures mostly consisted of joint and bursal injections peripherally and of epidural injections in the axial spine. Overall, 13 of 14 (93%) procedures provided at least "good" pain relief, and 5 patients elected to repeat their procedures. One patient experienced transient postprocedure hypertension; no major complications occurred. Interventional procedures, particularly corticosteroid injections, appear to be safe and effective for managing focal musculoskeletal pain in patients with ALS. Tailored procedural techniques and multidisciplinary coordination can enhance comfort and optimize outcomes in this complex population.}, }
@article {pmid42468211, year = {2026}, author = {Seo, Y and Lee, J and Lee, Y and Kim, S and Lee, JS and Ro, H and Cho, SH and Park, JS and Kim, MJ and Park, HC}, title = {FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {202}, number = {}, pages = {119761}, doi = {10.1016/j.biopha.2026.119761}, pmid = {42468211}, issn = {1950-6007}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss and declining motor function; however, effective therapies remain limited. To support unbiased therapeutic discovery, we aimed to develop a high-throughput phenotypic screening platform based on a transgenic zebrafish model expressing the human ALS-associated FUS-R521C mutant (mtFUS). This model was generated using a modified QF-based binary expression system and exhibited early-onset pathological features, including elevated oxidative stress, progressive neuronal degeneration, and impaired locomotor activity, thereby recapitulating the key aspects of FUS-associated ALS. Transcriptomic profiling revealed molecular signatures resembling those reported in patient-derived motor neurons, including dysregulated neuroactive ligand-receptor signaling, immune activation, and stress-response pathway alterations. Using this platform, we identified tribenzylamine (TBA) as a candidate compound that improves locomotor performance and significantly reduces reactive oxygen species levels. Integrated transcriptomic and biochemical analyses suggested that TBA induces coordinated molecular changes, including normalization of neuronal activity-related gene expression, modulation of immune and metabolic pathways, and restoration of hormone-related signaling. TBA reversed FUS-induced reductions in key neuronally active sex steroids, including estrogen and progesterone, and increased estrogen-responsive gene expression, suggesting a partial recovery of neuronally active sex steroid homeostasis. These findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify TBA as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.}, }
@article {pmid42468901, year = {2026}, author = {Halabian, N and Park, C and Omoto, L and Bocca, LF and Palacios, G and Wu, K and Hamani, C and Rabin, J and Abrahao, A and Davidson, B and Lipsman, N and Meng, Y}, title = {Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.}, journal = {Biological psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.biopsych.2026.07.008}, pmid = {42468901}, issn = {1873-2402}, abstract = {Therapeutic focused ultrasound (FUS) leverages the non-invasive ultrasonic waves to modify the biological tissue. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), permitting passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses afflicting the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). We discuss the research developments to date and future directions.}, }
@article {pmid42469515, year = {2026}, author = {Kreß, L and Abuzant, M and Zeller, D and Sommer, C}, title = {Beyond ALS: split-hand syndrome in immune-mediated motor neuropathies.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42469515}, issn = {1432-1459}, support = {Z-2/CSP_22//Interdisziplin&#xe4;res Zentrum f&#xfc;r Klinische Forschung, Universit&#xe4;tsklinikum W&#xfc;rzburg/ ; Z-3 BC-18//Interdisziplin&#xe4;res Zentrum f&#xfc;r Klinische Forschung, Universit&#xe4;tsklinikum W&#xfc;rzburg/ ; Z-2/AdvCSP-4//Interdisziplin&#xe4;res Zentrum f&#xfc;r Klinische Forschung, Universit&#xe4;tsklinikum W&#xfc;rzburg/ ; }, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Middle Aged ; Aged ; *Muscle, Skeletal/physiopathology ; Prospective Studies ; *Hand/physiopathology ; Adult ; Nerve Conduction Studies ; Diagnosis, Differential ; }, abstract = {BACKGROUND AND AIMS: Split-hand syndrome describes selective wasting and weakness of the abductor pollicis brevis (APB) or first dorsal interosseous (FDI) muscles with relative preservation of the abductor digiti minimi (ADM). Beyond clinical definition, two neurophysiological ratios and one index have been proposed to quantify this pattern. It is considered a potential diagnostic criterion for amyotrophic lateral sclerosis (ALS). Its occurrence in immune-mediated neuropathies, as differential diagnoses, remains unclear. We aimed to investigate clinical and electrophysiological manifestations of split-hand syndrome in multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) compared to ALS.<br><br>METHODS: We prospectively examined 26 MMN, 16 MADSAM, and 22 ALS patients. All underwent neurological examination and neurophysiological measurements of compound muscle action potentials (CMAP) from the APB, FDI, and ADM bilaterally after median (APB) and ulnar nerve (FDI, ADM) stimulation. Split-hand ratios (APB/ADM; FDI/ADM) and split-hand index (SI) were calculated.<br><br>RESULTS: Clinical split-hand syndrome was present in 16/26 (62%) MMN, 7/16 (44%) MADSAM, and 12/22 (54%) ALS patients. Electrophysiological criteria (abnormal split-hand ratios or SI;&#x2009;&#x2265;&#x2009;1 parameter fulfilled) were similarly frequent across groups (MMN 17/26, 65%, MADSAM 11/16, 69%, and ALS 16/22, 73%). CMAP ratios and SI did not differ between groups in the overall analysis and showed no correlation with disease duration or severity. Diagnostic models showed limited discriminatory power (area under the curve&#x2009;&#x2264;&#x2009;0.61).<br><br>INTERPRETATION: Split-hand syndrome occurs in MMN, MADSAM, and ALS at comparable frequencies and lacks robust or consistent diagnostic discrimination across disease groups.}, }
@article {pmid42469634, year = {2026}, author = {Li, MA and Song, YZ and Li, T and Wu, J and Tao, Y and Hu, R and Qiao, CM and Cui, C and Zhao, WJ and Shen, YQ}, title = {Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s10020-026-01572-8}, pmid = {42469634}, issn = {1528-3658}, support = {KYCX25_2743//Postgraduate Research &amp; Practice Innovation Program of Jiangsu Province/ ; 82171429//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder driven by neuroinflammation involving activated microglia and astrocytes, which accelerates the loss of motor neurons. While Secretory leukocyte protease inhibitor (SLPI) is known for its immunomodulatory properties, its specific role in ALS pathogenesis has not been fully established. This study aimed to characterize the expression patterns and functional significance of SLPI in ALS models.<br><br>METHODS: The study utilized SOD1[G93A] mice to analyze the spatiotemporal dynamics of SLPI expression in the gastrocnemius muscle, lumbar spinal cord, and serum across different disease stages. In vitro functional assays were conducted using siRNA-mediated knockdown of SLPI in BV2 (microglia), MA (astrocytes), and NSC-34 (motor neurons) cell lines. Additionally, recombinant SLPI protein was applied to LPS-stimulated BV2 cells to investigate its effect on the TLR4/ NF-&#x3ba;B signaling pathway.<br><br>RESULTS: In SOD1[G93A] mice, SLPI was significantly upregulated in the gastrocnemius muscle from the pre-symptomatic stage (60 days) through the late stage (130 days). In the lumbar spinal cord, SLPI showed a transient initial increase but declined sharply by the end-stage; a similar significant reduction was observed in late-stage serum levels. In vitro, SLPI knockdown exacerbated pro-inflammatory cytokine production in all three cell types and impaired the antioxidant capacity of NSC-34 motor neurons. Mechanistically, recombinant SLPI attenuated inflammation in BV2 cells by modulating the TLR4/NF-&#x3ba;B pathway.<br><br>CONCLUSIONS: The dynamic changes in SLPI levels suggest its potential relevance as a candidate molecule for disease staging. Meanwhile, its protective effects in regulating inflammation suggest that it could be a promising therapeutic candidate for mitigating ALS-associated neuroinflammation.}, }
@article {pmid42465739, year = {2026}, author = {You, Y and Zhu, H and Zhang, Q and Wang, J and Dong, C and Yang, Z and Zhang, J and Zhang, Y and Zhang, M and Lu, M and Du, C}, title = {Development and efficacy of ex vivo expanded autologous regulatory T cells for the treatment of amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1854252}, pmid = {42465739}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology/genetics ; *T-Lymphocytes, Regulatory/immunology/transplantation/metabolism ; Animals ; Humans ; Mice ; Disease Models, Animal ; Female ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options, in which neuroinflammation critically drives disease progression. Regulatory T cells (Tregs) exert potent immunosuppressive and neuroprotective effects, offering great potential for ALS treatment. However, clinical application of Treg therapy is hampered by low peripheral cell abundance and unstable expansion quality. Here, we established and optimized a GMP-grade protocol for sorting and expanding peripheral blood-derived Tregs, and validated cryopreserved apheresis products as feasikble starting materials. Although ALS patient-derived Tregs showed reduced expansion capacity compared with healthy donor counterparts, they maintained comparable purity, stable regulatory phenotypes, and robust immunosuppressive function. Transcriptomic analysis confirmed the lineage fidelity and low pro-inflammatory characteristics of expanded Tregs. Therapeutic efficacy was verified in SOD1G93A ALS and GvHD mouse models with delayed disease progression and relieved inflammation. This study provides standardized GMP manufacturing strategies and solid preclinical evidence to support the ongoing clinical trial (NCT06671236) and facilitate Treg immunotherapy translation for ALS.}, }
@article {pmid42466415, year = {2026}, author = {Mei, A and Jewett, D and Jewett, A and Kaur, K and Malarkannan, S}, title = {Multi-hit genetic lesions and a stress-imprinted immune transcriptome define the inflammatory pathology in ALS patients.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42466415}, issn = {2693-5015}, abstract = {Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease whose peripheral immune architecture remains incompletely defined. Here, we integrated whole-genome sequencing and single-cell RNA sequencing to define genomic and immune correlates of ALS. Genome-wide analysis of a monozygotic twin pair discordant for ALS pathology identified shared ALS-associated variants, as well as patient-enriched variants in genes linked to RNA metabolism, neurodegeneration, and immune inflammation, supporting a multilayered genetic architecture. Single-cell profiling of 40,484 peripheral blood mononuclear cells from three ALS patients and two healthy individuals, including 33,667 cells retained after quality control, resolved 13 immune clusters and revealed broad remodeling of the peripheral immune compartment, with relative enrichment of natural killer, mucosal-associated invariant T, and γδ T-cell populations. Across immune subsets, ALS samples exhibited inflammatory and stress-adapted transcriptomic programs, including TNF-α/NF-κB, IFN-γ, hypoxia, and ribosomal stress pathways. These data support a model in which multi-hit genetic susceptibility converges on a stress-induced immune transcriptome, marked uniquely by innate lymphocyte activation in ALS patients.}, }
@article {pmid42466609, year = {2026}, author = {Li, D and Zhou, Z and Liang, G and Zeng, D and Zhou, Z and Li, X and Qiu, T and Zhang, Y and Lin, J and Chen, Y and Li, Z}, title = {Association Between Allostatic Load, Genetic Susceptibility, and Liver Cancer Incidence: A Large-Scale Prospective Cohort Study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.70583}, pmid = {42466609}, issn = {1097-0215}, support = {240421166496919//Shantou Medical Science and Technology Planning Project/ ; A2023481//Medical Scientific Research Foundation of Guangdong Province, China/ ; B2025664//Medical Scientific Research Foundation of Guangdong Province, China/ ; //Shantou University Medical College 2025 Teaching Reform Project/ ; }, abstract = {Allostatic load (AL) reflects the cumulative physiological burden of chronic stress throughout life, potentially influencing cancer onset and prognosis. However, its association with primary liver cancer (PLC) risk and potential interaction with genetic susceptibility remains unclear. To investigate this, we analyzed 374,632 UK Biobank participants. AL was evaluated using a composite score of 13 cardiovascular, metabolic, and immune biomarkers, while a weighted polygenic risk score (PRS) categorized genetic susceptibility. Multivariable Cox proportional hazards models and restricted cubic splines were utilized to estimate hazard ratios (HRs) and evaluate dose-response relationships. Over a median 12.4-year follow-up, a significant dose-response correlation between AL and PLC risk was observed. In the fully adjusted model, a 1-unit increase in AL was associated with a 17% increased risk (HR = 1.17, 95% CI: 1.12-1.23), and participants in the highest AL quartile exhibited a 2.60-times higher risk than those in the lowest (HR = 2.60, 95% CI: 1.72-3.95). Despite no multiplicative interaction, stratified analyses revealed AL's impact was most substantial in individuals with intermediate genetic risk (HR = 2.00, 95% CI: 1.38-2.90), who constitute the population majority. Additionally, the risk was heightened in overweight/obese individuals and more pronounced among non-smokers. Ultimately, cumulative physiological stress, indicated by AL, is strongly associated with PLC, supporting the "wear-and-tear" theory of its development. This research highlights a "malleable zone" in individuals with moderate genetic risk, suggesting that lowering AL may meaningfully aid in preventing PLC.}, }
@article {pmid42467162, year = {2026}, author = {Barker-Jones, B and Navvuga, P and Baji, P and Marques, E and Hollingworth, W}, title = {Comparing User-Written Codes for Performing Economic Evaluations in Stata.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, pmid = {42467162}, issn = {1179-2027}, support = {RP-PG-0610-10048//National Institute for Health and Care Research/ ; PB-PG-0213-30021//National Institute for Health and Care Research/ ; }, abstract = {BACKGROUND: Several user-written Stata codes exist for trial-based economic evaluations, but they lack assessment and guidance. This study aimed to identify and compare publicly available user-written Stata codes for trial-based economic evaluations.<br><br>METHODS: A focused literature search of Ovid Medline, SSC Archive, The Stata Journal and Google Scholar was conducted to identify relevant codes to June 2025. Codes were applied to data from two clinical trials, both featuring missing data and covariate adjustment. Codes were compared in terms of their ability to estimate key economic parameters and produce graphical outputs and functionality in handling four common statistical challenges: correlated costs and effects, covariate adjustment, skewed costs and effects, and missing data.<br><br>RESULTS: We identified eight codes reported in four publications: codes for assessing health economic agreement (Gallacher et al.), sampling uncertainty for cost-effectiveness analysis (Glick et al.) and codes addressing missing data (Mutubuki et al. and Faria et al.). Gallacher et al.'s codes reported lower incremental quality-adjusted life years (QALYs) and net monetary benefit than Glick's et al.'s codes. Mutubuki et al. and Faria et al.'s codes produced comparable incremental costs and QALYs, though Faria et al. yielded wider confidence intervals in cost estimates.<br><br>DISCUSSION: Differences in estimates across statistical approaches show that code choice can influence economic evaluation results. Some codes were better suited for generating basic economic outputs, whereas others provide more comprehensive analyses or address specific statistical challenges including missing data. However, no single code provided all key outputs while addressing the main statistical challenges.}, }
@article {pmid42461927, year = {2026}, author = {Zhong, F and Ni, C and Wang, B}, title = {Optimal pooling strategies for respiratory virus testing: A comparative cost-effectiveness analysis.}, journal = {PLOS global public health}, volume = {6}, number = {7}, pages = {e0006646}, pmid = {42461927}, issn = {2767-3375}, abstract = {Pooled testing represents a cost-efficient strategy for large-scale respiratory virus screening. However, determining the optimal pool size (OPS) across varying prevalence rates and diagnostic performance metrics remains a critical challenge in respiratory virus surveillance. We evaluated four hierarchical OPS algorithms, all employing the original solution method (OSM), and proposed a modified solution method (MSM) based on objective function optimization. Through Monte Carlo simulations and logit modeling, we generated COVID-19 infection data representative of community transmission patterns. These data were analyzed using a comparative cost-effectiveness framework to assess OSM and MSM approaches. Our analysis across various prevalence rates (0.1-30.0%), sensitivities (0.8-1.0), and specificities (0.97-1.00) revealed Hanel et al.'s algorithm consistently yielded the largest OPS values under OSM. MSM revealed minimal deviations from OSM in most scenarios, though it effectively corrected Kim et al.'s inflated OPS values at high prevalence (~30%) with low sensitivity/specificity. Three algorithms produced comparable OPS configurations, outperforming OSM. Hanel's and Regen's algorithms emerged as the most cost-effective options, with Hanel's method being optimal for low additional costs in second-stage testing and Regen's for high additional costs. MSM significantly reduced inter-algorithm cost differences compared to OSM. This study provides a comprehensive evaluation of OPS determination algorithms in pooled PCR testing for respiratory viruses, demonstrating robust OPS configurations and enhanced cost-effectiveness through MSM implementation. The proposed MSM addresses existing limitations in pooled testing strategies, facilitates efficient resource allocation, and contributes to improved respiratory virus surveillance and pandemic response.}, }
@article {pmid42462180, year = {2026}, author = {Baskar, K and Steffke, C and Bernsen, S and Elmas, Z and Hesebeck-Brinckmann, J and Schuster, J and Meyer, T and Weydt, P and Weishaupt, J and Brenner, D and Catanese, A}, title = {Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS.}, journal = {Neurology(R) neuroimmunology &amp; neuroinflammation}, volume = {13}, number = {5}, pages = {e200618}, pmid = {42462180}, issn = {2332-7812}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/genetics ; Biomarkers/cerebrospinal fluid ; Female ; Male ; C9orf72 Protein/genetics ; Middle Aged ; Aged ; Neuroglia ; *Neuroinflammatory Diseases/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Adult ; *Inflammation/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; }, abstract = {BACKGROUND AND OBJECTIVES: CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform-capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes-could validate previously proposed biomarkers and identify additional candidates relevant to ALS.<br><br>METHODS: Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls.<br><br>RESULTS: The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases-particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature.<br><br>DISCUSSION: Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.}, }
@article {pmid42463858, year = {2026}, author = {Picchiarelli, G and Demestre, M and Zuko, A and Been, M and Higelin, J and Dieterlé, S and Goy, MA and Mallik, M and Sellier, C and Scekic-Zahirovic, J and Zhang, L and Rosenbohm, A and Sijlmans, C and Aly, A and Mersmann, S and Sanjuan-Ruiz, I and Hübers, A and Messaddeq, N and Wagner, M and van Bakel, N and Boutillier, AL and Ludolph, A and Lagier-Tourenne, C and Boeckers, TM and Dupuis, L and Storkebaum, E}, title = {Author Correction: FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41593-026-02396-9}, pmid = {42463858}, issn = {1546-1726}, }
@article {pmid42464213, year = {2026}, author = {Özbilici, Z and Issı, ES}, title = {SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-05142-7}, pmid = {42464213}, issn = {1471-2377}, abstract = {BACKGROUND: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings.<br><br>CASE PRESENTATION: A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G&#x2009;>&#x2009;A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement.<br><br>CONCLUSIONS: This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.}, }
@article {pmid42464712, year = {2026}, author = {Gao, N and Cui, B and Yun, Y and Yu, W and Gao, X and Sun, X and Shao, K and Lin, P and Liu, F and Li, W and Zhao, Y and Yu, D and Yan, C and Liu, S and Lou, J}, title = {Corticospinal Subfiber Neurite Density Index Detects Upper Motor Neuron Degeneration in Prediagnostic Patients With Sporadic Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {7}, pages = {e70703}, pmid = {42464712}, issn = {1468-1331}, support = {82471429//National Natural Science Foundation of China/ ; ZR2024MH013//Natural Science Foundation of Shandong Province/ ; 2025CXPT133//the Key Research and Development Program of Shandong Province, China/ ; Z-2017-24-2509//the Yantu Neuroscience Specialized Research Fund Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/blood/diagnosis ; Female ; Male ; *Pyramidal Tracts/diagnostic imaging/pathology ; Middle Aged ; *Neurites/pathology ; Retrospective Studies ; Aged ; Neurofilament Proteins/blood ; Diffusion Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; *Motor Neurons/pathology ; *Nerve Degeneration/pathology/diagnostic imaging ; }, abstract = {BACKGROUND: Using multi-shell diffusion MRI, we aimed to identify whether corticospinal tract (CST) subfiber damage can be detected in prediagnostic amyotrophic lateral sclerosis (ALS) patients. We also explored whether the combination of serum neurofilament light chain (NfL) levels and CST subfiber abnormalities may provide better diagnostic performance in differentiating prediagnostic ALS patients from disease controls (DCs) and healthy controls (HCs) than single markers.<br><br>METHODS: In this retrospective study, prediagnostic ALS was used as an operational term for patients who presented at baseline with chronic progressive limb weakness or bulbar symptoms, had no clinically evident typical UMN signs, and were subsequently confirmed to have sporadic ALS according to the Awaji criteria during longitudinal follow-up. Patients whose final diagnosis was not ALS after follow-up were classified as disease controls. Probabilistic tractography was performed on baseline MRI data to assess CST subfiber damage in 47 ALS patients, 20 DCs, and 51 HCs.<br><br>RESULTS: Compared with Controls, ALS patients had significantly lower neurite density index (NDI) values of CST subfibers, particularly those originating from the primary and supplementary motor cortex. The diagnostic performance of the combined model incorporating serum NfL and CST subfiber NDI values in differentiating prediagnostic ALS patients from HCs and DCs was 0.925 and 0.928, respectively, which was better than that of single markers (0.634-0.886 and 0.699-0.856, respectively).<br><br>CONCLUSIONS: Our findings suggest that CST subfibers NDI values are promising neuroimaging markers for detecting in&#xa0;vivo UMN degeneration in prediagnostic ALS. Moreover, combining blood and neuroimaging markers may further improve early diagnostic performance.}, }
@article {pmid42458498, year = {2026}, author = {Wang, H and Wen, R and Parker, E and Yang, L}, title = {TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-03083-9}, pmid = {42458498}, issn = {1478-811X}, support = {32300959//National Natural Science Foundation of China/ ; SL2024A04J00578//Guangzhou Scientific Research Grant/ ; 22KJ04//SCNU Young Faculty Development Program/ ; }, abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.}, }
@article {pmid42458512, year = {2026}, author = {Jo, M and Kim, S and Woo, J and Park, JS and Kim, SH and Nahm, M and Kim, SR and Lee, S and Kim, HJ}, title = {Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-03082-w}, pmid = {42458512}, issn = {1478-811X}, support = {RS-2024-00454715//National Research Foundation of Korea/ ; RS-2024-00343239//National Research Foundation of Korea/ ; 26-BR-02-03//Korea Brain Research Institute/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD.<br><br>METHODS: The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-&#x3ba;B) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS.<br><br>RESULTS: DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-&#x3ba;B-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE.<br><br>CONCLUSION: DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.}, }
@article {pmid42458576, year = {2026}, author = {Akan, T and Aishwarya, R and Bhuiyan, MS and Conrad, SA and Vanchiere, JA and Bhuiyan, MAN}, title = {From unlabeled to labeled: self-supervised deep learning in computational pathology.}, journal = {BioData mining}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13040-026-00586-6}, pmid = {42458576}, issn = {1756-0381}, support = {R01HL172970, R01HL145753, R01HL145753-01S1, and R01HL145753-03S1//Foundation for the National Institutes of Health/ ; P20GM121307//Foundation for the National Institutes of Health/ ; }, abstract = {PURPOSE: The advancement of decision support systems for pathology and their implementation in clinical practice have been limited by the necessity for extensive, manually annotated datasets. Self-supervised learning (SSL) automates the extraction and interpretation of histopathological features from unannotated images, facilitating efficient model development without dependence on expert labeling. In this study, we introduce the SSL-HistoNet model that learns disease-relevant morphological representations from histopathological images through self-supervised learning.<br><br>MATERIALS AND METHODS: We applied it to WGA-stained skeletal muscle tissues from mouse models of amyotrophic lateral sclerosis (ALS) and Type I diabetes to explore its ability to capture pathological muscle phenotypes in an annotation-free setting. Following pretraining on unlabeled data, the SSL encoder was further integrated with an attention-guided classifier to evaluate its capacity to identify pathological muscle alterations.<br><br>RESULTS: SSL-HistoNet achieved a precision of 0.98, a recall of 0.98, and an AUC of 0.98, demonstrating performance comparable to or outperforming state-of-the-art supervised models. Alongside high discriminative performance, exploratory feature analyses demonstrated consistent class-level changes in morphology-related patterns identified through representation learning.<br><br>CONCLUSION: These findings highlight the capability of SSL-HistoNet as an annotation-free framework for outlining disease-specific tissue structures, reducing manual labeling demands and mitigating inter- and intra-observer variability in histological processes.<br><br>CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid42459525, year = {2026}, author = {Majumdar, S and Samaiya, PK and Ahmed, S and Prajapati, SK}, title = {Imaging biomarkers in neurodegenerative diseases: advances and challenges.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1813588}, pmid = {42459525}, issn = {1663-4365}, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), represent a major global health burden. Imaging biomarkers have emerged as important tools for improving the diagnosis, monitoring, and biological characterization of neurodegenerative diseases. Structural MRI, diffusion tensor imaging (DTI), functional MRI (fMRI), positron emission tomography (PET), hybrid PET/MRI and molecular imaging have transformed our ability to investigate neurodegeneration in vivo non-invasively. This review highlights updated information on how each imaging modality offers a unique window into different disease pathophysiology including regional atrophy, amyloid-β, tau, dopaminergic terminal degeneration, synaptic density (SV2A), and neuroinflammation. We also focused on the translational and evidence supporting biomarkers, appropriate use criteria for amyloid and tau PET imaging, and standardized quantification methods such as the Centiloid scale. The growing role of multimodal fusion, where imaging is increasingly integrated with scalable fluid biomarkers to enable "blood-first" strategies where high-risk patients are selectively referred to advanced imaging, improving feasibility and equity. Despite tremendous progress, there are still issues with their standardization, sensitivity, specificity, and clinical translation. Moreover, the review emphasizes the frontiers of α-synuclein and glial state-specific PET ligands, advanced diffusion models, and dynamic connectivity analysis to support precision medicine and mechanism-based trial design for NDDs.}, }
@article {pmid42459857, year = {2026}, author = {Hu, M and You, L and Zhang, X and Xuan, Z and Ma, S and Wu, X}, title = {Experimental evidence of electroacupuncture in ALS mouse models: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1780176}, pmid = {42459857}, issn = {1664-2295}, abstract = {OBJECTIVE: This study aimed to systematically evaluate the therapeutic efficacy of electroacupuncture (EA) in amyotrophic lateral sclerosis (ALS) and to elucidate the underlying neurobiological mechanisms by synthesizing preclinical evidence.<br><br>METHODS: According to the PICOS principle, relevant studies were searched in the following databases: PubMed, Web of Science, Embase, Cochrane Library, Scopus, and CNKI. Search terms and strategies were determined based on MeSH terms. The methodological quality of the included studies was assessed using the SYRCLE's Risk of Bias tool and the CAMARADES checklist. Meta-analysis was performed using Stata 15.0 and Rstudio software.<br><br>RESULTS: Seventeen studies involving 372 animals were included. The quality scores of the included studies ranged from 5 to 8, with an average score of 7. The meta-analysis of the primary outcome, the rotarod test score, showed a significant improvement in the EA group compared to the control group [SMD&#x202f;=&#x202f;3.31, 95% CI (2.05, 4.57), Z&#x202f;=&#x202f;5.151, p&#x202f;<&#x202f;0.001], indicating that EA can enhance motor function in ALS mice. Regarding secondary outcomes, EA intervention alleviated neuroinflammation, promoted neuronal survival, improved axonal regeneration inhibition, and stabilized RNA metabolism homeostasis. Consequently, it slowed disease progression, improved motor performance, prolonged survival time, and effectively protected motor neurons at the histopathological level (p&#x202f;<&#x202f;0.05). These findings underscore the potential of EA as a promising multimodal therapeutic strategy for ALS. For the heterogeneity observed in the rotarod test, sensitivity analysis, subgroup analysis, and meta-regression did not identify its source. However, potential publication bias was detected, which might contribute to the heterogeneity. The heterogeneity for other outcome measures might originate from differences in stimulation parameters (e.g., waveform), acupoint selection, or treatment duration.<br><br>CONCLUSION: This meta-analysis demonstrates that EA confers significant neuroprotective benefits in preclinical ALS models, primarily through multi-target modulation of key pathological processes such as neuroinflammation, aberrant cell death signaling, and RNA metabolism. These preclinical findings underscore the potential of electroacupuncture as a complementary neuroprotective strategy and warrant further investigation in rigorous clinical trials.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251229183.}, }
@article {pmid42459893, year = {2026}, author = {Ogino, M}, title = {Single-subject auditory ERP-BCI performance enhancement in ALS via an AI coding assistant prompt.}, journal = {Frontiers in human neuroscience}, volume = {20}, number = {}, pages = {1869918}, pmid = {42459893}, issn = {1662-5161}, abstract = {INTRODUCTION: Auditory event-related potential (ERP) brain-computer interfaces (BCIs) offer communication support for individuals with amyotrophic lateral sclerosis (ALS) who eventually progress to completely locked-in states. However, individual-specific BCI pipeline optimization is technically demanding and time-consuming, leaving substantial room for performance improvement in practice. A central challenge is increasing selection speed while maintaining reliable classification accuracy, since slower selections reduce the sense of agency and undermine the motivational and feedback dynamics essential for sustained BCI use.<br><br>METHODS: We investigated whether an AI coding assistant could address this challenge for individual patients. A three-class auditory ERP-BCI was optimized for a single ALS patient using Claude Code (Anthropic, Inc.), which iteratively generated and evaluated 23 optimization scripts over approximately 24 hours with minimal human-in-the-loop oversight. The resulting AI-Designed ERP classifier (AIDE) was evaluated on 189 EEG trials spanning 3.5 years using five cross-validation strategies.<br><br>RESULTS: For the baseline models, halving the stimulus repetitions to shorten selection time degraded classification accuracy; AIDE prevented this degradation, achieving 85.03% mean cross-validation accuracy (selection time 17 s; ITR 2.92 bits/min). This doubled the information transfer rate from 1.43 to 2.92 bits/min. Accuracy exceeded 84% across four of five cross-validation strategies. Feature space visualization revealed that the AI autonomously selected and combined EEG features established in prior studies into an effective discriminative architecture, without domain-specific algorithmic guidance from the human researcher. In addition, online test confirmed 66.7% accuracy for AIDE versus 50.0% for the baseline model.<br><br>DISCUSSION: These findings provide proof of concept that single-subject BCI performance can be improved via a single prompt, offering an efficient pathway to individualized optimization in clinical and research settings.}, }
@article {pmid42460499, year = {2026}, author = {Leichsenring, F and Heim, N and Steinert, C}, title = {Conceptual problems and questionable evidence in defining non-inferiority margins - a reply to Flückiger et al.}, journal = {Psychotherapy research : journal of the Society for Psychotherapy Research}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/10503307.2026.2701025}, pmid = {42460499}, issn = {1468-4381}, abstract = {From 19 meta-analyses comparing active bona fide treatments, Flückiger et al. (2026) recently calculated a between-group effect size (SMD) of -0.17 for primary outcomes and of -0.16 for secondary outcomes. They suggested using these effect sizes as empirically derived non-inferiority margins. However, Flückiger et al.'s approach is conceptually problematic and lacks empirical support. Without a rationale, empirically found differences between active treatments cannot per se be regarded as non-inferiority margins.}, }
@article {pmid42460524, year = {2026}, author = {Cai, X and Bai, Y and Ma, F and Xu, R and Xie, Y and Cao, X}, title = {Mechanisms and Therapeutic Targeting of the cGAS-STING Pathway in Central Nervous System Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X472988260627201746}, pmid = {42460524}, issn = {1875-6190}, abstract = {OBJECTIVE: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a core DNA-sensing axis in innate immunity and has been increasingly implicated in the pathogenesis of multiple Central Nervous System (CNS) disorders. This review summarizes current knowledge of cGAS-STING signaling in CNS disorders and evaluates its therapeutic potential.<br><br>METHODS: Relevant studies on cGAS-STING signaling in CNS disorders were collected from PubMed and Web of Science, with emphasis on disease mechanisms, neuroinflammatory regulation, and pathway-targeted therapeutic strategies.<br><br>RESULTS: In the CNS, cGAS-STING signaling exhibits marked region-, cell-, and pathology-dependent heterogeneity. Aberrant DNA sensing activates this pathway and amplifies neuroinflammation, cellular stress, and tissue injury in Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), ataxia-telangiectasia (A-T), and ischemic and hemorrhagic stroke. Pharmacological inhibition of cGAS, cyclic GMP-AMP (cGAMP), or STING, together with emerging delivery strategies, has shown promise in preclinical models.<br><br>DISCUSSION: Clinical translation remains limited by incomplete validation of pathway specificity, limited human evidence, restricted brain delivery, and inconsistent efficacy assessment.<br><br>CONCLUSION: The cGAS-STING pathway links aberrant DNA sensing to innate immune activation and CNS pathology. Clarifying its disease-, cell-, and stage-specific roles may support future targeted therapeutic strategies for CNS disorders.}, }
@article {pmid42460525, year = {2026}, author = {Liu, Y and Yang, J and Su, J and Hao, L}, title = {High Levels of Plasma Neurturin Partially Mediate the Protective Effect of Reduced Ruminococcus2 Abundance on Multiple Sclerosis: A Mendelian Randomization Study.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X468669260626223524}, pmid = {42460525}, issn = {1875-6190}, abstract = {BACKGROUND: Genetic evidence implicates the contribution of the gut-brain axis to neurodegenerative diseases (NDDs). Alterations in gut microbiota and inflammation are key pathophysiological contributors. Elucidating the genetic basis and the role of cytokines can provide insights into mechanisms linking gut microbial composition to neurodegeneration.<br><br>METHODS: Using aggregated statistics from five large-scale Genome-Wide Association Studies (GWAS) on Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and amyotrophic lateral sclerosis, bidirectional two-sample Mendelian Randomization (MR) was used to examine the associations. A two-step multivariable Mendelian randomization approach incorporates data from 91 cytokines to explore potential mediators.<br><br>RESULTS: The study reveals 18 positive and 17 negative effects between gut microbiota and NDDs, as well as 10 positive and 10 negative effects between cytokines and NDDs. Remarkably, mediation analysis identified a causal pathway, with evidence that plasma neurturin levels partially mediate the association from genus Ruminococcus2 to multiple sclerosis, with a mediation proportion of 19.19% (OR = 1.038, 95% CI = 1.001-1.086, P = 0.044). No pleiotropy or heterogeneity was detected.<br><br>DISCUSSION: These MR findings provide compelling evidence for a genetically anchored gutimmune-brain network in NDDs, with cytokines as intermediates. Bidirectional effects highlight disease-specific microbial signatures and inflammatory contexts. The Ruminococcus2-neurturin pathway in multiple sclerosis may offer mechanistic specificity, aligning with neurotrophic and anti-inflammatory signaling pathways.<br><br>CONCLUSION: This study emphasizes the importance of gut microbiota alterations in NDDs and explores inflammation's partial intermediary role. The findings suggest potential targets for personalized neurodegeneration prevention strategies.}, }
@article {pmid42460529, year = {2026}, author = {Chen, H and Yang, Z and Meng, H and Hu, Z and Ke, Z and Ye, Q and Xu, Y and Wu, J and Liu, Z}, title = {White Matter Functional Dysregulation in Amyotrophic Lateral Sclerosis: Machine Learning-Based Biomarkers and Transcriptomic Signatures.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X465668260629073047}, pmid = {42460529}, issn = {1875-6190}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor system degeneration, yet its white matter (WM) functional pathophysiology remains underexplored.<br><br>METHODS: This study utilized resting-state functional magnetic resonance imaging to decode WM functional abnormalities in 50 ALS patients and 55 healthy controls. Next, machine learning analysis was applied to evaluate the utility of these WM functional patterns in diagnosing ALS and predicting disease progression, and their pathophysiological mechanisms were preliminary explored through neurotransmitter mapping and imaging transcriptomics.<br><br>RESULTS: ALS patients exhibited reduced activity in central WM regions (including bilateral corticospinal tracts), accompanied by elevated activity in anterior and posterior WM territories. The aberrant topological properties and disrupted functional connectivity are predominantly localized within bilateral precentral/postcentral WM networks. A support vector machine model incorporating these features achieved 75.24% classification accuracy and predicted the rate of disease progression (r = 0.56, p = 0.001). The spatial pattern of WM dysfunction in ALS was associated with both the spatial distribution of disease-related neurotransmitters and the expression profiles of specific genes.<br><br>DISCUSSION: Our findings reveal distinct WM functional dysfunction patterns in ALS and their molecular-genetic underpinnings, providing novel insights into the pathophysiological mechanisms of ALS.<br><br>CONCLUSION: ALS involves specific patterns of WM dysfunction, and these WM-centric biomarkers may facilitate the development of therapeutic monitoring frameworks for this devastating disease.}, }
@article {pmid42461162, year = {2026}, author = {Zhang, R and Zhang, N and Li, B and Liu, Q and Xu, C and Li, B and Zhang, J}, title = {Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.}, journal = {Nursing in critical care}, volume = {31}, number = {4}, pages = {e70573}, pmid = {42461162}, issn = {1478-5153}, support = {25ZZJJLW-015//Medical Research Council Foundation of the 305 Hospital of the PLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/complications ; *Epilepsy/nursing/complications ; Male ; Intensive Care Units ; *Critical Care Nursing/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34 days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.}, }
@article {pmid42461445, year = {2026}, author = {Mitsumoto, H and Cheung, K and Matsumoto, T and Lanza, I and Oskarsson, B and Johnson, S and Petterson, XT and Jang, GE and Andrews, HF}, title = {Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {22}, number = {4}, pages = {}, pmid = {42461445}, issn = {1573-3890}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/blood ; *Muscle Cramp/drug therapy/metabolism/blood ; *Metabolomics/methods ; Female ; Male ; Middle Aged ; Aged ; Cross-Over Studies ; Medicine, Kampo ; *Drugs, Chinese Herbal/therapeutic use ; }, abstract = {INTRODUCTION: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS.<br><br>OBJECTIVES: This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68.<br><br>METHODS: Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68.<br><br>RESULTS: Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, &#x3b2;-aminoisobutyric acid, &#x3b1;-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68.<br><br>CONCLUSION: This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.}, }
@article {pmid42461653, year = {2026}, author = {Kneepkens, SCM and Lingham, G and van Hemert, DJ and Loughman, J and Strang, NC and Tham, YC and Harrington, SC and Guisasola, L and French, A and He, X and Mackey, DA and Hagen, LA and Baraas, RC and Pärssinen, O and Yam, JC and Saunders, KJ and Guggenheim, JA and Saw, SM and Lan, WZ and Klaver, CCW and Flitcroft, DI and , }, title = {Global Axial Length Centile Charts.}, journal = {JAMA ophthalmology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaophthalmol.2026.2539}, pmid = {42461653}, issn = {2168-6173}, abstract = {IMPORTANCE: Myopia is increasingly common worldwide and poses major public health challenges because axial elongation drives sight-threatening complications. Because axial length (AL) is the primary target for myopia management, population-specific AL reference charts are needed.<br><br>OBJECTIVE: To generate region- and sex-specific reference centile charts for AL in children and adolescents.<br><br>This was a pooled cohort analysis using individual-participant data from population- and school-based studies conducted in East Asia, Europe, and Australia contributing to the CREAM-Kids Consortium. A total of 147&#x202f;404 children and adolescents contributing 559&#x202f;799 AL measurements were included. Most participants were from East Asia (84%; ages 6-18 years), followed by Europe (12%; ages 6-21 years) and Australia (4%; ages 6-21 years). After assessment of comparability, European and Australian datasets were combined. Data were included from 1999 to 2024, with the analysis taking place from December 2024 to May 2026.<br><br>EXPOSURES: AL, age, sex, and geographic region.<br><br>MAIN OUTCOMES AND MEASURES: Region- and sex-specific AL centiles across age and agreement between modeled centiles and empirical values.<br><br>RESULTS: AL distributions among the 147&#x202f;404 included individuals varied by sex and region. In female individuals, the 50th centile AL at age 7 years was 22.35 mm in Europe and Australia and 22.67 mm in East Asia; by age 18 years, the 50th centile ALs were 23.31 mm and 24.36 mm, respectively. Regional differences were larger at higher centiles: for female individuals at age 7 years, East Asia vs Europe and Australia differences were 0.33 mm at the 3rd centile and 0.50 mm at the 97th centile; at age 18 years, differences were 0.73 mm and 1.27 mm, respectively. Modeled centile curves closely matched empirical values (intraclass correlations >0.99) with minimal bias across sex and region subgroups (-0.08 mm to 0.04 mm).<br><br>CONCLUSIONS AND RELEVANCE: While not based solely on population-based cohorts, the region- and sex-specific AL centile charts developed in this pooled cohort study provide reference values for childhood and adolescence that may be used to support clinical and research applications, including identifying atypical axial elongation and informing targeted strategies for myopia prevention and management.}, }
@article {pmid42451086, year = {2026}, author = {Soni, N and Debnath, N and Rekapally, E and Jabbar, A and Tyagi, SC and Bissa, B and Tyagi, N}, title = {Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.}, journal = {Nutrients}, volume = {18}, number = {13}, pages = {}, doi = {10.3390/nu18132082}, pmid = {42451086}, issn = {2072-6643}, support = {971566; 24 TPA1304527 and 25 TPA1481771 to Neetu Tyagi.//American Heart Association/ ; }, mesh = {Humans ; *Vitamin D/metabolism/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy/etiology ; *Signal Transduction ; Vitamin D Deficiency/complications ; Animals ; Oxidative Stress/drug effects ; Receptors, Calcitriol/metabolism ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents ; }, abstract = {Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.}, }
@article {pmid42451691, year = {2026}, author = {Singh, AA and Arukha, AP and Song, M}, title = {Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {13}, pages = {}, doi = {10.3390/molecules31132323}, pmid = {42451691}, issn = {1420-3049}, mesh = {Humans ; *Antioxidants/pharmacology/chemistry ; *Indoles/chemistry/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Oxidation-Reduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.}, }
@article {pmid42453524, year = {2026}, author = {Yang, HI and Hsueh, KW and Ding, DC and Harn, HJ and Lin, YC and Chang, CY and Tsai, ST and Lin, SZ}, title = {Therapeutic potential of adipose-derived stem cell transplantation in amyotrophic lateral sclerosis: A combined clinical case and preclinical study.}, journal = {Tzu chi medical journal}, volume = {38}, number = {3}, pages = {332-339}, pmid = {42453524}, issn = {2223-8956}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal neurodegenerative disease with no adequate treatment. Transplantation of adipose-derived stem cells (ADSCs) may be an effective therapeutic strategy for delaying progression or restoring neurological function in ALS.<br><br>MATERIALS AND METHODS: We evaluated the safety and therapeutic efficacy of intravenous (i.v.) and intracerebral (i.c.) ADSC injection in a late-stage ALS patient and in a SOD1 transgenic (Tg) mouse model. Magnetic resonance imaging (MRI) and computed tomography (CT) were conducted to examine potential cerebral hemorrhage and tumor generation in the treated patient. In addition, maximal inspiratory pressure, maximal expiratory pressure, tidal volume, and respiratory rate were measured as indices of respiratory function.<br><br>RESULTS: ADSC transplantation was safe, with MRI and CT showing no hemorrhage or tumorigenesis up to 12 months. The patient's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score improved from 7 to 9 at 3 months and remained above baseline for 6 months. Respiratory function was preserved during this period. In SOD1 Tg mice, i.c. and i.v. ADSC infusion significantly prolonged survival (165.0 &#xb1; 10.4 and 147.3 &#xb1; 4.5 days vs. 129.7 &#xb1; 3.9 days) and improved motor scores (P < 0.01).<br><br>CONCLUSION: This preliminary finding suggests potential therapeutic feasibility, but further studies with larger cohorts are needed to confirm its safety and efficacy.}, }
@article {pmid42454381, year = {2026}, author = {Mai, R and Zhang, X and Yu, G and Chen, Z and Zhao, W and Shi, Z and Gao, X and Liang, Z and Fu, C}, title = {Robust Covalent Organic Frameworks Comprising Accessible Catalytic Sites Enable Fast-Charging and Long-Cycling Aluminum-Sulfur Batteries.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e74063}, doi = {10.1002/adma.74063}, pmid = {42454381}, issn = {1521-4095}, abstract = {Rechargeable aluminum-sulfur (Al-S) batteries are recognized as a promising option for large-scale energy storage due to high theoretical energy density and cost-effectiveness. However, the sulfur cathodes suffer from sluggish reaction kinetics and severe shuttle effect during cycling. Here we report robust two-dimensional covalent organic frameworks (COFs) as sulfur hosts that features accessible catalytic nitrogen sites and confined microporous channels. The fine regulation of different microporous sizes was achieved by controlling different-length organic ligands of various COFs, finally preparing two kinds of COFs. The sensitive comparation between both COFs demonstrates that smaller microporous channels in COFs possess higher confinement effect for polysulfides due to the stronger capillary forces, facilitating higher Coulombic efficiency and better cycling stability in Al-S batteries. Meanwhile, experimental characterizations and theoretical calculations reveal that accessible catalytic nitrogen sites in COFs promote the multistep conversion kinetics of the sulfur cathode during cycling. Consequently, the small-sized COF confined sulfur cathode exhibits a reversible capacity of 1120 mAh g[-1] at 0.2C and a 93.5% capacity retention after 100 cycles, supporting high capacity and exceptional cycling stability. This work provides a new avenue on rational design of emerging COF materials in Al-S batteries.}, }
@article {pmid42454435, year = {2026}, author = {Walls, M and Claffey, A and Galvin, M}, title = {Moral distress in healthcare professionals working with motor neuron disease.}, journal = {Palliative &amp; supportive care}, volume = {24}, number = {}, pages = {e196}, doi = {10.1017/S1478951526103058}, pmid = {42454435}, issn = {1478-9523}, mesh = {Humans ; *Motor Neuron Disease/psychology/complications/therapy ; *Health Personnel/psychology/statistics &amp; numerical data ; Cross-Sectional Studies ; Female ; Male ; Adult ; Europe ; Surveys and Questionnaires ; Middle Aged ; Ethical Dilemmas ; Quality of Life/psychology ; }, abstract = {OBJECTIVES: To (1) identify clinical situations that may contribute to the experience of moral distress (MD) among professionals working with motor neuron disease (MND), (2) measure the occurrence and intensity of MD, and (3) explore associations with professional quality of life, turnover intention, and associated risk and/or protective factors.<br><br>METHODS: A cross-sectional online survey was distributed to healthcare professionals working in MND services across Europe. Data were analyzed using descriptive and inferential statistics.<br><br>RESULTS: In total, 230 responses from professionals across 17 European countries were analyzed from the international survey. And 67% of respondents indicated that MD resonated with their experience of working with MND. Those who considered leaving or changing their position due to the challenges associated with caring for this patient population were also more likely to report resonance with MD (&#x3c7;[2]&#xa0;=&#xa0;7.772, p&#xa0;=&#xa0;0.020). The intensity of MD was associated with reduced professional quality of life (burnout [&#x3b2;&#xa0;=&#xa0;0.106, p&#xa0;<&#xa0;0.05], and secondary traumatic stress [&#x3b2;&#xa0;=&#xa0;2.881, p&#xa0;<&#xa0;0.001]). A total of 24 clinical scenarios were identified as potential contributors to experiences of MD in this population. Across all professional groups, service-/organization-level factors were the most common and distressing barriers to providing effective MND care.<br><br>SIGNIFICANCE OF RESULTS: This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe. MD was associated with reduced professional quality of life and increased intentions to leave or change positions, underscoring its potential implications for workforce retention and sustainability. The findings show that system/organization, patient/condition and family-level causes are the primary drivers of MD in this population. Future research should focus on evaluating the effectiveness of interventions designed to address these key drivers and mitigate the impact of MD among healthcare professionals working with MND.}, }
@article {pmid42454523, year = {2026}, author = {Ahmed, RM and Tse, NY and Bocchetta, M and Dobson-Stone, C and Kwok, JB and Hodges, JR and Irish, M and Rohrer, JR and Piguet, O and Halliday, G}, title = {Changes in body composition in genetic C9orf72 carriers: The role of the hypothalamus and thalamus.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71669}, doi = {10.1002/alz.71669}, pmid = {42454523}, issn = {1552-5279}, support = {//National Health and Medical Research Council/ ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Body Composition/genetics ; Magnetic Resonance Imaging ; Female ; Male ; *Thalamus/diagnostic imaging ; *Frontotemporal Dementia/genetics ; *Hypothalamus/diagnostic imaging ; Heterozygote ; Middle Aged ; Absorptiometry, Photon ; Aged ; }, abstract = {BACKGROUND: Patients with sporadic frontotemporal dementia (FTD) display changes in metabolism and body composition. No studies have examined body composition changes in pre-symptomatic C9orf72 mutation carriers METHODS: Asymptomatic C9orf72 expansion carriers between 2017 and 2022 (n = 28 non-carriers, 16 expansion-positive), underwent dual-energy X-ray absorptiometry (measurement of changes in body composition) and brain magnetic resonance imaging (MRI).<br><br>RESULTS: Changes in body composition were identified in the C9orf72 expansion carrier group compared to non-carrier group (average 11-12 years prior to onset): lower android-to-gynoid ratio (p&#xa0;=&#xa0;0.009), and visceral adipose tissue area (p&#xa0;=&#xa0;0.010). Lower android-to-gynoid ratio and lean mass were associated with lower volumes across the cortex, subcortex, and thalamus.<br><br>CONCLUSIONS: The current study highlights that genetically at-risk C9orf72 patients exhibit altered body composition. These findings align with the growing recognition that changes in genetic frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) extend beyond cognitive/motor symptoms and include early alterations in broader physiological function.}, }
@article {pmid42455190, year = {2026}, author = {Lei, Y and Huang, J and Li, M and Zhang, Y and Ye, Z and He, X and Tang, Z and Wei, J}, title = {Effects of respiratory muscle training on respiratory function in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42455190}, issn = {1432-1459}, support = {No. EWT201947//Department of Science and Technology of Hubei Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/complications/therapy ; *Breathing Exercises/methods ; *Respiratory Muscles/physiopathology ; }, abstract = {BACKGROUND: Respiratory decline is prognostically important in amyotrophic lateral sclerosis (ALS), but the efficacy of respiratory muscle training (RMT) remains uncertain. We synthesized randomized evidence on respiratory and related outcomes.<br><br>METHODS: We searched databases, specialized registers, and trial registries through June 19, 2025, for randomized RMT trials in ALS. Risk of bias was assessed with the Cochrane tool. Random-effects meta-analyses reported standardized mean differences (SMDs) with 95% confidence intervals (CIs), and certainty was rated with GRADE.<br><br>RESULTS: Six studies were included; five concurrently randomized trials contributed quantitative data, whereas Pinto 2013 was retained for qualitative context. RMT improved maximal expiratory pressure (MEP; SMD 0.387, 95% CI 0.192-0.581; P&#x2009;=&#x2009;0.008) and showed small favorable effects on maximal inspiratory pressure (MIP; SMD 0.156, 95% CI 0.089-0.224; P&#x2009;=&#x2009;0.005), sniff nasal inspiratory pressure (SNIP; SMD 0.216, 95% CI 0.039-0.392; P&#x2009;=&#x2009;0.034), peak expiratory flow (PEF; SMD 0.205, 95% CI 0.088-0.323; P&#x2009;=&#x2009;0.017), and ALSFRS-R (SMD 0.214, 95% CI 0.039-0.388; P&#x2009;=&#x2009;0.030). Forced vital capacity showed a borderline favorable trend (SMD 0.129, 95% CI&#x2009;-&#x2009;0.003 to 0.262; P&#x2009;=&#x2009;0.053). Low heterogeneity estimates were imprecise because most endpoints included only three to four small studies. Certainty was moderate for MIP, low for MEP, FVC, and PEF, and very low for SNIP and ALSFRS-R. Exploratory analyses identified no reliable effect modifiers.<br><br>CONCLUSIONS: RMT was associated with small, directionally consistent improvements mainly in pressure- and flow-based outcomes, whereas effects on FVC and longer-term clinical outcomes remain uncertain. RMT may be considered an individualized adjunct to ALS respiratory care, not a disease-modifying therapy. Larger, longer, standardized trials with patient-important endpoints are needed.}, }
@article {pmid42455475, year = {2026}, author = {Maity, D and Gowtham, A and Mishra, Y and Kaundal, RK}, title = {Exosome Biology at the Interface of Neurodegeneration and Therapeutic Innovation.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42455475}, issn = {1559-1182}, mesh = {Humans ; *Exosomes/metabolism ; Animals ; *Neurodegenerative Diseases/therapy/metabolism/pathology ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are defined by progressive neuronal loss, protein misfolding, and chronic neuroinflammation, yet effective disease-modifying therapies remain absent. Exosomes have emerged as key mediators of central nervous system communication and are increasingly central to the biology of neurodegeneration. These nanoscale vesicles transport proteins, lipids, and nucleic acids across cellular and anatomical barriers, influencing synaptic function, immune signaling, and metabolic homeostasis. Under pathological conditions, exosomes facilitate the spread of misfolded proteins such as amyloid-β, p-tau, α-synuclein, and TDP-43, thereby accelerating network-level degeneration. At the same time, their cargo exhibits disease-specific molecular signatures detectable in peripheral biofluids, supporting their development as minimally invasive biomarkers for early diagnosis and longitudinal monitoring. Advances in exosome engineering further underscore their potential as therapeutic delivery vehicles capable of crossing the blood-brain barrier and targeting pathogenic pathways with RNA-based therapeutics, proteins, or gene-editing systems. Together, these findings position exosomes as pivotal contributors to both the mechanistic progression and translational targeting of neurodegenerative diseases.}, }
@article {pmid42456096, year = {2026}, author = {Soliven, REMR and Igarashi, Y and Norii, T and Nakanishi, H and Suga, R and Takiguchi, T and Okada, I and Nakae, R and Yokobori, S}, title = {Performance of termination-of-resuscitation rules in foreign body airway obstruction-related out-of-hospital cardiac arrest: a prospective multicenter registry analysis.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/10903127.2026.2703842}, pmid = {42456096}, issn = {1545-0066}, abstract = {OBJECTIVES: Termination-of-resuscitation (TOR) rules were derived mainly from cardiac-origin out-of-hospital cardiac arrest (OHCA), but their interpretation in foreign body airway obstruction (FBAO)-related OHCA remains uncertain. This condition is a potentially reversible hypoxic arrest in which standard TOR criteria may perform differently. We evaluated the 2025 American Heart Association basic life support (BLS)-TOR and advanced life support (ALS)-TOR criteria in FBAO-related OHCA.<br><br>METHODS: This secondary analysis of the prospective multicenter MOCHI registry included patients with FBAO-related OHCA transported to 25 Japanese hospitals from April 2020 to March 2023. For the primary TOR analysis, we included patients who had not achieved return of spontaneous circulation (ROSC) before emergency medical services (EMS) arrival, because TOR rules are intended for patients who remain in cardiac arrest at the time of EMS assessment. Patients were retrospectively classified according to BLS-TOR and ALS-TOR criteria. Primary measures were the specificity of TOR-positive status for predicting unfavorable neurological outcome, defined as the proportion of patients with favorable neurological outcome (Cerebral Performance Category 1-2) who were classified as TOR-negative, and the proportion of TOR-positive patients who nevertheless achieved favorable neurological outcome.<br><br>RESULTS: Of 248 patients with FBAO-related OHCA (median age, 81.5 years; 83.1% witnessed), 49 (19.8%) survived to 30 days and 9 (3.6%) achieved favorable neurological outcome. The BLS-TOR rule classified 150/229 evaluable patients as TOR-positive; 2 achieved favorable neurological outcome (1.3%; 95% CI, 0.4-4.7%; specificity, 77.8% (95% CI, 45.3-93.7%)), and 20 survived to 30 days (13.3%; 95% CI, 8.8-19.7%). The ALS-TOR rule classified 12/242 patients as TOR-positive; none achieved favorable neurological outcome, but 4 survived to 30 days (33.3%; 95% CI, 13.8-60.9%).<br><br>CONCLUSIONS: In FBAO-related OHCA, BLS-TOR would have classified two patients with favorable neurological outcome as TOR-positive. The ALS-TOR rule was restrictive, but small numbers and 30-day survival among TOR-positive patients preclude firm safety conclusions. Termination-of-resuscitation criteria warrant cautious, etiology-aware interpretation when FBAO is suspected.}, }
@article {pmid42456270, year = {2026}, author = {Martinez, D and Georgiou, GK and Inoue, T and Parrila, R and Protopapas, A}, title = {The genesis of reading fluency in beginning readers.}, journal = {Journal of experimental child psychology}, volume = {272}, number = {}, pages = {106593}, doi = {10.1016/j.jecp.2026.106593}, pmid = {42456270}, issn = {1096-0457}, abstract = {Although reading fluency plays a crucial role in reading comprehension, little is known about its early development. In this study, we first aimed to replicate Hudson et al.'s (2009, 2012) model of reading fluency development among beginning readers and, second, to expand it by incorporating components of articulation rate, sub-lexical orthographic knowledge, and reading accuracy, all of which are theoretically linked to reading fluency development. Three hundred and thirty English-speaking Grade 1 students (51.5% female; Mage = 74.82 months; SD = 3.60) were assessed at three time points (September [T1], January [T2], and May [T3]). At T1, we administered measures of rapid automatized naming (RAN), processing speed, phonemic blending fluency, and letter-sound fluency, at T2, measures of phonogram fluency and sub-lexical orthographic knowledge, and, finally, at T3, word reading fluency, nonword reading fluency, and text reading fluency. Using path analysis, we tested three models: a baseline model based on Hudson et al.'s model and two expanded models that included the additional measures. Our results replicated the core relations proposed by Hudson et al. and further demonstrated significant contributions from sub-lexical orthographic knowledge and reading accuracy to text reading fluency through word reading fluency. These findings are consistent with theoretical frameworks such as Ehri's (2014) orthographic mapping framework and the lexical quality hypothesis (Perfetti, 2007), showing the contributions but also limitations of the components of the reading fluency model.}, }
@article {pmid42456455, year = {2026}, author = {Jung, MJ and Oh, WO}, title = {Strategic simulation-based management of triage clinical reasoning in novice emergency nurses: A randomized block design study.}, journal = {Nurse education in practice}, volume = {95}, number = {}, pages = {104928}, doi = {10.1016/j.nepr.2026.104928}, pmid = {42456455}, issn = {1873-5223}, abstract = {AIM: To develop and evaluate the effectiveness of the Triage Clinical Reasoning Simulation Program (Triage-CRSP).<br><br>BACKGROUND: Globally, emergency department (ED) triage is largely performed by general nurses, with increasing emphasis on clinical reasoning (CR) to assess care urgency; however, novice emergency nurses have limited triage-related competencies.<br><br>DESIGN: This study consisted of two phases: program development and effectiveness evaluation. The first phase involved developing Triage-CRSP. The second phase evaluated its effectiveness using a randomized block design, with the completion of KTAS (Korea Triage Acuracy Scale) training as the blocking factor.<br><br>METHODS: The theoretical framework of this program was based on O'Neill et al.'s clinical decision-making and novice clinical reasoning models. The simulation program was developed using a six-step approach to curriculum development. A total of 60 emergency nurses with less than three years of experience were stratified by completion of KTAS training and randomly allocated to either the intervention or control group; under a single-blind design, the intervention group received the developed Triage-CRSP, while the control group received the existing KTAS simulation.<br><br>RESULTS: The 'Triage-CR pattern' was identified as a structured multi-step clinical reasoning process. The intervention group demonstrated significantly greater improvements in triage clinical reasoning knowledge, recognition of critical clinical cues, emergency nursing performance and overall triage competence compared with the control group.<br><br>CONCLUSIONS: The simulation-based triage clinical reasoning program was effective in enhancing multiple dimensions of triage practice among novice emergency nurses.}, }
@article {pmid42456683, year = {2026}, author = {Bouzigues, A and Grassi, M and Cantoni, V and Premi, E and Bellini, S and Binetti, G and Logroscino, G and Russell, LL and Ferry-Bolder, E and Foster, PH and van Swieten, JC and Jiskoot, LC and Seelaar, H and Sanchez-Valle, R and Laforce, R and Graff, C and Galimberti, D and Vandenberghe, R and de Mendonça, A and Di Fede, G and Santana, I and Gerhard, A and Langheinrich, T and Levin, J and Nacmias, B and Otto, M and Bertoux, M and Lebouvier, T and Ducharme, S and Butler, C and le Ber, I and Bruffaerts, R and Solje, E and Kinnunen, M and Krüger, J and Finger, E and Tartaglia, MC and Masellis, M and Rowe, JB and Synofzik, M and Moreno, F and Ghidoni, R and Migliaccio, R and Rohrer, JD and Borroni, B and , }, title = {Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study.}, journal = {The Lancet. Neurology}, volume = {25}, number = {8}, pages = {731-740}, doi = {10.1016/S1474-4422(26)00197-3}, pmid = {42456683}, issn = {1474-4465}, mesh = {Humans ; *Frontotemporal Dementia/genetics/mortality/diagnosis ; Retrospective Studies ; C9orf72 Protein/genetics ; tau Proteins/genetics ; Female ; Male ; Middle Aged ; Aged ; Cohort Studies ; Progranulins/genetics ; Mutation ; Kaplan-Meier Estimate ; }, abstract = {BACKGROUND: What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation.<br><br>METHODS: In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method.<br><br>FINDINGS: Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6&#xb7;94 years (95% CI 6&#xb7;59-7&#xb7;80) from symptom onset. The median survival estimate for patients with GRN mutations was 6&#xb7;63 years (6&#xb7;08-7&#xb7;98), for patients with a C9orf72 expansion was 7&#xb7;04 years (6&#xb7;45-8&#xb7;77), and for patients with MAPT mutations was 8&#xb7;56 years (7&#xb7;06-13&#xb7;50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level.<br><br>INTERPRETATION: Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed.<br><br>FUNDING: Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.}, }
@article {pmid42457567, year = {2026}, author = {Akiyama, T and Aoki, M}, title = {Cracking a New Era of Therapeutic Development in ALS.}, journal = {The Tohoku journal of experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1620/tjem.2026.J082}, pmid = {42457567}, issn = {1349-3329}, }
@article {pmid42458007, year = {2026}, author = {Chen, W and Jiang, L and Duan, C and Kang, M and Ye, J and Wang, L and Pan, Y and Qu, H and Liao, X and Zhou, X and Li, Y and Gan, Z and Chen, J and Schacht, I and Place, RF and Li, LC and Wang, Y}, title = {Oligonucleotide-siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial.}, journal = {Nature medicine}, volume = {32}, number = {7}, pages = {2619-2628}, pmid = {42458007}, issn = {1546-170X}, support = {No.Z231100004823036//Beijing Municipal Science and Technology Commission/ ; 20230484245//Beijing Nova Program/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease partly caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Here we developed RAG-17, an siRNA-targeting SOD1, using an accessory oligonucleotide conjugate platform for enhanced central nervous system (CNS) delivery. Preclinically, RAG-17 rescued motor neuron degeneration, delayed disease progression, preserved motor function and extended survival in SOD1[G93A] ALS rodents, even with advanced-stage treatment. In cynomolgus monkeys, intrathecal RAG-17 led to dose-dependent, durable reductions in SOD1 mRNA (CNS) and protein (cerebrospinal fluid (CSF)). In a first-in-human trial in patients with SOD1-ALS (n = 6), participants were assigned to two cohorts-cohort 1 (n = 3) received an initial 60 mg dose (seven doses total) and cohort 2 (n = 3) received an initial 90 mg dose (six doses total). The dose was escalated in 30 mg steps to maintenance doses of 150 mg (n = 5) or 180 mg (n = 1). Thus, the primary safety endpoint was met, showing acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) occurred in 33% of participants (two of six). All TEAEs were mild to moderate, including muscle tremor (two patients) and elevated alanine aminotransferase (one patient), all of which resolved. No serious adverse events were reported. Furthermore, no other clinically meaningful changes were observed in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, physical or neurological examinations or ECG. The key secondary endpoints showed CSF SOD1 reductions of 69% (cohort 1, day 240) and 56% (cohort 2, day 210), and plasma neurofilament light chain reductions of 62% (cohort 1) and 52% (cohort 2), from baseline; no patient required invasive mechanical ventilation or died by the end of the study. These results demonstrate a favorable safety outcome, supporting the continued clinical evaluation of RAG-17 for SOD1-ALS. ClinicalTrials.gov registration: NCT05903690 .}, }
@article {pmid42458453, year = {2026}, author = {Bolsinger, MM and Vivek, N and Singh, J and Challa, A and Zhu, A and Rothell, T and Wang, S and Zhang, T and Zhu, S and Robbins, N and Fenwick, L and Ruttenberg, G and Bogoniewski, A and Taha, HB}, title = {Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of translational medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12967-026-08562-8}, pmid = {42458453}, issn = {1479-5876}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome diagnosed clinically using standardized criteria, with neuropathological confirmation of motor neuron loss and TDP-43 aggregates in postmortem brain tissue. Extracellular vesicles (EVs) have emerged as potential minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. Following PRISMA guidelines, we searched PubMed and EMBASE from inception to May 21st, 2026. Forty-one studies met inclusion criteria. Where published summary statistics were available, these were used directly; where they were not, data were reconstructed from figures or obtained from authors and re-analyzed to derive standardized effect sizes and exploratory diagnostic accuracy estimates. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. EV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in EVs from ALS vs. controls (SMD = 1.30) with high heterogeneity (I = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. EV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. This work highlights the need for standardized protocols, transparent data sharing, and independent validation.}, }
@article {pmid42437951, year = {2026}, author = {Williams, KJ}, title = {Anti-inflammatory agents in atherosclerosis-and a need for reform: Extraordinary claims require extraordinary evidence.}, journal = {Journal of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/joim.70128}, pmid = {42437951}, issn = {1365-2796}, support = {//Ruth and Yonatan Ben-Avraham Fund/ ; }, abstract = {Since 1858, human atherosclerotic plaques have been shown to contain immune cells. But are these cells suitable therapeutic targets? Dozens of clinical trials of anti-inflammatory agents other than colchicine have been performed in patients with clinically evident atherosclerosis. None of these trials led any regulatory body in any jurisdiction to allow a cardiovascular indication for any of these agents. This discouraging work provides a background to evaluate new data on colchicine. In 2024-2025, new clinical trials of colchicine in patients with atherosclerosis showed benefit, no benefit, or harm. In 2025-2026, over a dozen meta-analyses so far have appeared, drawing on ∼34 trials, but do not agree with each other. One of these meta-analyses, Xie et al.'s in the Journal of Internal Medicine, provides a compelling graphical display of the pre-specified primary outcomes of six long-term clinical trials as they were published over time. The pattern of early positive trials, then newer negative (null) trials, suggests regression to the truth. Jeon and Cho et al.'s population-wide study in the Journal of Internal Medicine of patients with Type 2 diabetes and gout found no benefit from colchicine over nonsteroidal anti-inflammatory drugs on major adverse cardiovascular events. This information suggests several areas for reform of research on inflammation in atherosclerosis. Fully informed consent should require that clinical trials of anti-inflammatory agents in atherosclerotic arterial disease must disclose to trial participants the failures of this approach in over 50 clinical trials to date, spanning decades. Additionally, the field might reconsider its commitment to the Big Idea that inflammation must be a definitive therapeutic target in atherosclerosis. The track record so far for inflammation inhibition in atherosclerosis is extensive and disappointing-a fact that merits wider discussion. Therapeutic successes from targeting cholesterol-rich, apolipoprotein-B-containing lipoproteins-the proven causative agents of this disease-provide extraordinary evidence. Current data for colchicine and other anti-inflammatory therapies do not.}, }
@article {pmid42438447, year = {2026}, author = {Jewett, G and Chan, E and Jagt, K and Petrillo Ballantyne, J and Wesolosky, J and Perera, T and Karnik, V and Hahn, C and Luk, C and Mobach, T}, title = {An intrathecal therapeutics clinic for administration of tofersen in amyotrophic lateral sclerosis: A Canadian nurse practitioner and neurologist collaborative model.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-10}, doi = {10.1017/cjn.2026.10647}, pmid = {42438447}, issn = {0317-1671}, }
@article {pmid42439979, year = {2026}, author = {Langreen, S and Uecker, M and Juhl, S and Dingemann, J and Kiblawi, R}, title = {Is hypoalbuminemia a risk factor for small bowel anastomotic leaks in infants? A multivariate analysis.}, journal = {Pediatric surgery international}, volume = {42}, number = {1}, pages = {}, pmid = {42439979}, issn = {1437-9813}, mesh = {Humans ; *Hypoalbuminemia/complications ; Retrospective Studies ; *Anastomotic Leak/etiology/epidemiology ; Risk Factors ; Female ; *Intestine, Small/surgery ; Male ; Infant ; Multivariate Analysis ; Anastomosis, Surgical ; Infant, Newborn ; Incidence ; Serum Albumin ; }, abstract = {PURPOSE: Anastomotic leaks (AL) are critical complications following bowel anastomosis with an incidence of up to 10.5% in infants. Previous studies in animal models and adults have suggested a link between postoperative fluid overload and hypoalbuminemia with anastomotic leaks. In infants, the role of hypoalbuminemia on anastomotic integrity after small bowel anastomosis remains unclear.<br><br>METHODS: Retrospective study of infants&#x2009;<&#x2009;1 year, undergoing elective small-bowel anastomosis between 2015 and 2024 (Ethics No.-11362-_BO_K_202). Data on demographics, weight gain, serum albumin levels and use of diuretic medication during the first five postoperative days were collected. Univariate and multivariate analysis were performed to detect risk factors for ALs in infants.<br><br>RESULTS: 13 of 219 patients (5.9%) developed ALs. Demographics were similar comparing patients with and without leaks. In univariate analysis, serum albumin levels were significantly lower (20.3&#xa0;g/l vs. 26,3&#xa0;g/l, p&#x2009;<&#x2009;0.0001) in patients with AL compared to patients without AL and multivariate analysis confirmed a significant association between low serum albumin levels and AL occurrence, CONCLUSION: In infants, small bowel anastomotic leaks are associated with low postoperative serum albumin. Whether hypoalbuminemia should be regarded as an early warning sign of an undiagnosed, developing anastomotic leak or represents a causal risk factor can only be determined with further studies.}, }
@article {pmid42441689, year = {2026}, author = {de Vienne, D and de Vienne, DM}, title = {Age-based risk estimates for C9orf72RE-related diseases: Theoretical developments and added value for genetic counseling.}, journal = {PLoS genetics}, volume = {22}, number = {7}, pages = {e1012230}, doi = {10.1371/journal.pgen.1012230}, pmid = {42441689}, issn = {1553-7404}, abstract = {The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). In genetic counseling, children of mutation carriers are often told that they have a 50% risk of carrying the mutation, but this figure does not take into account the fact that penetrance is age-related, with a unimodal distribution of disease onset around 58 years of age. Using a Bayesian approach, we developed a theory to calculate the probability of carrying the mutation for asymptomatic relatives (children/siblings and grandchildren/niblings) as well as the probability of developing ALS/FDT within a given time frame, based on their age. Using published data on age-related penetrance, we then calculated these probabilities and developed an online simulator that makes it easy to calculate them on a case-by-case basis. The conditional probabilities obtained can be very different from Mendelian values. For example, a 70-year-old asymptomatic child born to a carrier has approximately a 6% risk of being a carrier, which is far from 50%. For grandchildren, taking into account both their age and that of their parents also leads to figures that are much lower than those obtained if only their age were considered. For consultands, the decision to undergo testing is based in part on risk estimates. In this regard, the refined estimates and simulator we propose may prove to be valuable tools for genetic counseling for families affected by ALS/FTD linked to the C9orf72RE mutation. In addition, the formulas used in this study could also be used to calculate risk estimates for other diseases caused by autosomal dominant mutations with age-dependent penetrance.}, }
@article {pmid42441693, year = {2026}, author = {Fisher, K and Ligay, A and Stratford, M and Hirani, R and Ober, DT and Al-Seykal, I and Frishman, WH and Etienne, M}, title = {Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.}, journal = {Cardiology in review}, volume = {}, number = {}, pages = {}, doi = {10.1097/CRD.0000000000001392}, pmid = {42441693}, issn = {1538-4683}, abstract = {Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies.}, }
@article {pmid42442024, year = {2026}, author = {Andreeva, T and Tuparev, N and Taneva, SG}, title = {Multimodal biophysical markers of neurodegeneration: Morphology, mechanics, and thermodynamics.}, journal = {Current opinion in structural biology}, volume = {100}, number = {}, pages = {103330}, doi = {10.1016/j.sbi.2026.103330}, pmid = {42442024}, issn = {1879-033X}, abstract = {The identification of novel noninvasive biomarkers remains a major challenge in the diagnosis of neurodegenerative diseases. Significant efforts focus on fluid biomarkers, including proteins, peptides, and miRNAs, detectable in blood plasma and peripheral blood cells. Here, we review recent findings on blood plasma and peripheral blood cells physical parameters in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis emphasizing atomic force microscopy and calorimetry assay. Alterations in morphology, nanostructure, and stiffness of red blood cells and platelets, together with thermodynamic signatures of red blood cells and plasma, provide sensitive indicators of disease-related changes. These integrated biophysical parameters not only distinguish neurodegeneration from healthy states but also enable discrimination among different neurodegenerative disorders, highlighting their potential as minimally invasive diagnostic markers.}, }
@article {pmid42442469, year = {2026}, author = {Kerner, D and Carey, L and Hughes, J}, title = {Using CoI to Address Emerging Problems in Academic Pharmacy.}, journal = {American journal of pharmaceutical education}, volume = {}, number = {}, pages = {102051}, doi = {10.1016/j.ajpe.2026.102051}, pmid = {42442469}, issn = {1553-6467}, abstract = {Pharmacy education is currently facing numerous challenges, such as concerning first-time pass rates on licensure examinations, decreasing applicant pools, new accreditation standards, progression concerns, and changing financial and regulatory landscapes. These complex and shared issues require collaborative and innovative approaches across the academy. One potential strategy is the development of Communities of Inquiry (CoI), a collaborative model grounded in Garrison et al.'s theoretical framework of social, cognitive, and teaching presence. CoI emphasize active engagement, shared problem-solving, reflective discourse, and collective responsibility for learning and innovation. This manuscript describes the theoretical foundation of the CoI model and its application within pharmacy academia. Existing applications of CoI principles in pharmacy education literature, including faculty development initiatives and webinar-based learning experiences, are also reviewed. Additionally, a real-world example of a successful CoI is presented through the development of a NAPLEX Preparation CoI. Communities of Inquiry represent an effective framework for addressing new challenges in pharmacy education. Faculty, administrators, and professional organizations are encouraged to establish and participate in CoIs. As pharmacy education continues to evolve, the CoI approach presents a promising strategy for fostering innovation, meeting accreditation standards, and enhancing student outcomes through community-driven solutions.}, }
@article {pmid42442754, year = {2026}, author = {Sonnenberg, A and Bakis, LK and Kohen, R}, title = {Gastrointestinal Diagnoses and Symptoms in Medicare Patients With Neuropsychiatric Diseases.}, journal = {Journal of clinical gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MCG.0000000000002422}, pmid = {42442754}, issn = {1539-2031}, abstract = {BACKGROUND AND AIMS: Many patients with psychiatric and neurological diseases suffer from gastrointestinal symptoms. Our study aimed to analyze the frequency of gastrointestinal disease in patients with underlying neuropsychiatric diagnoses.<br><br>METHODS: The study utilized the 2018 Inpatient Standard Analytic File of the Centers for Medicare and Medicaid Services (CMS), which contains the electronic health records of 6,462,321 unique patients. The concurrence of 2 diagnoses was assessed by calculating odds ratios (OR) with their 95% CIs, adjusted for the confounding influences of demographic characteristics (age, sex, ethnicity).<br><br>RESULTS: Dementia was most strongly associated with dysphagia (2.85, 2.83 to 2.88). Schizophrenia was associated with functional GI disorders (1.62, 1.60 to 1.64), constipation (1.67, 1.65 to 1.69), and dyspepsia (2.02, 1.88 to 2.17). Bipolar disorder was most significantly associated with irritable bowel syndrome (1.83, 1.79 to 1.87) and dyspepsia (1.88, 1.77 to 2.01). Depression was significantly associated with all types of upper and lower GI symptoms with significant ORs ranging from 1.33 to 2.14. Amyotrophic lateral sclerosis was strongly associated with complaints of functional GI disorder (2.32, 2.18 to 2.46), constipation (2.37, 2.23 to 2.51), dysphagia (11.77, 11.19 to 12.39), flatulence and bloating (2.75, 2.14 to 3.54). Parkinson disease was mostly associated with constipation (1.79, 1.77 to 1.82) and dysphagia (2.96, 2.92 to 3.00). In Alzheimer disease, only symptoms of dysphagia (2.15, 2.12 to 2.17) stood out. Multiple sclerosis was associated with most GI diagnoses (OR ranging from 1.32 to 2.06), except for abdominal pain and reflux symptoms.<br><br>CONCLUSIONS: Concurrence of gastrointestinal and neuropsychiatric diagnoses is common. Caring for patients with neuropsychiatric diseases, physicians need to be aware of and proactively search for the presence of concurrent gastrointestinal disease.}, }
@article {pmid42442908, year = {2026}, author = {Dongre, S and Soni, N and Bissa, B}, title = {Role of ESCRT pathway and autophagy in neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {187}, number = {}, pages = {1-16}, doi = {10.1016/bs.irn.2026.05.022}, pmid = {42442908}, issn = {2162-5514}, mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Autophagy/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.}, }
@article {pmid42443201, year = {2026}, author = {Wang, Y and Hu, W and Huang, R and Wu, F and Su, H and Zang, J and Huang, X and Liu, Y and Ren, H and Li, J and Zhang, M and Zhang, Y and Wang, G and Hao, Z}, title = {Nuclear condensates formed by truncated mutant NEK1s impede ribosomal RNA biogenesis and drive motor dysfunction.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-75500-z}, pmid = {42443201}, issn = {2041-1723}, support = {32000676//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {NIMA-related kinase 1 (NEK1), a serine/threonine kinase, is a risk variant for amyotrophic lateral sclerosis (ALS). While the full-length NEK1 is involved in diverse cellular processes, such as DNA damage response and microtubule stability, the pathogenic mechanism of NEK1 nonsense mutations in ALS remains elusive. Here, we demonstrate that three truncated forms of NEK1 derived from ALS-related NEK1 nonsense mutations translocate from the cytoplasm to the nucleus, exhibit nucleolar localization, and simultaneously form liquid-like nucleoplasmic foci. In contrast to the diffuse cytoplasmic distribution of wild-type NEK1, these nuclear-localized truncated mutants are prone to undergo liquid-liquid phase separation both in cells and in vitro. Mechanistically, the truncated NEK1s interact with the nucleolar protein FBL, thereby impairing ribosomal RNA biogenesis and translation. Transgenic flies expressing truncated mutant NEK1s display motor dysfunction and reduced survival length, and a knock-in transgenic mouse model expressing ALS-related NEK1 mutant similarly exhibits motor deficits accompanied by ribosomal RNA dysregulation. These findings suggest that ALS-related NEK1 mutants expressing truncated forms of NEK1 cause cell toxicity by interfering with ribosomal RNA metabolism and reveal a gain-of-function mechanism in ALS pathogenesis involving NEK1.}, }
@article {pmid42443387, year = {2026}, author = {Kim, WS and Halliday, GM}, title = {Astrocytic lipid dysregulation as an early driver of neurodegeneration.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42443387}, issn = {1759-4766}, abstract = {Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.}, }
@article {pmid42444959, year = {2026}, author = {Akpa, B}, title = {The role of radiologic assessment in evaluating and monitoring respiratory function in amyotrophic lateral sclerosis (ALS) patients: a narrative review.}, journal = {Journal of thoracic disease}, volume = {18}, number = {6}, pages = {672}, pmid = {42444959}, issn = {2072-1439}, abstract = {BACKGROUND AND OBJECTIVE: Respiratory failure is the primary cause of mortality in amyotrophic lateral sclerosis (ALS), usually caused by progressive neuromuscular respiratory weakness. Standard pulmonary function tests (PFTs) such as maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and both supine and upright forced vital capacity (FVC) are crucial for objective measurements of diaphragmatic weakness but have limitations, including dependence on the patient's performance and the inability to detect early, subclinical diaphragmatic impairment or be used effectively in patients with bulbar symptoms. Radiological assessments, particularly dynamic imaging, have emerged as potential objective tools for evaluating respiratory function. This review comprehensively summarizes findings on the use of diaphragmatic ultrasound (DUS), dynamic chest magnetic resonance imaging (MRI) and deep learning (DL)-based chest computed tomography (CT) for assessing lung function in ALS patients.<br><br>METHODS: Key radiological metrics include diaphragm thickness (DT), thickening fraction during inspiration, real-time diaphragmatic excursion, lung diameter changes and changes in pulmonary length and area. These measures have been compared with conventional PFTs in various studies to validate their use for diagnostic accuracy, particularly in early stages of disease.<br><br>KEY CONTENT AND FINDINGS: DUS is a non-invasive, widely available tool that strongly correlates with PFT measurements, especially FVC, MIP, and sniff nasal inspiratory pressure (SNIP). Dynamic measures, such as excursion and velocity, appear more sensitive to early dysfunction than thickness alone. Chest dynamic MRI has also shown significant correlations with spirometric parameters. Small cohort studies indicate that dynamic chest MRI is a superior, sensitive tool for detecting early respiratory impairment in asymptomatic patients with normal spirometry.<br><br>CONCLUSIONS: Radiological assessments, primarily DUS, DL-based chest CT and dynamic MRI, offer valuable, objective, and non-invasive methods for monitoring respiratory muscle strength in ALS. These techniques serve as complementary tools to traditional PFTs, particularly in selected clinical scenarios such ALS patients with early disease, bulbar involvement and unable to perform PFTs. Further longitudinal research with larger cohorts is needed to standardize protocols and validate their role as early parameters to guide the timely initiation of supportive interventions like non-invasive ventilation (NIV).}, }
@article {pmid42445484, year = {2026}, author = {Ahmed, R and Kayande, A and Patil, R and Shelar, A and Zore, GB}, title = {Context-dependent reprogramming of ALS adhesin expression in Candida albicans: a multi-inducer analysis linking morphogenesis to virulence plasticity.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1848556}, pmid = {42445484}, issn = {1664-302X}, abstract = {Candida albicans employs the ALS (Agglutinin-Like Sequence) gene family to encode cell-surface adhesins that are central to host colonization, tissue invasion, and biofilm formation. Although individual ALS genes have been studied under specific conditions, no systematic, multi-inducer temporal analysis of the entire family has been reported to date. In this study, we present the first comprehensive temporal expression profiling of seven ALS genes (ALS1-ALS5, ALS7, and ALS9) under six host-relevant inducers, temperature (37 °C), neutral pH, serum, glucose, N-acetylglucosamine (NAG), and proline, across four time points (45 min, 90 min, 3 h, 6 h) in both yeast (30 °C) and hyphal (37 °C) growth phases. Morphological analysis confirmed that 37 °C and serum were the most potent hyphal inducers (94.13 ± 0.94% hyphae with serum at 37 °C). Quantitative PCR revealed a temporally stratified regulatory program: early-phase adhesins (ALS1, ALS2) showed transient induction during the first 90 min, whereas invasion-associated genes exhibited sustained late-phase activation. Notably, ALS3 displayed exceptional upregulation under glucose at 37 °C (25.17 ± 1.76-fold at 6 h; p < 0.001) and responded robustly to all inducers except serum. ALS7 reached 9.48-fold induction specifically under thermal stress, while ALS5 was preferentially expressed at 30 °C (6.70-fold under neutral pH), indicating niche-specific functional specialization. In silico promoter analysis linked these expression patterns to binding motifs for key transcription factors (Efg1, Cph1, Rim101, and Nrg1). Phylogenetic analysis revealed functional conservation of ALS2/ALS4 versus evolutionary divergence in ALS6/ALS7/ALS9. STRING-based protein interaction networks confirmed the central involvement of ALS proteins in adhesion and biofilm regulatory circuits. These findings establish a molecular framework for niche-specific virulence, identifying ALS3 as a prime therapeutic target for anti-adhesion strategies in invasive candidiasis. We hypothesize that C. albicans employs a temporally stratified and inducer-specific transcriptional program of the ALS family to adapt its surface architecture to diverse host microenvironments.}, }
@article {pmid42447123, year = {2026}, author = {Wohnrade, C and Thau-Habermann, N and Gschwendtberger, T and Rückoldt, J and Huang, Z and Schreiber, S and Haastert-Talini, K and Petri, S}, title = {Neuromuscular ultrasound as a biomarker in the SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0353397}, pmid = {42447123}, issn = {1932-6203}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/genetics/physiopathology ; Mice ; *Superoxide Dismutase/genetics ; Disease Models, Animal ; Superoxide Dismutase-1 ; Biomarkers/metabolism ; Ultrasonography ; Mice, Transgenic ; Humans ; Sciatic Nerve/diagnostic imaging/pathology ; Muscle, Skeletal/diagnostic imaging/pathology ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {A progression marker that indicates early disease-related changes and treatment responses in the to date incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS) is highly desirable. Translation of therapeutics that have been successful in in vivo models into trials in human patients has proven difficult in recent decades. This failure can be attributed, at least in part, to the lack of specific biomarkers for ALS diagnosis and progression in human ALS patients as well as in in vivo models. Neuromuscular ultrasound is an easily accessible, non-invasive tool to support diagnosis of ALS in humans. Our current study shows for the first time that the disease can be detected in an ALS mouse model with the help of neuromuscular ultrasound. We characterized disease progression regarding changes in the peripheral nerves and muscles of the hind limb in the SOD1G93A mouse model of ALS using different techniques (neuromuscular ultrasound, electroneurography, motor function tests, phenotypic assessments and histology). By neuromuscular ultrasound, we measured the cross-sectional area and diameter of the sciatic nerve and analyzed hind limb muscle texture and thickness. Our results show that motor neuron loss and muscle atrophy - analogous to ALS in humans - can be measured by ultrasound in the SOD1G93A mouse model. Changes in nerve and muscle morphology appear at the same time or even before changes in the established tests (including electroneurographic measurements) performed in vivo in this model. Correlations with histologic features of disease progression make neuromuscular ultrasound a sensitive, non-invasive outcome marker for preclinical studies.}, }
@article {pmid42447443, year = {2026}, author = {Hicks-Courant, K}, title = {Taking Responsibility.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502100}, doi = {10.1200/JCO-25-02100}, pmid = {42447443}, issn = {1527-7755}, abstract = {This essay is about how caring for my complicated father with amyotrophic lateral sclerosis (ALS) unexpectedly shaped how I approached my work as a gynecologic oncologist.}, }
@article {pmid42447895, year = {2026}, author = {Arnolds, KB and Peinemann, F}, title = {[Infant-driven versus Practitioner-driven Feeding of Preterm Infants: A Systematic Review of Randomized Controlled Trials].}, journal = {Zeitschrift fur Geburtshilfe und Neonatologie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2894-2931}, pmid = {42447895}, issn = {1439-1651}, abstract = {HINTERGRUND: Voraussetzung für eine erfolgreiche orale Ernährung ist die Berücksichtigung des individuellen Entwicklungsstands der Frühgeborenen. Pflegekräfte und Eltern sollten geschult sein, wie sie Verhaltenssignale des Säuglings während des Fütterns erkennen und darauf angemessen reagieren können. Diese Art der Ernährung wird in dieser Arbeit als "signalorientiertes und co-reguliertes" Füttern von Frühgeborenen bezeichnet. Im Unterschied zeichnet sich das "herkömmliche" Füttern dadurch aus, dass eine vorab festgelegte Flüssigkeitsmenge zu einer festgelegten Zeit verabreicht wird.<br><br>ZIELSETZUNG: Es soll untersucht werden, ob das "signalorientierte und co-regulierte" F&#xfc;ttern im Vergleich zum "herk&#xf6;mmlichen" F&#xfc;ttern zu einer fr&#xfc;heren vollst&#xe4;ndigen oralen Ern&#xe4;hrung f&#xfc;hren kann.<br><br>METHODEN: Wir haben am 26. Juni 2024 in den elektronischen Datenbanken MEDLINE und Cochrane Library nach thematisch relevanten randomisierten Studien gesucht. Als prim&#xe4;rer Endpunkt wurde die Anzahl der Tage bis zur vollst&#xe4;ndigen oralen Ern&#xe4;hrung und als Effektma&#xdf; die mittlere Differenz gew&#xe4;hlt. Die Metaanalyse wurde unter Verwendung der inversen Varianzmethode und des Random-Effects-Modells durchgef&#xfc;hrt, und wir verwendeten den GRADE-Ansatz (Grading of Recommendations Assessment, Development, and Evaluation) f&#xfc;r die Bewertung der Evidenz.<br><br>ERGEBNISSE: In der Studienauswahl fanden sich 12 randomisierte Studien, die den Einschlusskriterien entsprachen. Von diesen wurden 5 Studien in eine Metaanalyse einbezogen. Die gesch&#xe4;tzte mittlere Differenz favorisierte die Gruppen mit signalorientiertem und co-reguliertem F&#xfc;ttern im Vergleich zu den Gruppen mit herk&#xf6;mmlicher F&#xfc;tterung: -4,93 (95%-Konfidenzintervall -6,60 bis -3,26, p<0,00001, I[2] =66%). Die Qualit&#xe4;t der Evidenz wurde als moderat eingestuft.<br><br>SCHLUSSFOLGERUNGEN: Die Daten der Studienteilnehmer sind mit einem leicht vorteilhaften Effekt f&#xfc;r die signalorientierte und co-regulierte Ern&#xe4;hrung von Fr&#xfc;hgeborenen im Vergleich zur herk&#xf6;mmlichen Ern&#xe4;hrung von Fr&#xfc;hgeborenen vereinbar. Zuk&#xfc;nftige Studien k&#xf6;nnten weitere Daten zu unerw&#xfc;nschten Ereignissen w&#xe4;hrend der Ern&#xe4;hrung und Informationen zur h&#xe4;uslichen Nachsorge erg&#xe4;nzen.}, }
@article {pmid42448407, year = {2026}, author = {Rangappa, N and Upadhyay, R and Lakshman, N and Ramasamy, S and Sevanan, M and Justin, A and Chinnathambi, S}, title = {Small molecular therapeutic targets for neurodegenerative diseases.}, journal = {Advances in protein chemistry and structural biology}, volume = {153}, number = {}, pages = {135-167}, doi = {10.1016/bs.apcsb.2025.10.012}, pmid = {42448407}, issn = {1876-1631}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/genetics ; Animals ; *Molecular Targeted Therapy ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis disease are characterized by progressive neuronal loss, protein aggregation, and synaptic dysfunction. These diseases share common pathological mechanisms including oxidative stress, mitochondrial impairment, chronic neuroinflammation, protein misfolding, and epigenetic dysregulation. Current therapies offer only symptomatic relief and fail to halt disease progression. Recent advances in transcriptomics and proteomics have enabled the identification of shared molecular pathways and druggable targets across multiple neurodegenerative diseases. The key targets, such as BDNF-TrkB, TREM2, SIRT1, PINK1-Parkin, GSK-3β, NLRP3, and mTOR have shown promise in preclinical models, offering opportunities for broad-spectrum therapeutic development. Importantly, blood-brain barrier disruption and neuroinflammatory crosstalk exacerbate disease pathology and hinder drug delivery. Innovative strategies involving nanocarriers, gene therapy, and epigenetic modulation are emerging to overcome these barriers. This review highlights the convergence of disease mechanisms, discusses common molecular signatures and therapeutic vulnerabilities, and explores novel small molecular interventions targeting shared pathways mainly in AD and PD. A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.}, }
@article {pmid42449472, year = {2026}, author = {de Albuquerque Bueno, MG and Dos Santos, DF and Rossor, AM and Laura, M and Horga, A and Frezatti, RSS and de Sousa Ferreira, EV and Blake, JC and Morrow, JM and Reilly, MM and Marques Júnior, W and Tomaselli, PJ}, title = {VRK1-Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement.}, journal = {Journal of the peripheral nervous system : JPNS}, volume = {31}, number = {3}, pages = {e70145}, doi = {10.1111/jns.70145}, pmid = {42449472}, issn = {1529-8027}, support = {MR/S005021/1//International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD)/ ; 25000.160.096/2014-07//Programa Nacional de Apoio &#xe0; Aten&#xe7;&#xe3;o da Sa&#xfa;de da Pessoa com Defici&#xea;ncia (PRONAS)/ ; 465 458/20114-9//National Institute of Sciences and Technology (INCT)-Translational Medicine/ ; 310378/2021-4//Conselho Nacional de Pesquisa (CNPq)/ ; FE-CLI-24-0005-05//Biogen/ ; }, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/genetics/physiopathology/diagnostic imaging/pathology ; *Protein Serine-Threonine Kinases/genetics ; Adult ; Middle Aged ; Magnetic Resonance Imaging ; *Intracellular Signaling Peptides and Proteins/genetics ; *Muscle, Skeletal/physiopathology/diagnostic imaging/pathology ; Nerve Conduction Studies ; Young Adult ; Electromyography ; Neural Conduction/physiology ; Adolescent ; Child ; }, abstract = {INTRODUCTION: Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia.<br><br>OBJECTIVES: This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families.<br><br>METHODS: Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI).<br><br>RESULTS: Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities.<br><br>INTERPRETATIONS: Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.}, }
@article {pmid42450002, year = {2026}, author = {Kim, Y and Jung, YK}, title = {Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, doi = {10.3390/ijms27135730}, pmid = {42450002}, issn = {1422-0067}, support = {RS-2025-00519823//National Research Foundation of Korea/ ; RS-2024-00439842//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy ; Animals ; Proteostasis ; *Protein Aggregation, Pathological/metabolism ; *Protein Aggregates ; Proteotoxic Stress ; Ubiquitin/metabolism ; Proteolysis ; Oxidative Stress ; }, abstract = {Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.}, }
@article {pmid42450899, year = {2026}, author = {Gerymski, R}, title = {Does Life Lose Its Meaning When the Heart Fails? Illness Perception, Perceived Stress and Meaning in Life in Polish Patients with Heart Failure.}, journal = {Healthcare (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, doi = {10.3390/healthcare14131889}, pmid = {42450899}, issn = {2227-9032}, support = {Fifty percent of the study was conducted free of charge by the author (R.G.). The other half of the study was financed by the Institute of Psychology at the Opole University (no grant number provided)//University of Opole/ ; }, abstract = {Background/Objectives: Heart failure (HF) is a highly unpredictable disease that significantly impacts patients' well-being. One of the fundamental problems faced by cardiac patients is trying to answer the question of how to lead a meaningful life. Meaning in life is a crucial predictor of well-being, ill-being and quality of life for everyone, not just cardiac patients. Therefore, identifying its predictors is crucial. Based on Leventhal et al.'s common-sense model of self-regulation of health and illness, and Lipowski's disease perception concept, this study verified the role of illness perception and perceived stress in existential meaning in Polish HF patients. Methods: This manuscript presents the results of a cross-sectional study. Overall, 336 HF patients from Poland were examined. Four questionnaires were used: the Meaning in Life Questionnaire (MLQ), the Multidimensional Existential Meaning Scale (MEMS), the Perceived Stress Scale (PSS-10) and the Disease-Related Appraisals Scale (DRAS). Results: Negative illness perception and positive cognitive assessment of the illness were shown to be significant predictors of meaning in life in patients with HF. Furthermore, this relationship was mediated by perceived stress. Additionally, the positive correlation between negative illness assessment and positive illness perception was found. Conclusions: This study demonstrates that cognitive assessment of the disease can be associated with the existential resources of heart failure patients. It also highlights the importance of working on the existential sphere of cardiac patients and accurately verified theoretical assumptions regarding the relationship between illness perception and meaning in life, providing a basis for future longitudinal studies and meaning-oriented psychological help focused on individuals with HF.}, }
@article {pmid42436372, year = {2026}, author = {Roy, T and Ramesh, M and Nizam, NAA and Tandiono, S and Al-Jamal, KT and Al-Chalabi, A and Iacoangeli, A and Al Khleifat, A}, title = {Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.}, journal = {BMC neuroscience}, volume = {27}, number = {1}, pages = {}, pmid = {42436372}, issn = {1471-2202}, support = {303476//National Institute for Health and Care Research/ ; MRC (MR/Z505705/1)//South London and Maudsley NHS Foundation Trust/ ; LS Association Milton Safenowitz Research Fellowship (RE19765)//NIHR Maudsley Biomedical Research Centre/ ; RE23378//LifeArc/ ; 1819242//Dementia Consortium/ ; 1122462/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/Z505705/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/virology ; *Exosomes/metabolism/virology ; *Endogenous Retroviruses/genetics ; Female ; Male ; Middle Aged ; Aged ; Biomarkers/blood ; Gene Products, env/blood ; }, abstract = {Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.}, }
@article {pmid42436431, year = {2026}, author = {Parks, ASE and Conn, LG and Abrahao, A and Zinman, L and Sale, JEM}, title = {"Straddling two worlds": complexities of spousal caregiving in amyotrophic lateral sclerosis during younger middle age.}, journal = {BMC palliative care}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12904-026-02230-w}, pmid = {42436431}, issn = {1472-684X}, abstract = {BACKGROUND: Family support is central to amyotrophic lateral sclerosis (ALS) care. Spouses often assume the role of primary caregiver, facing daily challenges as their partner's needs progressively increase. Younger ALS caregivers appear to have distinct experiences and needs, yet age- or life-stage variations and processes of caregiving are seldom considered in studies of ALS family caregiver experience.<br><br>METHODS: We undertook a qualitative study, guided by constructivist grounded theory methodology, to explore the dynamics of family caregiving following an ALS diagnosis in a younger middle-aged family member (&#x2264;55 years). Data were coded to identify psychosocial processes, including how family caregivers engage in caregiving.<br><br>RESULTS: In-depth interviews were conducted with ten spousal caregivers between August 2023 and August 2025. Overall, our theoretical understanding of spousal caregiving for younger middle-aged adults with ALS (YMAs) was captured by the core category 'straddling two worlds,' reflecting how caregivers navigated multiple interconnected dichotomies: present and future, familiar and new norms, current and anticipated losses, and the worlds of the living and the dying. To contend with an uncertain future, caregivers anchored themselves in the present as they navigated a shifting sense of normalcy. Middle age expectations and social norms shaped how caregivers engaged in caregiving and experienced losses that were often unending and ambiguous.<br><br>CONCLUSIONS: Caregiving for a spouse with ALS in younger middle age involves temporal, practical, emotional, and existential processes. Caregivers of YMAs may benefit from interventions that help them tolerate uncertainty, stay grounded in the present, maintain normalcy, and grieve losses throughout the caregiving trajectory.}, }
@article {pmid42436563, year = {2026}, author = {Gregory, JM}, title = {Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02376-x}, pmid = {42436563}, issn = {2051-5960}, }
@article {pmid42436608, year = {2026}, author = {Teng, Z and Bushman, BJ}, title = {Rethinking Longitudinal Studies of Media Violence and Aggression: A Rejoinder to Lacko et al.'s (2026) Comment.}, journal = {Aggressive behavior}, volume = {52}, number = {4}, pages = {e70078}, pmid = {42436608}, issn = {1098-2337}, mesh = {*Aggression/psychology ; Humans ; *Violence/psychology ; Longitudinal Studies ; Media Exposure ; }, abstract = {Lacko et al. responded to the concerns raised in our commentary, providing an opportunity to reflect on broader methodological and theoretical issues in longitudinal research on media violence and aggression. This exchange highlights five lessons for future research: (1) longitudinal studies should place greater emphasis on developmental processes; (2) analytical approaches and the interpretation of findings are important; (3) examining the longitudinal effects of media violence on aggression requires high-quality longitudinal data; (4) greater transparency and openness in both data and analytical methods strengthen the field; and (5) future research should place greater emphasis on understanding when, how, and for whom media violence influences aggression. We hope these lessons will contribute to more rigorous longitudinal research and a deeper understanding of the developmental processes linking media violence and aggression.}, }
@article {pmid42436960, year = {2026}, author = {Gromprasit, A and Thremthakanpon, W and Siripocaratana, K and Wanitcharoenporn, W and Jitprapaikulsarn, S and Sutthapakti, B and Laoruengthana, A}, title = {Accuracy and Reliability of Magnetic Resonance Imaging Measurement of Medial Femoral Condyle for Femoral Component Sizing in Oxford Unicompartmental Knee Arthroplasty.}, journal = {Arthroplasty today}, volume = {40}, number = {}, pages = {102088}, pmid = {42436960}, issn = {2352-3441}, abstract = {BACKGROUND: Accurate femoral component sizing is critical for Oxford unicompartmental knee arthroplasty (UKA) because inappropriate sizing can lead to early implant failure. Therefore, we developed a magnetic resonance imaging (MRI) measurement of medial femoral condyle (MRMFC) technique and compare its accuracy to existing methods.<br><br>METHODS: This study included 54 Oxford UKAs. Five sizing methods were assessed: radiographic templating, intraoperative sizing spoon, anthropometric estimation (based on patient height and gender), Yang et al.'s MRI method, and the MRMFC. The MRMFC determined 3 reference points of medial femoral condyle on the sagittal plane of MRI. The primary outcome was an overhang or underhang of femoral component over posterior femoral condyle as determined on postoperative lateral radiographs which &#xb1;2 mm are considered as ideal size.<br><br>RESULTS: The MRMFC method yielded the highest accuracy (50/54; 92.6%; 95% CI: 82.1-97.9), followed by the intraoperative sizing spoon (38/54; 70.4%, 56.4-82.0), Yang et al. MRI method (32/54; 59.3%, 45.0-72.4), anthropometric estimation (30/54; 55.6%, 41.4-69.1), and radiographic templating (25/54; 46.3%, 32.6-60.4). Pairwise testing demonstrated that MRMFC was better than the sizing spoon (P = .008), radiographic templating (P < .001), Yang et al. MRI method (P < .001), and anthropometric estimation (P < .001). The sizing spoon was superior to radiographic templating (P = .029). No significant differences were observed among radiographic templating, Yang et al. MRI method, and anthropometric estimation.<br><br>CONCLUSIONS: The MRMFC demonstrated the highest accuracy and reproducibility in preoperative planning for Oxford UKA. Intraoperative spoon sizing, however, remains a simple and practical method and performed moderately well with significantly better than radiographic templating.}, }
@article {pmid42432003, year = {2026}, author = {Chen, J and Xu, P and Chen, M and Lu, Z and Li, X and Stampas, A and Zong, Y and Zhou, P}, title = {Compound muscle action potential scan dataset in adults with spinal cord injury and healthy controls.}, journal = {Scientific data}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41597-026-07864-2}, pmid = {42432003}, issn = {2052-4463}, support = {ZR2024QH582//Natural Science Foundation of Shandong Province/ ; ZR2024YQ077//Natural Science Foundation of Shandong Province/ ; tsqn202211226//Taishan Scholar of Shandong Province/ ; tstp20221144//Taishan Scholar of Shandong Province/ ; 25S11907200//Science and Technology Commission of Shanghai Municipality/ ; KFKT-2024-KF-013//Chinese Association of Rehabilitation Medicine/ ; 82572355//National Natural Science Foundation of China/ ; }, abstract = {Certain neurological conditions, such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), result in motor unit loss in muscles. The stimulus-evoked compound muscle action potential (CMAP) scan captures comprehensive information on motor unit recruitment that enables rapid and non-invasive assessment of motor unit status. However, few publicly available CMAP scan datasets exist to support research on motor unit number estimation (MUNE). To address this gap, we collected CMAP scan data from the first dorsal interosseous (FDI) muscle of 13 individuals with SCI and 13 healthy participants, and established a dedicated CMAP scan dataset. The dataset includes CMAP waveforms evoked by each nerve stimulus from which CMAP scan curve and typical parameters were extracted for direct use. All SCI participants underwent multiple clinical assessments and exhibited a spectrum of impairment severity from mild to severe, resulting in diverse CMAP features. We anticipate that this dataset will facilitate the development of advanced CMAP scan-based assessment techniques and aid in the investigation of neuromuscular impairment.}, }
@article {pmid42432423, year = {2026}, author = {Sugisawa, R and Sekiguchi, K and Noda, Y and Matoba, S and Suehiro, H and Kozuki, J and Tanaka, T and Chihara, N}, title = {Quantitative Spatiotemporal Analysis of Ultrasound Images of Fasciculations in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70338}, pmid = {42432423}, issn = {1097-4598}, support = {JP256f0137011//Japan Agency for Medical Research and Development/ ; 25K14534//Japan Society for the Promotion of Science/ ; 24K14297//Japan Society for the Promotion of Science/ ; }, abstract = {INTRODUCTION/AIMS: Fasciculations are a hallmark of amyotrophic lateral sclerosis (ALS), yet quantitative description of individual events on muscle ultrasound (MUS) is limited. We characterized the spatiotemporal kinematics of individual fasciculations to determine whether they differ between ALS and other neurogenic conditions.<br><br>METHODS: We retrospectively analyzed biceps brachii MUS recordings from 680 examinations (January 2020-June 2025), identifying 74 ALS and 40 non-ALS neurogenic recordings with fasciculations (167 and 62 segments). After propensity score matching for age and muscle strength, 62 matched pairs were analyzed. The Lucas-Kanade optical flow algorithm, which estimates frame-to-frame displacement vectors from local intensity gradients, was applied at 1-pixel intervals (57,600 points per 240&#x2009;&#xd7;&#x2009;240 region; &#x2248;60&#x2009;&#x3bc;m) to quantify twitch durations, peak displacement velocity, and directional anisotropy as a measure of spatial movement coherence.<br><br>RESULTS: ALS fasciculations showed prolonged total duration (582.8&#x2009;&#xb1;&#x2009;112.8&#x2009;ms vs. 489.2&#x2009;&#xb1;&#x2009;128.7&#x2009;ms, p&#x2009;<&#x2009;0.001), reduced directional anisotropy (0.534&#x2009;&#xb1;&#x2009;0.245 vs. 0.627&#x2009;&#xb1;&#x2009;0.215, p&#x2009;=&#x2009;0.028), and lower peak displacement velocity (6.55&#x2009;&#xb1;&#x2009;6.56 vs. 9.53&#x2009;&#xb1;&#x2009;9.07&#x2009;&#x3bc;m/ms, p&#x2009;=&#x2009;0.039). MANOVA showed significant multivariate differences (Pillai's trace&#x2009;=&#x2009;0.317&#x2009;&#xb1;&#x2009;0.030, p&#x2009;<&#x2009;0.001) with moderate group separation (Mahalanobis distance&#x2009;=&#x2009;1.10&#x2009;&#xb1;&#x2009;0.05).<br><br>DISCUSSION: ALS fasciculations showed spatially heterogeneous and temporally prolonged contraction patterns, suggesting motor units in a transitional state of incomplete reinnervation, distinct from the more stable architecture of chronic neurogenic disorders. This framework may complement existing ultrasound assessment and aid the study of motor unit pathology in ALS.}, }
@article {pmid42432439, year = {2026}, author = {Kavale-Henderson, LA and Buckberry, J and Buckley, H and Cameron, C and King, C and Koon, H and Petchey, P and Snoddy, AME and Loch, C}, title = {"An Injurious and Utterly Unfit Environment": A Case Study Comparing Dental Evidence of Childhood Stress in Nineteenth Century Working-Class Peoples From British and Colonial New Zealand Contexts.}, journal = {American journal of biological anthropology}, volume = {190}, number = {3}, pages = {e70315}, pmid = {42432439}, issn = {2692-7691}, support = {21-UOO-01//Ministry of Business, Innovation and Employment/ ; //University of Otago/ ; }, mesh = {Humans ; New Zealand ; History, 19th Century ; United Kingdom ; Child ; Adult ; Male ; *Tooth/pathology ; *Stress, Psychological/pathology/history ; Female ; Child, Preschool ; Young Adult ; Infant ; Adolescent ; Transients and Migrants/history ; }, abstract = {OBJECTIVES: During the nineteenth century, the health and living conditions of many working-class European peoples declined in association with growing industrialization and urbanization. Emigration to British colonies grew as people sought to escape such hardships. This research presents the first direct comparison of dental markers of stress in a case study of migrants to a British colony (Otago, New Zealand) alongside a contemporaneous assemblage representing an origin population (London, United Kingdom).<br><br>MATERIALS AND METHODS: Dental markers of childhood stress, accentuated lines, were observed in thin-sections of archeological teeth from adults (n&#x2009;=&#x2009;9) and children (n&#x2009;=&#x2009;16) interred in London, United Kingdom (UK), and adult European migrants interred in Otago, New Zealand (NZ) (n&#x2009;=&#x2009;24) using standard histological techniques.<br><br>RESULTS: All individuals interred in London, and 92% (22/24) of those in New Zealand exhibited evidence of accentuated line formation within the first 2.5&#x2009;years of life. There was no difference in median accentuated line occurrence between adults and children interred in the UK. However, NZ adults had a lower median occurrence of accentuated lines over the first 2.5&#x2009;years since birth (5 ALs/individual) than UK adults (13 ALs/individual). Accentuated lines most frequently occurred in infancy for all three groups examined. However, temporal trends in accentuated line occurrence differed between groups in association with age.<br><br>DISCUSSION: These results highlight the impact of childhood stresses on working-class people growing up during the nineteenth century, underlining potential differences in the childhood experiences of hardship in individuals that remained in Britain and those that departed for foreign soils.}, }
@article {pmid42432671, year = {2026}, author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N}, title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.}, journal = {Journal of nanobiotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12951-026-04551-7}, pmid = {42432671}, issn = {1477-3155}, abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.}, }
@article {pmid42432783, year = {2026}, author = {Choi, Y and Lee, S and Ashim, J and Yu, W and Cho, E and Lee, HW and Park, JS and Yoon, JH and Kim, HJ and Cheon, M}, title = {Cross-disease LC-MS/MS plasma proteomics identifies reproducible shared and disease-enriched biomarker signatures in neurodegenerative disorders.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02377-w}, pmid = {42432783}, issn = {2051-5960}, support = {RS-2024-00454715//the National Research Foundation of Korea (NRF) grant funded by the Korean government/ ; RS-2024-00343239//the National Research Foundation of Korea (NRF) grant funded by the Korean government/ ; RS-2023-00230402//the Ministry of Environment of Korea/ ; 26-BR-04-01//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; 26-BR-02-03, 26-BR-02-05, 26-BR-04-01//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; 26-BR-02-03, 26-BR-02-05, 26-BR-04-01, 26-BR-06-02//the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT/ ; RS-2024-00512888//the Korea Technology and Information Promotion Agency for SMEs (TIPA) funded by the Ministry of SMEs and Startups/ ; }, abstract = {Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.}, }
@article {pmid42432887, year = {2026}, author = {Ye, H and Wang, JL and Xu, QH and Gao, YL}, title = {Refining the link between REM sleep behavior disorder and neurodegeneration: Genetic correlation, Mendelian randomization, and colocalization evidence.}, journal = {Medicine}, volume = {105}, number = {28}, pages = {e48922}, doi = {10.1097/MD.0000000000048922}, pmid = {42432887}, issn = {1536-5964}, mesh = {Humans ; *REM Sleep Behavior Disorder/genetics/complications ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; Linkage Disequilibrium ; Genome-Wide Association Study ; Alzheimer Disease/genetics ; Parkinson Disease/genetics ; }, abstract = {Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00-1.03, P = 1.10E-02), Parkinson disease (OR = 1.10, 95% CI: 1.03-1.16, P = 2.96E-03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02-1.17, P = 1.61E-02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03-2.06, P = 3.53E-02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.}, }
@article {pmid42432946, year = {2026}, author = {Jeong, J and Song, KJ and Lee, JC and Shin, SD and Kim, YJ}, title = {A simulation study on optimizing stationary camera locations for physician-directed telemedical supervision of prehospital advanced life support: Single-versus dual-camera setups.}, journal = {Medicine}, volume = {105}, number = {28}, pages = {e49685}, doi = {10.1097/MD.0000000000049685}, pmid = {42432946}, issn = {1536-5964}, support = {2020R1F1A1076561//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Telemedicine ; *Emergency Medical Services/methods ; Prospective Studies ; *Emergency Medical Technicians/education ; Smartphone ; *Video Recording/instrumentation/methods ; }, abstract = {Prehospital telemedicine, particularly real-time video conferencing, offers significant benefits in prehospital and disaster settings by enabling rapid data transmission. Using a smartphone mounted on a tripod as a stationary camera provides stable footage, comprehensive scene evaluation, and reduced technical complexity, thus complementing smart glasses and built-in cameras. However, the optimal camera location for visualizing key procedures remains unexplored. This study aims to compare the optimal stationary camera location and the effectiveness of single-camera versus dual-camera setups in visualizing key procedures for physician-directed telemedical supervision of prehospital advanced life support (ALS). This prospective, non-randomized simulation study involved 9 advanced emergency medical technicians performing ALS procedures in 20 simulations. Each simulation was recorded simultaneously from 4 stationary camera locations: right head, left head, right leg, and left leg. Reviewers evaluated the visibility of 6 key procedures (airway management, breathing support, chest compressions, intravenous access, electrocardiogram rhythm monitoring, and teamwork) using a 1 to 5 scale. Mixed models and generalized linear mixed models were applied to analyze the visibility scores and compare the effect sizes of the different camera setups. The median visibility scores and proportion of optimal visibility (scores of 4-5) varied significantly across the 4 camera locations for most procedures. However, the mixed model and generalized linear model analyses for overall visibility did not reveal significant differences in effect sizes between individual camera locations. Dual-camera setups showed significant improvement over single-camera setups, with an adjusted odds ratio of 4.89 (95% confidence interval: 1.92-12.4) for the right head + left head combination and 3.74 (95% confidence interval: 1.50-9.32) for the right head + left leg combination. Although no single-camera location provided optimal visualization for all procedures, dual-camera setups were more effective than single cameras in capturing field activity. These findings support the use of dual-camera setups to enhance physician-directed telemedical supervision of prehospital ALS, with potential applicability to disaster settings, and may inform the development of future protocols for prehospital telemedicine.}, }
@article {pmid42434198, year = {2026}, author = {Sleutjes, BTHM and Jacobsen, AB and Tankisi, H and Sirin, NG and Oge, AE and Henderson, RD and van Doorn, PA and van den Berg, LH and van Eijk, RPA}, title = {Quantifying motor unit loss prior to functional impairment in muscles affected by amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {538-542}, pmid = {42434198}, issn = {2467-981X}, abstract = {OBJECTIVES: The compound muscle action potential (CMAP) scan is a non-invasive method for deriving motor unit number estimates (MUNE) to track disease progression in muscles affected by amyotrophic lateral sclerosis (ALS). It remains to be established whether and how long motor unit loss precedes functional impairment.<br><br>METHODS: In 56 patients with ALS, we compared the longitudinal trajectories of MUNE derived from thenar CMAP scans, and fine motor function (FMF) using a functional rating scale. Linear and sigmoidal disease trajectories were modelled from which time differences were estimated between these measures to reach their half-maximum scores.<br><br>RESULTS: The normalized linear decline per month was 0.02 (95% CI 0.01 to 0.03) for FMF and 0.03 (95% CI 0.03 to 0.04) for MUNE. Half-maximum of FMF was reached after 26.3&#xa0;months (95% CI 18.9 to 35.1) for the linear model, while MUNE had a shorter time required to reach 50% of its maximum with 13.0&#xa0;months (95% CI 10.3 to 16.4). The head-to-head comparison between FMF and MUNE showed that MUNE values reached 50% of its maximum 13.1&#xa0;months (95% CI 7.0-20.8) earlier. Results were similar for sigmoidal disease trajectories.<br><br>CONCLUSIONS: Simulated disease trajectories of MUNE values derived from CMAP scans in muscles affected by ALS indicated that MUNE may reach 50% of its maximum in approximately 60% of the time compared to functional impairment.<br><br>SIGNIFICANCE: These explorative findings underscore how neurophysiological measures may be of use for early disease monitoring, with relevance for both care and research settings.}, }
@article {pmid42434808, year = {2026}, author = {Baker, B and Emerson, S and Tran, T and Mohapatra, N and Wang, D and Zaw, T and Doshi, A and Lopez, JM and Hassan, D and Kumar, P and Farmer, D and Wang, A}, title = {Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.}, journal = {Nanomedicine (London, England)}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/17435889.2026.2698782}, pmid = {42434808}, issn = {1748-6963}, abstract = {Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.}, }
@article {pmid42435104, year = {2026}, author = {Qiao, Y and Ma, ZS}, title = {Deterministic selection and compositional turnover in Parkinson's disease-associated gut dysbiosis.}, journal = {Antonie van Leeuwenhoek}, volume = {119}, number = {8}, pages = {}, pmid = {42435104}, issn = {1572-9699}, support = {NSFC Grant# 72274192//National Natural Science Foundation of China/ ; }, mesh = {*Parkinson Disease/microbiology/complications ; *Dysbiosis/microbiology ; Humans ; *Gastrointestinal Microbiome ; *Bacteria/classification/genetics/isolation &amp; purification ; }, abstract = {The scientific understanding of links between Parkinson's disease (PD) and gut microbiome dysbiosis has advanced significantly, yet the ecological mechanisms driving these microbial changes remain poorly understood. To address this gap, we postulated that PD-associated gut dysbiosis arises as harmful microbes outcompete beneficial bacteria, and consequently any therapeutic strategies must both suppress opportunistic pathogens and restore protective, fiber-degrading microbes to effectively rebalance the gut microbiome in PD. To evaluate ecological patterns consistent with this hypothesis, we apply Sloan's near-neutral model (SNM), Ning et al.'s stochasticity framework, and ecological network analysis to reanalyze six published gut microbiome datasets (1957 samples total: 804 healthy controls, 1153 PD cases). We first applied SNM to categorize bacterial species as neutral, positively selected, or negatively selected. While the overall proportions of these categories were similar between groups (neutral: ~ 40%, positively selected: ~ 47%, negatively selected: ~ 13%), stochasticity framework analysis revealed significantly stronger deterministic selection in PD microbiomes. Shared species analysis (SSA) resolved this apparent paradox by demonstrating substantial compositional shifts within each species category, indicating that while classification frequencies remained stable, the specific microbes occupying these ecological niches changed significantly in PD. This divergence between SNM category proportions and NSR values highlights a subtle yet critical aspect of community assembly dynamics. Ecological network analysis further revealed that neutral species had fewer antagonistic co-occurrence links, consistent with their ecological equivalence, while negatively selected species maintained higher relative abundances in both groups. Together, these findings indicate that PD-associated gut microbiomes are characterized by stronger deterministic assembly signatures and substantial compositional turnover within near-neutral ecological categories. These patterns are consistent with altered ecological assembly signatures in PD-associated dysbiosis.}, }
@article {pmid42435587, year = {2026}, author = {Domínguez-García, A and Delgado-Uriarte, JC and Cervantes-Arriaga, A}, title = {Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.}, journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion}, volume = {78}, number = {4}, pages = {100050}, doi = {10.1016/j.ric.2026.100050}, pmid = {42435587}, issn = {2564-8896}, abstract = {Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.}, }
@article {pmid42430680, year = {2026}, author = {Chang, CY and Price, TR and Jia, A and Cragg, JJ}, title = {Neurology® Journal Club: Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk.}, journal = {Neurology}, volume = {107}, number = {3}, pages = {e218358}, doi = {10.1212/WNL.0000000000218358}, pmid = {42430680}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/chemically induced ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects/therapeutic use ; Time Factors ; Cohort Studies ; Risk Factors ; Norway/epidemiology ; }, abstract = {This article critically appraises the study by Nakken et al., "Duration of Current Statin Use and Amyotrophic Lateral Sclerosis (ALS) Risk." Previous observational studies and Mendelian randomization studies examining statin use and ALS risk have reported mixed results. Millions of adults receive statins for cardiovascular prevention and may be concerned when neuromuscular symptoms suggestive of ALS appear. Using linked nationwide health survey and prescription data, this Norwegian population-based cohort study applied time-dependent models to evaluate statin use and subsequent ALS risk. Short-term statin use was associated with increased ALS risk, whereas long-term use was associated with lower risk. The authors interpreted this as evidence of reverse causation rather than a causal or protective effect of statins. Key strengths of the study include its large population-based design, the use of a negative control, and time-dependent Cox modeling. However, limitations inherent to observational study designs and potential residual confounding should be considered. In this article, we summarize the findings, highlight key statistical concepts, and discuss the study's major strengths and limitations.}, }
@article {pmid42431020, year = {2026}, author = {Romano, C and Johar, L and Hundhausen, K and Kimonis, V}, title = {Clinical studies in 82 individuals with valosin-containing protein (VCP) associated multisystem proteinopathy and literature review.}, journal = {Neuromuscular disorders : NMD}, volume = {65}, number = {}, pages = {106469}, doi = {10.1016/j.nmd.2026.106469}, pmid = {42431020}, issn = {1873-2364}, abstract = {Valosin-containing protein (VCP) pathogenic variants cause a multisystem proteinopathy characterized by myopathy, Paget disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis (ALS). We evaluated 82 affected individuals, 14 presymptomatic carriers, and 36 unaffected first-degree relatives from 48 families to identify sensitive measures for disease monitoring. Mean age of onset was ∼42 years for myopathy, Paget disease, or ALS, and 53 years for dementia. Functional assessments included the Inclusion Body Myositis Functional Rating Scale (IBMFRS), ALSFRS-R, Fatigue Severity Scale (FSS), and six-minute walk test (6MWT). Affected individuals demonstrated progressive functional decline, with IBMFRS decreasing 1.9% annually, FSS increasing 4.4%, and 6MWT decreasing 6% annually when modeled against disease duration. Women declined more rapidly on IBMFRS but showed slower ambulatory and fatigue progression. Potential genotype-specific effects were observed, with earlier onset and shorter survival in p.Arg155Cys compared to later onset in p.Arg155His. Strong correlations among IBMFRS, FSS, and 6MWT indicate these as accessible endpoints for longitudinal monitoring and clinical trials. Rapid decline with ALS and dementia necessitates multidisciplinary support, while longer survival after myopathy or Paget onset offers a window for preventive and supportive interventions.}, }
@article {pmid42431556, year = {2026}, author = {Singh, N and Gomes, J}, title = {Fisetin prevents deterioration of cellular functions in amyotrophic lateral sclerosis variants G262R and P438L of SQSTM1 in SH-SY5Y cells.}, journal = {Toxicology and applied pharmacology}, volume = {}, number = {}, pages = {117943}, doi = {10.1016/j.taap.2026.117943}, pmid = {42431556}, issn = {1096-0333}, abstract = {Oxidative stress is widely accepted as one of the important factors contributing to neurodegeneration, leading to fatal neurodegenerative diseases (NDD) such as Amyotrophic Lateral Sclerosis. Since flavonoids possess antioxidant properties, we investigated whether Fisetin (FS) and Quercetin (QR) protected cells from oxidative stress arising from pathogenic mutations G262R (G > A) and P438L (C > T) of SQSTM1 found in Indian ALS patients. SQSTM1 codes for p62 protein and is involved in multiple signaling pathways through its various domains. We studied changes in cell viability and cellular functions using immunoblotting, confocal microscopy, immunoprecipitation and FACS analysis in the presence and absence of FS and QR. Supplementation with FS and QR in SH-SY5Y cells expressing SQS-wild type and mutants increased cell viability and decreased ROS formation. Also, Nrf2 protein levels increased to offset oxidative stress response. In addition, we studied the effect of FS on the nuclear-cytoplasmic distribution of TDP-43 protein, which serves as a hallmark for ALS. FS corrected the nuclear-cytoplasm translocation of TDP-43 protein and decreased late apoptosis in mutants. Our study illustrates that both FS and QR shield cells from oxidative stress, and that FS imparted better protection against the pathogenic effect of SQSTM1 mutants in SH-SY5Y neuronal cells.}, }
@article {pmid42426573, year = {2026}, author = {Zhan, Y and Luo, Y and Lu, H and Lu, Y and Zhao, S and Pan, L and Liu, M}, title = {TSR and peroxidase genes confer resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl in Alopecurus aequalis.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71103}, pmid = {42426573}, issn = {1526-4998}, support = {//Modern Agricultural Industrial Technology System of Hunan Province (grants numbers 2022-31)/ ; //the National Key R&amp;D Program of China (No. 2023YFD1401100)/ ; //China Agriculture Research System (CARS-01)/ ; }, abstract = {BACKGROUND: Alopecurus aequalis poses severe threat to global wheat production due to evolving resistance to acetyl-CoA carboxylase (ACCase)- and acetolactate synthase (ALS)-inhibiting herbicides. In this study, the resistance mechanisms of a field-evolved resistant population (R) were systematically investigated using dose-response bioassays, target-site gene sequencing, inhibitor assays, antioxidant enzyme activity measurements, RNA sequencing (RNA-seq), quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and yeast functional validation.<br><br>RESULTS: Dose-response results revealed that the R population exhibited moderate resistance to fenoxaprop-P-ethyl (RI&#x2009;=&#x2009;9.58) and low-level resistance to mesosulfuron-methyl (RI&#x2009;=&#x2009;3.07). Cross-resistance testing indicated that the R population was resistant to other ACCase-inhibiting herbicides (haloxyfop-P-methyl, clodinafop-propargyl, clethodim, and pinoxaden) and the ALS-inhibiting herbicide rimsulfuron. Target-site sequence analysis identified two mutations in the R population: Ile-1781-Leu (ACCase) and Pro-197-Ser (ALS1). Pretreatment with the cytochrome P450 and GST inhibitor did not reverse resistance to fenoxaprop-P-ethyl or mesosulfuron-methyl. Compared to the susceptible (S) population, the R population had significantly lower H2O2 content and higher activities of peroxidase (POD) and catalase (CAT), indicating an enhanced reactive oxygen species (ROS) scavenging capacity. RNA-seq and qRT-PCR analyses identified three POD-annotated contigs (PODSPC4, POD12-1, POD12-2) that were upregulated in the R population. Yeast heterologous expression validated that AaPOD12-1 and AaPOD12-2 significantly increased yeast resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl.<br><br>CONCLUSION: These results demonstrate that resistance in the R population is co-mediated by target-site mutations and non-target-site resistance involving enhanced ROS scavenging, with AaPOD12-1 and AaPOD12-2 representing the first functionally characterized antioxidant enzyme genes associated with herbicide resistance in A. aequalis. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid42426879, year = {2026}, author = {Marynen, F and van Bijsterveld, MG and Van Loon, K and Kempenaers, S and Buelens, S and Roosen, J and Fieuws, S and van der Horst, ICC and van Mook, WN and Dewolf, P}, title = {Evaluating the impact of implementing an ECPR protocol on prehospital resuscitation quality: a randomized controlled simulation study.}, journal = {Advances in simulation (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s41077-026-00458-3}, pmid = {42426879}, issn = {2059-0628}, support = {R-aiders Grant (2023)//Belgian Society of Emergency and Disaster Medicine (BESEDIM)/ ; }, abstract = {BACKGROUND: Extracorporeal Cardiopulmonary Resuscitation (ECPR) is increasingly considered for prehospital cardiac arrest management; however, its impact on resuscitation performance remains unclear. This study aimed to determine whether integrating an ECPR protocol into prehospital cardiac arrest care affects the quality of resuscitation compared to application of the standard Advanced Life Support (ALS) protocol.<br><br>METHODS: A randomized controlled simulation study was conducted at the University Hospital Leuven in Belgium using standardized pre-hospital cardiac arrest scenarios. Participants, who were physicians functioning as part of resuscitation teams, were randomized into intervention and control groups. The study included a pre- and post-intervention phase. In the pre-phase, all participants followed the standard ALS protocol. Only the intervention group received training in the additional ECPR protocol between the phases. In the post-phase, the intervention group combined this protocol with standard ALS, whereas the control group continued with ALS alone. The primary outcome was overall resuscitation quality, which was assessed using the modified Peltonen score. The secondary outcomes included occurrence and timing of critical resuscitation actions.<br><br>RESULTS: A total of 40 physicians participated in the study. Resuscitation quality was not affected by the ECPR protocol; the modified Peltonen score showed no difference in the pre-post change between the groups (0.02, CI: -0.15; 0.19, p&#x2009;=&#x2009;0.83). However, secondary outcomes showed delayed actions related to the identification and management of the presumed cause of cardiac arrest in the intervention group, such as significantly later verbal suggestions to initiate causal treatments including PCI or thrombolysis.<br><br>CONCLUSIONS: In this simulation study, combining a prehospital ECPR protocol with standard ALS resulted in resuscitation performance comparable to ALS alone. Nonetheless, the protocol was associated with delayed diagnostic and therapeutic actions concerning the reversible causes of cardiac arrest, highlighting the need for ECPR training that integrates diagnostic and therapeutic vigilance with procedural execution.<br><br>TRIAL REGISTRATION: Clinical Trial Center UZ Leuven, S65846 - September 2021.}, }
@article {pmid42427030, year = {2026}, author = {Tan, X and Sun, S and Yan, Y and Li, W and Ding, N and Xu, L and He, L and Zhang, Y and Chen, W and Zheng, Y and Li, L}, title = {C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2026.07.002}, pmid = {42427030}, issn = {1525-0024}, abstract = {Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to ALS pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels, and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.}, }
@article {pmid42427320, year = {2026}, author = {Uchino, A and Kanemaru, K and Tarutani, A and Hasegawa, M and Naruse, H and Ishiura, H and Murayama, S and Saito, Y}, title = {Frontotemporal Lobar Degeneration-TDP Type C With Striatal Glial Cytoplasmic Inclusions and Motor Neuron Degeneration.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70090}, pmid = {42427320}, issn = {1365-2990}, support = {JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP25wm0625126//Japan Agency for Medical Research and Development/ ; JP24dk0207074h0001//Japan Agency for Medical Research and Development/ ; JP22H04923//MEXT/JSPS KAKENHI/ ; JPMH23FC1008//Research on rare and intractable diseases Program/ ; }, mesh = {Humans ; *Inclusion Bodies/pathology ; *Frontotemporal Lobar Degeneration/pathology ; *Neuroglia/pathology ; *DNA-Binding Proteins/metabolism ; *Motor Neurons/pathology ; *Corpus Striatum/pathology ; Male ; *Motor Neuron Disease/pathology ; Female ; Aged ; }, abstract = {We report an autopsy case of frontotemporal lobar degeneration (FTLD)-TDP type C with severe striatal involvement and annexin A11- and phosphorylated TDP-43-positive glial cytoplasmic inclusions. The patient developed progressive asymmetric rigidity accompanied by marked striatal atrophy and showed both upper and lower motor neuron involvement. These findings expand the clinicopathological spectrum of FTLD-TDP type C and may support the concept of an annexin A11-associated pathogenic continuum linking FTLD and amyotrophic lateral sclerosis.}, }
@article {pmid42427517, year = {2026}, author = {Chen, Y and Zhang, S}, title = {AART enables fast and accurate cross-platform proteomic translation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.29.735313}, pmid = {42427517}, issn = {2692-8205}, abstract = {Plasma proteomic profiling has been widely used for biomarker discovery, disease prediction and diagnosis, and patient stratification. However, technical differences across assay platforms often result in low-to-moderate agreement, limiting study reproducibility, data integration, and model transferability. Here we present AART, a cross-platform proteomic translation framework that integrates matched-protein ridge regression with proteome-wide residual learning. We benchmarked AART spanning three independent cohorts profiled using three major platforms, including Olink, SomaScan, and mass spectrometry. Across all six translation directions, AART achieved the best performance compared with baseline methods for both overlapping and non-overlapping protein translations, with a relative improvement of 92.0% on average over direct mapping and by up to 31.6% over cpiVAE, the strongest baseline. Proteins that were accurately translated and improved by AART were enriched for extracellular, vesicle-associated, and tissue-restricted plasma biology. In downstream applications, AART improved the reproducibility of proteomic association analyses relative to direct cross-platform comparison by 75.5% for type 2 diabetes and 370.6% for Alzheimer's disease. AART-enabled cohort integration enhanced diagnostic accuracy for amyotrophic lateral sclerosis by 92.6% compared with non-integration analysis. AART was overall one to three orders of magnitude faster than cpiVAE, facilitating biobank-scale applications. Together, these results establish AART as a fast, accurate, and scalable framework for cross-platform proteomic translation, enabling more reproducible, transferable, and integrated proteomic research.}, }
@article {pmid42427576, year = {2026}, author = {Wang, H and Sun, S and Mathé, EA and Zhu, Q}, title = {RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.29.735296}, pmid = {42427576}, issn = {2692-8205}, abstract = {Rare diseases (RD) impact over 30 million individuals in the United States, yet fewer than 5% of the identified conditions have FDA-approved treatments. Progress in RD research is hindered by small patient cohorts, biological heterogeneity, and the fragmented, inconsistently annotated publicly available omics data, which limits integrative analysis and translational discovery. Here, we present RD-OMICS, a data inventory with integrated and structured RD omics data from Gene Expression Omnibus (GEO), in the form of a knowledge graph. We developed a metadata harmonization pipeline that combines rule-based mapping and large language model (LLM)-assisted semantic categorization. The graph-based data model was defined to integrate different types of data including disease conditions, experiments, samples, platforms, projects, and publications into a centralized inventory graph. In this preliminary study, 11,049 GEO series for 126 rare diseases were processed and integrated into RD-OMICS, which includes 375,930 individual biospecimen samples, 1,578 sequencing and array platforms, 10,938 biological projects. Case studies demonstrate the use of RD-OMICS in supporting rare disease research, omics cohort construction, and transcriptome-based drug repurposing for amyotrophic lateral sclerosis (ALS). RD-OMICS provides a scalable foundation for transforming fragmented omics data into a structured, harmonized and interoperable resource, facilitating therapeutic development and other translational discoveries in rare diseases.}, }
@article {pmid42427672, year = {2026}, author = {Dixon, E and Azimian, F and Joby Chacko, A and Tatum, R and Boykin, C and Chen, YH and Lu, Q}, title = {Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.01.24.701325}, pmid = {42427672}, issn = {2692-8205}, abstract = {The hexanucleotide repeat expansion in C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). The C9orf72 protein forms a complex with SMCR8 and WDR41 (CSW), which functions as a GTPase-activating protein (GAP) regulating ARF1 and RAB small GTPases. While these findings implicated ARF1-GAP dysregulation in ALS/FTD and supported ARF1 suppression as potential intervention, small molecules that modulate ARF1-CSW interactions are lacking. In this study, we demonstrated upregulation of tyrosine-phosphorylated (Tyr-782) ASAP1 (also known as AMAP1, DDEF1, or Centaurin β4), an ARF-GAP, in human motor cortex of both sporadic ALS and ALS with C9orf72 mutations. Ectopic C9orf72 expression partially mimicked the effects of a known ARF1 inhibitor brefeldin A to disperse Golgi apparatus. Computer-aided rational drug design with high-throughput in-silico screening identified MCULE-5095997944 (Named as SCC944) as a ARF1-CSW modulator. SCC944 binds directly to ARF1 and reduced GTP-bound ARF1 levels upon ARF1 activation. SCC944 demonstrated brefeldin A-like ARF1-dependent alteration of organelle organization including Golgi, microtubules, and mitochondria, but also a protein trafficking pattern that is distinct from brefeldin A mechanism. These studies identified the first small molecule targeting ARF1-CSW interaction and further support ARF1 modulation as a potential therapeutic approach for ALS/FTD.}, }
@article {pmid42428129, year = {2026}, author = {Raemaekers, M and Geukes, SH and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Schippers, A and Crone, NE and Leinders, S and Berezutskaya, J and Ramsey, NF and Vansteensel, MJ}, title = {Association between motor cortex grey matter loss and inability to control an ECoG-based implanted Brain-Computer Interface in ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.23.26355654}, pmid = {42428129}, abstract = {BACKGROUND: The field of implantable Brain-Computer Interfaces (iBCIs) is rapidly advancing, with individuals with amyotrophic lateral sclerosis (ALS) as key beneficiaries. However, ALS-related cortical degeneration may impair iBCI effectiveness. This study investigated whether structural magnetic resonance imaging (MRI) and functional MRI (fMRI) metrics are associated with the quality of electrocorticography (ECoG) signals critical for iBCI use.<br><br>METHODS: Six late-stage ALS participants and 76 controls underwent T1-weighted structural MRI and task-based fMRI during right-hand movement or attempts thereof. ECoG data of ALS participants was benchmarked using ECoG data acquired in epilepsy patients. Grey matter thickness in the sensorimotor cortex and fMRI activation in the motor-hand area were measured.<br><br>RESULTS: Four ALS participants showed >0.4 mm thinning in the precentral gyrus, while the postcentral gyrus was spared. ECoG signal quality was significantly associated with precentral grey matter thickness, but not with fMRI activity.<br><br>CONCLUSIONS: These findings suggest that presurgical assessment of precentral grey matter thickness could potentially prove useful for iBCI candidate selection in advanced ALS.<br><br>PLAIN LANGUAGE SUMMARY: People with amyotrophic lateral sclerosis (ALS) can lose the ability to move and speak, but their thinking often remains intact. Implantable brain-computer interfaces (iBCIs) can help by translating brain signals into commands for communication devices. However, ALS damages the motor cortex, which may reduce the quality of these signals. In this study, we examined brain scans and electrical recordings from six people with advanced ALS. We found that thinning of the motor cortex was linked to weaker brain signals needed for iBCI control, while functional MRI activity was less predictive. This suggests that measuring motor cortex thickness before surgery could help identify who will benefit most from an iBCI, improving treatment decisions and future clinical trials.<br><br>TWO SENTENCE SUMMARY: We examine presurgical MRI/fMRI and ECoG recordings from people with advanced ALS receiving implanted brain-computer interfaces. Motor cortex thinning is associated with poorer ECoG signal quality, suggesting cortical thickness may help identify candidates likely to benefit.}, }
@article {pmid42428455, year = {2026}, author = {Cheng, P and Liu, S and Shen, Q}, title = {Laparoscopic temporary uterine artery occlusion combined with en bloc lesion resection for type III cesarean scar pregnancy: surgical technique.}, journal = {Gynecology and pelvic medicine}, volume = {9}, number = {}, pages = {16}, pmid = {42428455}, issn = {2617-4499}, abstract = {This article presents a refined laparoscopic surgical technique for the management of type IIIb cesarean scar pregnancy (CSP), as classified by Ban et al.'s 2023 criteria [residual myometrial thickness <3 mm, maximum sac diameter (MSD) ≥3 cm, bladder protrusion], in a 35-year-old female with vaginal bleeding and a history of two cesarean sections. The core protocol integrates temporary bilateral uterine artery occlusion (simple ligation of the main trunk with No. 1 absorbable Vicryl suture at 2 cm from the uterine wall) immediately before resection, adhesiolysis, en bloc excision of the ectopic mass with a 0.3 cm safe margin, and multilayer anatomical uterine repair. This technique addresses the key clinical challenge of massive intraoperative bleeding in highly vascular type IIIb CSP, with innovations in precise timing of occlusion and reversible minimally invasive ligation. Perioperative outcomes demonstrated excellent hemostasis (total blood loss 100 mL), complete lesion removal confirmed by frozen section, and intact uterine anatomy post-surgery. The study emphasizes the technique's value in hemorrhage control, anatomical restoration, and fertility preservation for patients with large type IIIb CSP (66 mm in this case). We provide a detailed step-by-step surgical guide, clarify patient selection criteria and contraindications, and discuss the technique's advantages, limitations, and potential to revise the standard of care for type III CSP. Postoperative 18-month follow-up showed successful natural conception and uncomplicated second-trimester pregnancy, validating its long-term fertility benefits.}, }
@article {pmid42428795, year = {2026}, author = {Craig, EJ and Ryan, VH}, title = {Dysregulated neuronal mRNA transport and translation in FTD/ALS.}, journal = {NPJ dementia}, volume = {2}, number = {1}, pages = {56}, pmid = {42428795}, issn = {3005-1940}, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, co-occurring neurodegenerative disorders. Dysregulation of mRNA metabolism, transport, and local translation is a significant mechanism contributing to FTD/ALS. Here, we review the processes of neuronal RNA transport and translation, their disruption in FTD/ALS, and mechanistic interplay between the two. Finally, we discuss current progress targeting transport and translation defects and identify potential future directions for therapeutic development.}, }
@article {pmid42428879, year = {2026}, author = {Hermosillo-Abundis, C and Arias-Carrion, O and Contreras-Ibáñez, C and Mendez-Rojas, MA}, title = {From Air to Brain: Environmental Nanoparticles as Modifiable Risk Factors for Neurodevelopmental, Neurodegenerative, and Mental Disorders.}, journal = {ACS omega}, volume = {11}, number = {26}, pages = {38267-38287}, pmid = {42428879}, issn = {2470-1343}, abstract = {Ultrafine particles (≤100 nm) and other environmental nanoparticles have emerged as biologically active pollutants that can cross biological barriers, including the blood-brain barrier and the placenta. Growing evidence implicates ultrafine particles in a wide range of neuropsychiatric conditions, yet their effects remain poorly integrated into clinical and public health frameworks. In this review, we distinguish between size-defined ultrafine particles (UFPs, ≤100 nm), composition-defined environmental nanoparticles originating from combustion and secondary formation processes, and engineered nanomaterials (ENPs), which differ in physicochemical properties, exposure scenarios, and regulatory status. This narrative systematic review synthesizes findings from human and experimental studies on the neuropsychiatric and neurodevelopmental effects of environmental nanopollutants. A structured search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to November 2025, following explicit inclusion and exclusion criteria. Eligible studies included peer-reviewed human and animal research assessing mental health or neurological outcomes of nanopollutant exposure. Epidemiological studies(?)primarily involving traffic-related air pollution and mixed combustion-derived ultrafine particle exposures(?)suggest associations with increased risk of cognitive impairment, autism spectrum disorder, depression, schizophrenia, and neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Prenatal and early life exposures were linked to cortical thinning, altered neurodevelopmental trajectories, and early proteinopathies. Underlying mechanisms include neuroinflammation, oxidative stress, and protein aggregation. Despite methodological heterogeneity, the evidence supports the urgent need for regulation and prevention. Environmental nanopollutants constitute an under-recognized, modifiable risk factor for neuropsychiatric and neurodegenerative conditions. A paradigm shift is needed to incorporate environmental exposure history into mental health research, risk assessment, and prevention strategies. Regulatory action targeting nanopollutant emission and exposure, particularly in vulnerable populations, is critical to mitigating long-term neurological consequences.}, }
@article {pmid42429266, year = {2026}, author = {Macpherson, CE and Muccini, J and Blacutt, ME and Bjalme-Evans, M and Lough, ME and Quinn, L}, title = {Gait speed and future ambulatory status in amyotrophic lateral sclerosis: a retrospective observational study with implications for power wheelchair referral.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/09593985.2026.2700400}, pmid = {42429266}, issn = {1532-5040}, abstract = {BACKGROUND OR INTRODUCTION: Amyotrophic lateral sclerosis (ALS) causes rapid and progressive loss of ambulation resulting in immobility. A power wheelchair (PWC) increases safety, independence, and quality of life, however, the PWC referral process is lengthy and complex. When the PWC is delayed, immobility complications can occur. One barrier is the lack of a universal predictive "gait speed threshold" to help clinicians determine when to initiate the PWC referral process.<br><br>OBJECTIVE OR PURPOSE: Identify a clinically relevant gait speed threshold associated with future loss of ambulation in people with ALS.<br><br>METHODS: This was a retrospective chart review of a single multidisciplinary ALS Center of Excellence from July 1, 2016 - July 1, 2019 (36-months). Participants were included in this study if they were adults (age&#x2009;>18&#x2009;years) with clinically definite ALS who were ambulatory at baseline. The primary outcome was gait speed on the 10-meter walk test. Secondary outcomes included the ALS Functional Rating Scale-Revised, forced vital capacity, falls, and ambulation status.<br><br>RESULTS: Of N&#x2009;=&#x2009;180 people with ALS identified during the study period, n&#x2009;=&#x2009;72&#x2009;met inclusion for analysis with a mean age 66.1&#x2009;&#xb1;&#x2009;11.9&#x2009;years, 64% male, 76% with an ALS phenotype of spinal onset, and 24% bulbar onset. A gait speed threshold of 0.79&#x2009;m/s maximized the combined sensitivity and specificity for classifying ambulatory status at the subsequent 6-month visit. Faster gait speeds (>1.2-1.4&#x2009;m/s) were associated with greater odds of remaining ambulatory at 6-months based on Bayesian logistic regression.<br><br>CONCLUSION: A gait speed threshold of 0.79&#x2009;m/s was associated with increased likelihood of subsequent loss of ambulation, though modest predictive accuracy limits its use as a stand-alone indicator. Gait speed may serve as one component of clinical decision-making regarding PWC planning and referral in people with ALS. Larger multicenter studies are needed to confirm and generalize results across ALS phenotypes.}, }
@article {pmid42429841, year = {2026}, author = {Li, D and Ye, Q}, title = {Re: Effects of resistance training with/without photobiomodulation on muscle and respiratory function in difficult-to-control asthma: a randomized trial.}, journal = {Lasers in medical science}, volume = {41}, number = {1}, pages = {}, pmid = {42429841}, issn = {1435-604X}, support = {2022KY1159, 2025KY1423, 2025KY1417 and 2025HY1019//Zhejiang Provincial Medical and Health Plan/ ; 2022020405//Ningbo High-Level Medical and Health Team Major Tackling Project and the Talent Development Program/ ; 2026-A36//Ningbo Municipal Key Modern Medical Discipline Development Project/ ; No.2024Z222//Key Technology Breakthrough Program of 'Ningbo Sci-Tech Innovation Yongjiang 2035'/ ; Yongweifa 2024-102-77//Ningbo Municipal Specialized Training Program for Young Technical Backbone Talents in Health/ ; }, mesh = {Humans ; *Resistance Training ; *Asthma/therapy/physiopathology/radiotherapy ; *Low-Level Light Therapy/methods ; Muscle Strength/radiation effects ; }, abstract = {This letter discusses Costa et al.'s randomized trial of resistance training (RT) combined with photobiomodulation therapy (PBMT) for difficult-to-control asthma (DTCA). The triple-blind study shows RT+PBMT safely improves peripheral muscle strength and exercise capacity better than RT alone. PBMT has dose-dependent effects, but optimal parameters for chronic respiratory patients remain unclear. Some clinicians have proposed standalone PBMT for DTCA patients unable to complete resistance training, but this approach has not been validated in clinical trials. The absence of a PBMT-only group limits assessment for patients unable to tolerate RT. The intervention did not improve lung function or asthma control, acting only peripherally. RT+PBMT is a useful adjuvant therapy; future studies should optimize PBMT dosing, test standalone PBMT, and examine long-term outcomes, and compare different PBMT wavelengths, energy settings and irradiation sites to refine real-world treatment protocols.}, }
@article {pmid42429860, year = {2026}, author = {D'Andrea, T and Benedetti, MC and Mochi, M and De Turris, V and Rosa, A and Fucile, S}, title = {Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.}, journal = {Cellular and molecular neurobiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10571-026-01773-z}, pmid = {42429860}, issn = {1573-6830}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by motoneurons degeneration. Functional studies have linked ALS to hyperexcitability and excitotoxicity, but the cause of the disease is unknown, though familial ALS cases are linked to pathogenic variants in several genes, including SOD1, TARDBP and FUS. Here we focused on the effect of the severe FUS (P525L) mutation on the functional properties of human spinal neurons derived from induced pluripotent stem cells (hiPSCs). This mutation delayed functional maturation, as revealed by the observation that mutated neurons showed alterations of membrane potential, reduced spontaneous synaptic activity, and altered action potentials at early differentiation stages. FUS (P525L) mutation was associated with a significant alteration of inhibitory signalling transmission: mutated neurons showed a significantly lower current response to GABA and glycine compared to control isogenic WT neurons of the same age. Also, glutamatergic currents exhibited a different temporal evolution in control and mutated neurons, but at a lower extent in comparison to inhibitory neurotransmitters. The decrease in the glycine-evoked currents was confirmed by the reduction of the expression of the α1 subunit of glycine receptor, measured by immunofluorescence assay. Similar functional alterations were measured in spinal neurons differentiated form a second hiPSC line, confirming the causative role of the FUS (P525L) mutation. Our data indicate that the FUS (P525L) mutation reduces the maturation rates and the function of hiPSC-derived spinal neurons, with a strong decrease of inhibitory transmission, which may affect the excitatory/inhibitory balance, possibly predisposing to excitotoxicity and neurodegeneration.}, }
@article {pmid42430091, year = {2026}, author = {You, Y and Duan, D and Xiang, Q}, title = {The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42430091}, issn = {1559-1182}, mesh = {Humans ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; Mitochondria/metabolism ; *Translational Research, Biomedical ; *Translational Science, Biomedical ; }, abstract = {Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1α modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1α supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1α-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1α is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1α to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1α from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.}, }
@article {pmid42430317, year = {2026}, author = {Buczak, MK and Brignone, J and Caden Hamrick, W and Cole, KM and Bromberg, MB and Zhang, H and George, JA}, title = {Preliminary Investigation of Myoelectric Control of an Assistive Neck Exoskeleton by Individuals with Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2026.3712219}, pmid = {42430317}, issn = {1558-0210}, abstract = {Neck weakness limits head control and quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). The Utah Neck Exoskeleton can restore neck motion, but current control methods-joystick and gaze tracking-have limited accessibility and reliability. These preliminary offline analyses investigate neck electromyography (EMG) as an alternative control modality from ALS patients. EMG signals were recorded from four male participants with ALS while performing neck flexion/extension, axial rotation, and lateral deviation. The resulting dataset was used to train convolutional neural networks (CNNs) per patient to classify either head position or movement direction from EMG features offline. Position classification significantly outperformed direction classification, with a mean accuracy of 82.5% ± 0.010 across participants. Performance was consistent when controlling one, two, or all three neck degrees of freedom. A subset of participants with sufficient residual motor function also completed neck movements while talking or chewing. Classification accuracy decreased during talking and chewing, although these effects were not statistically significant. Importantly however, training CNNs with diverse data that included periods of talking and chewing improved algorithm robustness across all conditions. These findings suggest that neck EMG signals can reliably predict intended head movements in ALS, even in the presence of weak and often confounding muscle activity. Offline accuracy and real-time computational speed suggest the approach is feasible for future online user-in-the-loop studies. Altogether, this pilot work advances EMG-based assistive technology for individuals with severe motor impairments, laying the groundwork for clinically viable, intuitive control systems.}, }
@article {pmid42236288, year = {2026}, author = {Chinoy, A and Soo, A}, title = {Effectiveness of Surgical Sealants in Reducing Prolonged Air Leaks After Pulmonary Resection: A Systematic Review.}, journal = {Interdisciplinary cardiovascular and thoracic surgery}, volume = {41}, number = {7}, pages = {}, doi = {10.1093/icvts/ivag164}, pmid = {42236288}, issn = {2753-670X}, mesh = {Humans ; *Pneumonectomy/adverse effects ; *Tissue Adhesives/therapeutic use/adverse effects ; *Surgical Stapling/adverse effects ; Treatment Outcome ; *Fibrin Tissue Adhesive/therapeutic use ; *Anastomotic Leak/prevention &amp; control/etiology ; Time Factors ; Female ; }, abstract = {OBJECTIVES: Prolonged air leak (PAL) is the most common complication following pulmonary resection, leading to increased morbidity, hospital stay, and healthcare costs. Although staplers are currently the standard for lung parenchymal closure, ALs remain frequent. Surgical sealants have been introduced as adjuncts to staplers to reduce PAL, but evidence remains inconsistent. Prior systematic reviews frequently pooled together stapled and sutured resections, limiting applicability to contemporary practice. This review specifically evaluates whether surgical sealants reduce the incidence and duration of PAL when used with staplers in adult patients.<br><br>METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251064592). A literature search was conducted in PubMed, Ovid MEDLINE, and Cochrane Library for studies published between 2005 and June 2025. Eligible studies included adult patients undergoing stapler-based pulmonary resection comparing sealants plus staplers versus staplers alone. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB2) and risk of bias in non-randomized studies of interventions (ROBINS-I) tools.<br><br>RESULTS: Eight studies were included. Surgical sealants studied included fibrin-based (autologous fibrin sealant (FS), FS patch, human FS) and synthetic polymers (polyethylene glycol hydrogel sealant, cyanoacrylate-based sealant). Most studies reported a statistically significant reduction in PAL incidence and/or duration with sealant use. Some also showed reduced chest tube duration and hospital stay, though not always statistically significant. One study showed worse outcomes in the sealant group. No study reported increased complications. Subgroup analyses were limited.<br><br>CONCLUSIONS: Sealants used with staplers may reduce PAL incidence and duration, particularly in high-risk patients, without increased complications. However, variability in study design and limited subgroup data weaken current evidence. Larger, standardized randomized controlled trials are needed to confirm clinical benefit and inform routine use.}, }
@article {pmid42420185, year = {2026}, author = {Shan, D and Wang, H and Liu, F and Yan, C and Zhao, Y and Sun, X}, title = {Neuronal Intranuclear Inclusion Disease Mimicking Familial ALS: A Multigenerational Case Series With Diagnostic Pitfalls.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70336}, pmid = {42420185}, issn = {1097-4598}, support = {20201125//Qilu Young Scholar Program of Shandong University/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; ZR2022QH325//the Natural Science Foundation of Shandong Province/ ; }, }
@article {pmid42420559, year = {2026}, author = {Compagnion, AC and Ivanov, A and Rana, A and Espinoza, F and Sandmann, T and Martineau, FS and Monsorno, K and Facchinetti, R and Matera, A and Rougé, L and González Ibáñez, F and Catale, C and Bizzotto, M and Garel, S and Matteoli, M and Kashiwagi, Y and Koyama, R and Haass, C and Tremblay, ME and Beule, D and Jelescu, I and Zerbi, V and Di Paolo, G and Paolicelli, RC}, title = {Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {42420559}, issn = {1546-1726}, abstract = {TDP-43 proteinopathy is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal dementia where mislocalization of TDP-43 has been observed in neurons and glial cells. However, the role of TDP-43 in microglia and the consequences of its loss of function remain unexplored. Combining magnetic resonance imaging, and confocal, and electron microscopy, we uncovered structural changes and myelin abnormalities in the early postnatal brain of mice lacking microglial TDP-43. Spatial transcriptomics further revealed an enriched interferon-responsive signature associated with oligodendrocyte dysfunction. Early depletion of microglial TDP-43 led to motor deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin. It also led to cryptic exon inclusion in the Tyrobp mRNA, resulting in truncated DAP12 protein, thus causing defective TREM2 signaling. Our findings reveal a role for TDP-43 in regulating the TREM2-DAP12 axis in mice, highlighting a previously unrecognized mechanism through which TDP-43 controls microglial function.}, }
@article {pmid42421532, year = {2026}, author = {Jiang, Z and Zhang, R and Jiang, Z and Zeng, S and Wang, L and Zhao, S and Zhang, X and Yu, H}, title = {Accelerating reaction kinetics of AlCl3/acetamide electrolyte by co-solvation for Al-S batteries.}, journal = {Materials horizons}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6mh00252h}, pmid = {42421532}, issn = {2051-6355}, abstract = {Deep eutectic solvents such as AlCl3/acetamide (AcA) have demonstrated great potential as room-temperature electrolytes for Al-S batteries, but their high viscosities and low ionic conductivities severely impede the electrochemical reaction kinetics. Herein, we report an effective strategy to optimize AlCl3/AcA by screening fluorobenzene co-solvents. The optimal 1,2,3-trifluorobenzene (tFBn) effectively dilutes AlCl3/AcA and has a crowding effect that creates a local high-concentration zone for efficient transport of electro-active ions. Rather than merely functioning as a diluent, tFBn induces the localized aggregation of neutral molecules and ion clusters, which reduces the bulk viscosity by 50% and doubles the ionic conductivity. This localized high concentration, coupled with the rapid migration of ion clusters, accelerates the reaction kinetics and improves the long-cycling stability of Al stripping/plating. tFBn also promotes the transportation of Al-Cl species onto Al to regulate the interphase structures and reduce the resistance. Due to the accelerated reaction kinetics, the tFBn-modified AlCl3/AcA further improves the S utilization, reduces the polarization, and enhances the capacity retention of Al-S batteries. This study provides important insights into the design of high-performance electrolytes toward practical Al-S batteries.}, }
@article {pmid42421808, year = {2026}, author = {Ang, NKJ and Lim, JQ and Lye, TJY and Tan, DMY and Lim, CH}, title = {Endoscopic salvage for afferent loop syndrome: the antegrade lumen-apposing metal stent technique.}, journal = {VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy}, volume = {11}, number = {7}, pages = {298-303}, pmid = {42421808}, issn = {2468-4481}, abstract = {BACKGROUND AND AIMS: Afferent loop syndrome (ALS) is a rare postgastrectomy condition with biliopancreatic limb obstruction. Revision surgery carries high morbidity in patients with hostile anatomy. We aimed to demonstrate the feasibility of a double-scope, antegrade EUS-guided lumen-apposing metal stent (LAMS) enteroenterostomy as an endoscopic alternative in the management of complex ALS.<br><br>METHODS: A patient with extensive prior gastric surgery presented with ALS. With a double-scope antegrade technique, a pediatric gastroscope (GIF-XP190 N; Olympus, Tokyo, Japan) was used to cannulate the afferent limb to place a guidewire, and a linear echoendoscope (GF-UCT180; Fujifilm, Tokyo, Japan) was advanced into the blind loop. The pediatric gastroscope was reintroduced into the efferent limb, which was water-distended to approximately 3 cm in diameter to achieve sonographic apposition. Under combined EUS and fluoroscopic guidance, a 15- &#xd7; 15-mm electrocautery-enhanced LAMS (Boston Scientific, Marlborough, Mass, USA) was deployed to create an enteroenterostomy.<br><br>RESULTS: Postdeployment contrast confirmed optimal position and immediate patency without leak. Symptoms resolved rapidly; the patient resumed a diet within days and gained weight. Abdominal radiography showed progressive LAMS expansion without adverse events.<br><br>CONCLUSIONS: Double-scope antegrade EUS-guided LAMS placement safely decompressed the afferent limb in our patient, restoring enteral flow and avoiding high-morbidity reoperation. This technique merits consideration within multidisciplinary care and warrants larger comparative studies to define long-term outcomes.}, }
@article {pmid42422319, year = {2026}, author = {Nie, J and Peters, S and Ge, CB and Portengen, L and Rothman, N and Hu, W and Ou, R and Wei, Q and Zhang, L and Hou, Y and Lan, Q and Shang, HF and Vermeulen, R}, title = {Smoking and the risk of neurodegenerative diseases in a Chinese case-control study.}, journal = {BMJ neurology open}, volume = {8}, number = {2}, pages = {e001728}, pmid = {42422319}, issn = {2632-6140}, abstract = {BACKGROUND: While smoking is inversely associated with Parkinson's disease (PD) risk, its relationship with amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) remains unclear, particularly in Asian populations. We investigated these associations in a Chinese case-control study.<br><br>METHODS: We recruited newly diagnosed ALS (n=430), MSA (n=271), PD (n=523) cases and hospital-based controls (n=1033) in Sichuan, China. Logistic regression models were used to evaluate associations between smoking and disease risks, adjusting for demographic, lifestyle and occupational factors.<br><br>RESULTS: Compared with never-smokers, the adjusted ORs and 95% CIs of ALS for current and former smokers were 1.00 (0.61 to 1.65)&#x2009;and 1.79 (1.01 to 3.17), respectively. For MSA, ORs were 1.27 (0.73 to 2.23) for current smokers and 2.54 (1.41 to 4.60) for former smokers. Individuals who quit within 4 years before diagnosis showed the highest risk of ALS (OR=1.93, 95%&#x2009;CI 0.96 to 3.88)&#x2009;and MSA (OR=2.09, 95%&#x2009;CI 1.11 to 3.93). For both ALS and MSA, no consistent trend was found with increasing smoking duration or pack-years. In contrast, ever-smokers had a significantly lower PD risk (OR=0.49, 95%&#x2009;CI 0.33 to 0.71), particularly current smokers (OR=0.30, 95%&#x2009;CI 0.19 to 0.48). Longer smoking duration and higher cumulative smoking were also linked to PD risk with clear negative exposure-response patterns (P trend=0.039 and 0.029, respectively).<br><br>CONCLUSIONS: Consistent with findings in non-Asian populations, smoking was inversely associated with PD risks in the Chinese population. For ALS and MSA, we found evidence suggestive of positive relationships with cigarette smoking, but no clear exposure-response relationships were observed.}, }
@article {pmid42422504, year = {2026}, author = {Tomikawa, E and Takahashi, K and Hattori, H and Arai, T and Kawai, M and Nishimura, K and Goto, Y and Yagi, R and Miyamoto, Y and Miyoshi, T}, title = {Multinucleation and cytotoxicity induced by multikinase inhibition in highly proliferative cells.}, journal = {Journal of toxicologic pathology}, volume = {39}, number = {3}, pages = {93-101}, pmid = {42422504}, issn = {0914-9198}, abstract = {Phenotypic screening using motor neurons derived from the induced pluripotent stem (iPS) cell of a patient with amyotrophic lateral sclerosis led to the identification of Compound X, a novel agent with potent neuroprotective activity that is hypothesized to act by inhibiting hematopoietic progenitor kinase/germinal center kinase-like kinase (HGK). Unlike known HGK inhibitors, including Prostetin and GNE-495, Compound X and related Compounds Y and Z exhibited broader multi-kinase-inhibition profiles, including the strong inhibition of Aurora B kinase and strong-to-moderate inhibition of Src-family kinases in kinase panel screening. Owing to their roles in cytokinesis, we performed in vitro micronucleus tests to assess their genotoxicity. Compounds X, Y, and Z induced the multinucleation of cells at rates of 88.8, 71.5, and 91.8%, respectively, whereas Prostetin and GNE-495 resulted in rates of 0.5 and 1.3%, respectively, which were comparable to the control. A 5-day repeated-dose oral toxicity study of Compound X using mice, at doses of 125, 250, and 500 mg/kg/day, revealed decreased locomotor activity, hypothermia, and mortality at 500 mg/kg/day. Histopathology showed necrosis/hemorrhage in bone marrow cells; single-cell necrosis in the thymus, spleen, and mesenteric lymph nodes; nuclear pleomorphism and single-cell necrosis/necrosis in the gastrointestinal mucosa; and karyomegaly and a reduction in testicular germ cells. These toxicopathological findings suggest that Compound X induces nuclear pleomorphism and necrosis in highly proliferative cells. Although Compound X strongly suppressed HGK, its toxicity may be associated with broader multikinase inhibition, which is consistent with the finding that Prostetin and GNE-495 do not induce multinucleation in vitro.}, }
@article {pmid42422879, year = {2026}, author = {Grassmann, G and Amadei, M and Lardieri, A and Montemiglio, LC and Passeri, AA and Mattarelli, M and Di Rienzo, L and Miotto, M and Ruocco, G and Milanetti, E}, title = {Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation mechanism.}, journal = {Frontiers in molecular biosciences}, volume = {13}, number = {}, pages = {1849627}, pmid = {42422879}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by inclusions of TDP-43 protein. C-terminal fragments (CTFs) of TDP-43, generated by cleavage within its second RNA recognition motif (RRM2), have been found forming aggregates in patients. Aggregation has often been attributed to the C-terminal domain, but increasing evidence indicates that RRM2 fragments contribute to pathological inclusions. We performed extensive molecular dynamics simulations to investigate the changes resulting from the truncation that could lead to aggregation. We analyzed the full RRM2 domain (fRRM2, residues 192-261) and two fragments commonly observed in CTFs (tRRM2A, residues 220-261, and tRRM2B, residues 209-261). We found that truncation results in distinct aggregation-prone states. tRRM2B appears to rely on β -sheet elements associated with amyloid-like aggregation, whereas tRRM2A exhibits higher structural variability and a reduced β -content, suggesting a phase separation-like aggregation mechanism. We further simulated an extended fragment of tRRM2A, tRRM2A-l (residues 220-269). Although its predicted aggregation propensity remains largely unchanged, tRRM2A-l exhibits increased structural flexibility, and a stronger exposure of Nuclear Export Signal residues. Our results indicate that subtle differences in RRM2 fragment length influence potential misfolding pathways. Future studies and therapeutic strategies to prevent TDP-43 aggregation should carefully consider the specific domain adopted.}, }
@article {pmid42422903, year = {2026}, author = {Singh, T and Khare, SK and Siddhanta, S}, title = {Spectroscopic discrimination of bacterial species of variable pathogenicity through explainable machine learning.}, journal = {Nanoscale}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6nr00689b}, pmid = {42422903}, issn = {2040-3372}, abstract = {Rapid and accurate identification of bacterial pathogens and their degree of pathogenicity is essential for guiding antimicrobial therapy. Current culture-based methods require a timeframe of at least 24-48 h for species-level identification alone, which often leads to substantial disease progression and increases the propensity of antimicrobial resistance (AMR). Surface-Enhanced Raman Spectroscopy (SERS) shows promise in mitigating these drawbacks by providing a fast, non-invasive, label-free method to capture the biochemical fingerprints of bacteria achievable under clinical settings. However, the molecular complexity of SERS spectra, which has been an impediment for conventional data analysis, demands robust computational frameworks for reliable species-level identification. Here, we employ a comprehensive SERS analysis scheme with supervised machine learning and explainable artificial intelligence (XAI) to discriminate five clinically relevant pathogens, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Enterococcus faecalis, and to probe their degree of pathogenicity from a biomarker perspective. Among the tested models - Support Vector Machine (SVM), k-Nearest Neighbour (kNN), Random Forest (RF), and a 1D Convolutional Neural Network (CNN) - CNN achieved near-perfect classification accuracy, capturing subtle and spectrally relevant variations often inaccessible to traditional algorithms. Notably, the 1D-CNN also achieved 100% discrimination between MRSA and methicillin-sensitive S. aureus - two strains of the same species differing only in resistance phenotype. To ensure transparent decision-making and eliminate the black-box nature of machine learning models, SHapley Additive exPlanations (SHAP) analysis was applied to both RF and CNN models, which facilitated the convergence of both frameworks on the same discriminatory Raman regions, revealing conserved biochemical determinants of species identity. Complementary MCR-ALS decomposition further resolved the spectra into interpretable biochemical components and provided the rubric for biochemical differentiation. Together, this study aims to demonstrate an end-to-end explainable workflow that couples SERS with interpretable AI, offering a rapid, transparent approach for pathogenic disease diagnosis.}, }
@article {pmid42423631, year = {2026}, author = {Chu, HS and Oh, J}, title = {Identifying Gastrostomy Care and Home Gastrostomy Tube Feeding-Related Educational Content for Patients With Amyotrophic Lateral Sclerosis and Their Family Caregivers: A Delphi Panel With Professional Stakeholders.}, journal = {Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates}, volume = {}, number = {}, pages = {}, pmid = {42423631}, issn = {1538-9766}, abstract = {Enteral nutrition is delivered through a gastrostomy tube to provide nutritional support to patients with amyotrophic lateral sclerosis (ALS) who have developed severe dysphagia at home. Complications may arise from gastrostomy and enteral nutrition when family caregivers do not provide adequate care. This study identifies key areas of educational content that can improve the care of patients with ALS requiring gastrostomy and home enteral nutrition. We conducted a modified three-round e-Delphi survey with health care experts to clarify their perspectives on the educational content regarding gastrostomy and home enteral nutrition disseminated among patients with ALS and their family caregivers. The experts provided their opinions on specific educational content areas, and their responses were analyzed to identify areas of consensus and divergence. Accordingly, in Rounds 1-3 of the survey, 16 experts, including registered nurses (n = 6), advanced practice registered nurses (n = 3), clinical neurologists (n = 3), and dieticians (n = 4), participated. In Round 3, four categories and 39 educational components reached consensus. The results provide a framework for developing educational nursing interventions for family caregivers of patients with ALS receiving home enteral nutrition through gastrostomy tubes and for defining the essential elements of the educational content of such interventions.}, }
@article {pmid42423712, year = {2026}, author = {Lu, J and Wang, XTX}, title = {Tackling challenges in large language model-based data extraction via context engineering: A commentary on Jansen et al. (2025).}, journal = {Psychological bulletin}, volume = {152}, number = {4}, pages = {404-419}, doi = {10.1037/bul0000520}, pmid = {42423712}, issn = {1939-1455}, support = {//National Natural Science Foundation of China/ ; }, mesh = {*Large Language Models ; Humans ; }, abstract = {Systematic reviews, particularly meta-analyses, involve crucial yet labor-intensive and error-prone stages of data extraction. Recent advances in large language models (LLMs) have unlocked new avenues for automating this process, potentially enhancing both efficiency and reliability. Recently, Jansen et al. (2025) systematically evaluated the accuracy and error patterns of LLM-assisted data extraction across 22 reviews published in Psychological Bulletin. Their findings indicated that while achieving acceptable-to-good accuracy for some variables describing study characteristics, LLMs struggled with numerical variables, especially those related to effect sizes. In this commentary, we discuss the current challenges of automated data extraction and potential pathways to improve the work reported in Jansen et al.'s study. We situate our discussion within the framework of context engineering, aiming to refine the information provided to LLMs through dynamic optimization strategies tailored to specific tasks. We identify five key challenges that reflect either LLMs' unique patterns or standard practices in research synthesis: parsing semistructured data, understanding long contexts, performing arithmetic induction, engaging in complex reasoning, and ensuring the reproducibility of coding protocols. We then outline potential solutions inspired by context engineering implementations such as retrieval-augmented generation and tool-integrated reasoning. For illustration, we present four examples: extracting semistructured data via optical character recognition, reliably computing effect sizes through function calls, performing adaptive retrieval with LLM-based agents, and iteratively improving outputs through self-refinement. We conclude by calling for future research in automated data extraction to advance beyond simple instruction-following paradigms toward more reliable forms of context engineering. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42423935, year = {2026}, author = {Elvish, TM and Trowell, D and Bonacci, J and Turner, KJ and Kremer, P and Millett, EL and Pickering, C and Saunders, N}, title = {Biological and Race Strategy Characteristics Investigated in Elite Endurance Track Running: A Systematic Review.}, journal = {Sports medicine (Auckland, N.Z.)}, volume = {}, number = {}, pages = {}, pmid = {42423935}, issn = {1179-2035}, abstract = {BACKGROUND: Understanding biological and race strategy characteristics of endurance track runners competing at benchmark events provides high-performance athletics programmes and coaches with valuable insight into what is required to succeed.<br><br>OBJECTIVES: The aim of this systematic review was to identify biological and race strategy characteristics investigated in elite able-bodied endurance track runners (Aim 1) and, where examined, highlight whether these characteristics could differentiate performance success within this elite cohort (Aim 2).<br><br>METHODS: For this systematic review, searches across EBSCOhost (Academic Search Complete, CINAHL Complete, MEDLINE Complete and SPORTDiscus), Scopus, PubMed and Web of Science were completed until May 2023. Searches also involved World Athletics Research Centre, New Studies in Athletics, handsearching and scanning of reference lists of included studies. Eligible studies were required to be published in English and have investigated performance-related biological or race strategy characteristics among senior able-bodied endurance track runners (800-10,000&#xa0;m) capable of competing at benchmark events. Risk of bias of included studies was evaluated based on Sarmento et al.'s 16-item checklist. The review separated middle-distance runners (MDR) and long-distance runners (LDR), to account for the differing performance demands of these event groups. Studies were considered to address Aim 2 if they assessed for statistical associations between athlete characteristics and overall performance (e.g. race time) or compared characteristics between athletes with different competitive results (e.g. medallists and non-medallists).<br><br>RESULTS: Thirty-nine articles were included in this review, with 23 and 21 of these articles relevant to MDR and LDR, respectively. The most commonly reported characteristics were related to anthropometry (7 studies for MDR and LDR), biomechanics (7 studies for LDR), pacing (9 and 10 studies for MDR and LDR, respectively), qualification pattern (6 studies for MDR) and benchmark performance relative to athlete history (9 and 7 studies for MDR and LDR, respectively). However, the diversity of biological characteristics investigated and the generally small sample sizes makes it difficult to define an optimal biological profile for elite endurance runners. In contrast, race strategy characteristics investigated often included larger sample sizes providing a better understanding, especially in relation to pacing and for middle-distance events qualification patterns. Further, studies investigating whether characteristics differentiate performance among elite endurance track runners indicate that the most successful runners consistently demonstrate superior finishing ability. This is reflected in faster speeds during at least one 100-m segment of the final 400&#xa0;m of the race and the ability to complete the final segments of the race at a pace close to, or faster than, their season best or 32-month best performance. In long distance events, better performance was associated with faster personal best times across the previous 32&#xa0;months, indicating that having a high-ranking recent best time may be a prerequisite for succeeding at benchmark events. Faster 10,000-m runners had lower body mass and smaller arm and calf circumferences, suggesting a potential advantage of having lower non-functional mass. In middle distance events, success was associated with achieving superior qualification positions in the heats and semi-final, highlighting the importance of tactical positioning and efficient progression through qualification rounds. Faster male 800-m runners had a technique characterised by longer contact times and more compliant spring mechanics which may allow athletes to maintain or elevate speed during the sprint finish.<br><br>CONCLUSION: Biological and race strategy characteristics that profile elite endurance track runners and that, in several studies, showed association with performance success were discussed. These findings may assist high-performance athletics programmes and coaches in informing athlete development and investment. However, further research is required to establish a more holistic understanding of the biological profile of elite endurance track athletes and to determine which biological and race strategy characteristics may differentiate performance reliably among these elite runners.}, }
@article {pmid42424231, year = {2026}, author = {Szyłak, E and Czarnowska, A and Kulczyńska-Przybik, A and Kopitelow, J and Mroczko, B and Kochanowicz, J and Kułakowska, A}, title = {Neurofilament Light Chain as a Biomarker in Neurology.}, journal = {European neurology}, volume = {}, number = {}, pages = {1-18}, doi = {10.1159/000552933}, pmid = {42424231}, issn = {1421-9913}, abstract = {Neurofilament light chain (NfL) has emerged as a highly sensitive biomarker of neuroaxonal injury across diverse neurological disorders. This review synthesizes current evidence regarding its diagnostic, prognostic, and therapeutic-monitoring utility, while outlining major clinical limitations and emphasizing the complementary role of glial fibrillary acidic protein (GFAP). NfL concentrations increase following axonal damage and correlate with inflammatory activity, lesion burden, and long-term disability progression in multiple sclerosis. Elevated levels also reflect neurodegeneration in Alzheimer's disease, predict disease severity and survival in amyotrophic lateral sclerosis, and are associated with motor and cognitive decline in Parkinson's disease and multiple system atrophy. In acute neurological conditions, including traumatic brain injury and stroke, NfL serves as a robust indicator of the extent of neuronal injury. Interpretation is constrained, however, by substantial physiological variability related to age, renal function, body mass index, and comorbidities, limiting the utility of absolute cut-off values. GFAP provides complementary information by capturing astrocytic damage, and the GFAP/NfL ratio may aid in differentiating multiple sclerosis from neuromyelitis optica spectrum disorder. Integration of NfL with multimodal biomarkers- such as GFAP, tau proteins, proteomic and metabolomic signatures, and advanced neuroimaging-may enhance diagnostic specificity and prognostic accuracy. Future research priorities include establishing age-adjusted reference intervals, validating longitudinal thresholds, and incorporating NfL into therapeutic monitoring frameworks. Advances in these areas are expected to improve diagnostic precision and support broader clinical implementation of NfL.}, }
@article {pmid42425084, year = {2026}, author = {Hosokawa, M and Kawakami, R and Imami, K and Kurosawa, R and Yoshizawa, T and Ishihama, Y and Imamura, T and Hagiwara, M and Takeuchi, A}, title = {RNA-dependent SFPQ condensates coordinate multidimensional regulation of extra-long neuronal genes.}, journal = {Cell chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chembiol.2026.06.004}, pmid = {42425084}, issn = {2451-9448}, abstract = {The mammalian brain uniquely expresses a large repertoire of extra-long genes critical for neuronal development and function, yet these transcripts are particularly vulnerable to dysregulation linked to neurological disorders, such as autism spectrum disorder and amyotrophic lateral sclerosis. The molecular mechanisms that ensure their stable expression remain poorly understood. Here, we show that the RNA-binding protein SFPQ forms meshwork-like biomolecular condensates that scaffold a multidimensional gene regulatory complex essential for long-gene expression. Super-resolution microscopy and functional perturbation assays demonstrate that disruption of SFPQ condensates impairs both extra-long gene expression and splicing. Proximity-dependent biotin labeling combined with mass spectrometry (BioID-MS) reveals that SFPQ condensates recruit transcriptional elongation factors, splicing regulators, and chromatin remodelers. Notably, many of these interactors overlap with autism-associated genes, suggesting direct disease relevance. These findings define a higher-order nuclear architecture organized by SFPQ and provide mechanistic insight into long-gene transcriptopathies underlying neurological disorders.}, }
@article {pmid42425146, year = {2026}, author = {Hoppe, JM and Deniz, S and Czihal, M and Lottspeich, C}, title = {Contrast-Enhanced Ultrasound versus Contrast-Enhanced Computed Tomography in the Detection of Renal and Splenic Infarctions.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2908-8526}, pmid = {42425146}, issn = {1438-8782}, abstract = {PURPOSE: Intra-abdominal organ infarctions require prompt imaging for diagnosis. Contrast-enhanced computed tomography (CECT) is considered the gold standard but involves radiation, iodinated contrast, and logistical challenges in critically ill patients. Contrast-enhanced ultrasound (CEUS) enables real-time assessment of microvascular perfusion without ionizing radiation. The aim of this study was to evaluate the diagnostic performance of CEUS compared to CECT for detecting intra-abdominal organ infarctions.<br><br>MATERIALS AND METHODS: This retrospective observational study included patients treated at a tertiary care center (2010-2024) who underwent both CEUS and CECT for suspected intra-abdominal organ infarction. With CECT as reference standard, diagnostic performance parameters and agreement (Cohen's kappa) were calculated.<br><br>RESULTS: 24 patients (median age 60 years; 12 female) were included. CECT confirmed organ infarction in 16/24 patients (66.7%). CEUS correctly identified 15 of these cases (Sensitivity 93.8%; 95% confidence interval [CI]: 71.7-98.9%). Specificity was 75.0% (95% CI: 40.9-92.9%), with two false-positive CEUS findings. Positive and negative predictive values were 88.2% (95% CI: 65.7- 96.7%) and 85.7% (95% CI: 48.7-97.4%), respectively. Agreement of CECT and CEUS was substantial (Cohen's &#x3ba; = 0.71). Wedge-shaped perfusion defects were identified in 93.8% of CT-confirmed infarctions on both modalities.<br><br>CONCLUSION: CEUS demonstrates high sensitivity and good agreement with CECT for the detection of intra-abdominal organ infarctions. CEUS represents a valuable imaging modality, particularly when CECT is contraindicated or not available. Prospective studies are warranted to further define its role in clinical practice. Zielsetzung: Intraabdominelle Organinfarkte erfordern eine rasche bildgebende Diagnostik. Die kontrastmittelverst&#xe4;rkte Computertomographie (CECT) gilt als Goldstandard, ist jedoch mit Strahlenexposition, jodhaltigen Kontrastmitteln sowie logistischen Herausforderungen bei kritisch kranken Patienten verbunden. Der kontrastmittelverst&#xe4;rkte Ultraschall (CEUS) erm&#xf6;glicht eine Echtzeitbeurteilung der Perfusion ohne ionisierende Strahlung. Ziel dieser Studie war die Evaluation der diagnostischen Leistungsf&#xe4;higkeit der CEUS zur Detektion intraabdomineller Organinfarkte im Vergleich zur CECT.<br><br>MATERIAL UND METHODEN: In diese retrospektive Beobachtungsstudie (2010-2024) wurden Patientinnen und Patienten an einem terti&#xe4;ren Versorgungszentrum eingeschlossen, bei denen sowohl eine CEUS- als auch eine CECT-Untersuchung bei Verdacht auf intraabdominelle Organinfarkte durchgef&#xfc;hrt wurde. Mit der CECT als Referenzstandard wurden die diagnostischen Testparameter und &#xdc;bereinstimmung (Cohen's kappa) berechnet. Ergebnisse: 24 Patientinnen und Patienten wurden eingeschlossen (Medianalter 60 Jahre; 12 weiblich). Die CECT best&#xe4;tigte in 16/24 F&#xe4;llen (66,7%) einen Organinfarkt. Der CEUS identifizierte 15 F&#xe4;lle korrekt (Sensitivit&#xe4;t 93,8%, 95% Konfidenzintervall [KI]: 71,7-98,9%). Die Spezifit&#xe4;t betrug 75,0% (95% KI: 40,9-92,9%) bei zwei falsch-positiven CEUS-Befunden. Der positive und negative pr&#xe4;diktive Wert betrugen 88,2% (95% KI: 65,7- 96,7%) respektive 85,7% (95% CI: 48,7-97,4%). Die &#xdc;bereinstimmung zwischen CECT und CEUS war substantiell (Cohen's &#x3ba; = 0,71). Keilf&#xf6;rmige Perfusionsdefekte wurden in 93,8% der best&#xe4;tigten Infarkte in beiden Modalit&#xe4;ten identifiziert. Schlussfolgerung: Der CEUS zeigt eine hohe Sensitivit&#xe4;t und eine gute &#xdc;bereinstimmung mit der CECT bei der Detektion intraabdomineller Organinfarkte. Der CEUS stellt f&#xfc;r diese Fragestellung eine wertvolle Bildgebungsmodalit&#xe4;t dar, insbesondere wenn CECT kontraindiziert oder nicht verf&#xfc;gbar ist. Prospektive Studien sind erforderlich, um seine Rolle in der klinischen Praxis weiter zu definieren.}, }
@article {pmid42425169, year = {2026}, author = {Yu, W and Zhao, B and Ma, M and Gao, N and Yun, Y and Sun, X and Shao, K and Lin, P and Li, W and Zhao, Y and Yu, D and Zhao, C and Liu, F and Yan, C and Liu, S}, title = {Sex-associated neuroinflammatory and astrocytic responses in amyotrophic lateral sclerosis: evidence from clinical cohorts and a TDP-43 N390D mouse model.}, journal = {Brain, behavior, and immunity}, volume = {}, number = {}, pages = {106884}, doi = {10.1016/j.bbi.2026.106884}, pmid = {42425169}, issn = {1090-2139}, abstract = {BACKGROUND: Sex differences are increasingly recognized as important modifiers of neuroimmune processes in neurodegenerative disorders. However, the sex-associated clinical phenotypes and underlying neuroinflammatory mechanisms in amyotrophic lateral sclerosis (ALS) remain poorly understood. This study integrated multimodal clinical assessments, cerebrospinal fluid (CSF) neuroimmune biomarkers, neuroimaging-based glymphatic metrics, and complementary animal analyses to characterize shared and sex-associated alterations in male and female ALS patients.<br><br>METHODS: Two independent cohorts including 158 newly diagnosed ALS patients and 112 healthy controls (HCs) underwent evaluations of motor function, cognition, sleep disturbances, and emotional symptoms. Glymphatic function was assessed using choroid plexus volume (CPV), diffusion-derived analysis along the perivascular space (ALPS) index, and white-matter free-water (FW) fraction. In the original cohort, 12 CSF biomarkers spanning astrocytic activation, neuroinflammation, TDP-43 pathology, synaptic dysfunction, and axonal injury were quantified, and glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were further examined in an independent verification cohort. Complementary neuroimmune alterations were further examined in TDP-43 N390D knock-in mice using ELISA and immunofluorescence.<br><br>RESULTS: Male ALS patients showed markedly elevated CSF GFAP, IL-6, and IL-18 compared with female ALS patients and HCs after false discovery rate correction (q&#x202f;<&#x202f;0.05). Female ALS patients exhibited increased CSF IL-6 versus HCs, whereas GFAP and IL-18 levels were unchanged. Female ALS patients also demonstrated more severe depressive symptoms and post-traumatic stress disorder than male ALS patients and HCs (p&#x202f;<&#x202f;0.05). Both sexes displayed glymphatic impairment characterized by increased CPV and FW and reduced ALPS index, as well as pronounced sleep disturbances relative to HCs (all p&#x202f;<&#x202f;0.05), with no clear sex-related differences. Complementary animal data showed that, at a fixed chronological age, male TDP-43 N390D mice exhibited more severe motor impairment accompanied by higher brain levels of GFAP, IL-6, and IL-18 and more prominent astrocyte-associated IL-6 and IL-18 signals than female mutant mice. Although microglial activation was also observed in TDP-43 N390D mice, no clear sex-related difference was detected at the sampled age.<br><br>CONCLUSIONS: This multimodal clinical-translational study reveals sex-associated neuroinflammatory heterogeneity in ALS. Male patients exhibit a more pronounced GFAP-, IL-6-, and IL-18-related inflammatory profile, whereas female patients display more prominent affective disturbances. Glymphatic dysfunction and sleep impairment emerge as common pathological pathways across sexes. These findings highlight sex as a crucial biological variable shaping ALS heterogeneity and underscore the importance of incorporating sex-stratified analyses in future ALS neuroimmune research and clinical trials.}, }
@article {pmid42425598, year = {2026}, author = {Pucciarelli, DM and Patel, R and Sawicki, S and Jain, S and Saulino, P}, title = {Unusual presentation of amyotrophic lateral sclerosis years after a motor-vehicle collision.}, journal = {BMJ case reports}, volume = {19}, number = {7}, pages = {}, doi = {10.1136/bcr-2026-272139}, pmid = {42425598}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications ; Female ; Middle Aged ; *Accidents, Traffic ; Diagnosis, Differential ; *Muscle Weakness/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease caused by the destruction of motor neurons, typically presenting with unilateral lower motor neuron and upper motor neuron symptoms. Here, we report the case of a female in her mid-60s with a complex history of lower extremity weakness following a motor-vehicle collision 3 years before her current presentation with a subacute complaint of right-sided leg weakness. With an atypical symptom course consisting of resolved and recurrent weakness of her left leg, the patient had multi-level chronic, evolving spinal-column damage, severe weight loss, newly discovered rectal neoplasm and longstanding psychiatric pathology. With symptoms concerning for both medical and psychosomatic explanations, several potentially compounded aetiologies were considered. Here, we discuss important considerations for fluctuating chronic and subacute neurological complaints with a broad differential diagnostic spectrum and how a macro-perspective of symptoms over years can aid in the diagnosis of a challenging ALS presentation.}, }
@article {pmid42413223, year = {2026}, author = {Mohammadi, S and Trojsi, F and Ghaderi, S}, title = {Are T1-weighted and T2-weighted volumetric pipelines interchangeable methodologies for investigating amyotrophic lateral sclerosis pathology in vivo?.}, journal = {Brain research bulletin}, volume = {243}, number = {}, pages = {112036}, doi = {10.1016/j.brainresbull.2026.112036}, pmid = {42413223}, issn = {1873-2747}, abstract = {PURPOSE: To test the hypothesis that T1-w and T2-w volumetric pipelines are not interchangeable, particularly regarding their differential sensitivity to physiological traits and disease effects in the red nucleus (RN) and substantia nigra (SN).<br><br>METHODS: Thirty-one patients with ALS (mean age: 59.39&#x202f;&#xb1;&#x202f;8.73 years; 23 males) and 21 non-neurodegenerative controls (mean age: 53.43&#x202f;&#xb1;&#x202f;10.01 years; 16 males). Bilateral RN and SN volumes were automatically extracted using deep learning pipelines optimized for T1-w (OpenMAP-T1) and T2-w (pBrain) images. Volumes were normalized to total intracranial volume. A 2&#x202f;&#xd7;&#x202f;2&#x202f;&#xd7;&#x202f;2 repeated-measures general linear model (GLM) assessed interactions between Method, Region, Side, and Group, controlling for age, sex, BMI, and handedness.<br><br>RESULTS: There was no significant main effect of the disease group (p&#x202f;=&#x202f;0.829) or Method &#xd7;&#x202f;Group interaction (p&#x202f;=&#x202f;0.682), indicating both pipelines agreed on the absence of disease-specific macrostructural atrophy. However, a significant four-way Method &#xd7;&#x202f;Region &#xd7;&#x202f;Side &#xd7;&#x202f;Age interaction (P&#x202f;=&#x202f;0.031) was observed. In the RN, the T2-w pipeline detected robust age-related atrophy (Left: Slope = -1.84&#x202f;&#xd7; 10[-6]; Right: Slope = -1.70&#x202f;&#xd7;10&#x207b;&#x2076;), whereas the T1-w pipeline did not (p&#x202f;>&#x202f;0.05). Conversely, in the SN, T1-w consistently identified bilateral age-related loss, whereas T2-w yielded lateralized results (Right: p&#x202f;=&#x202f;0.011; Left: P&#x202f;=&#x202f;0.465).<br><br>CONCLUSIONS: T1-w and T2-w pipelines are not interchangeable. Though both confirm the absence of gross atrophy in this ALS cohort, their differing sensitivity to physiological aging highlights their distinct biological tissue properties, requiring method-specific interpretation.}, }
@article {pmid42414029, year = {2026}, author = {Hata, T and Ogawa, N and Yabata, H and Kobashi, S and Nakayama, M and Ishigaki, H and Yamakawa, I and Itoh, Y and Nishino, I and Urushitani, M}, title = {Case of concurrent ALS and human T-cell leukaemia virus type 1-associated myositis.}, journal = {BMJ case reports}, volume = {19}, number = {7}, pages = {}, pmid = {42414029}, issn = {1757-790X}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/pathology ; *Human T-lymphotropic virus 1 ; Aged ; Fatal Outcome ; *HTLV-I Infections/complications ; *Myositis/virology/complications/diagnosis ; Muscle, Skeletal/pathology ; Immunoglobulins, Intravenous/therapeutic use ; Magnetic Resonance Imaging ; }, abstract = {A woman in her late 70s presented with progressive limb weakness, muscle atrophy and hyper-reflexia. Laboratory findings revealed elevated creatine kinase and positive serum human T-cell leukaemia virus type 1 (HTLV-1) antibody. Clinical and electrophysiological findings met revised El Escorial criteria for amyotrophic lateral sclerosis (ALS), but muscle MRI showed inflammatory changes. Muscle biopsy revealed both neurogenic and inflammatory features. While methylprednisolone showed no benefit, intravenous immunoglobulin therapy produced transient improvement in weakness with normalisation of creatine kinase levels. The patient died from respiratory failure 3 years after symptom onset. Autopsy confirmed typical ALS-TDP pathology with phosphorylated TDP-43 inclusions in motor neurons. HTLV-1 Tax-positive lymphocytes infiltrated skeletal muscles but not the central nervous system, establishing dual pathology of ALS-TDP with HTLV-1-associated myositis. The improvement most likely reflected treatment of the HTLV-1-associated myositis rather than the underlying motor neuron disease. This case highlights the importance of evaluating treatable conditions in HTLV-1-seropositive ALS patients.}, }
@article {pmid42414528, year = {2026}, author = {Smith, CL and Robinson, JL and Lee, EB}, title = {Annexin A11 and TDP-43: core players in neurodegeneration.}, journal = {Acta neuropathologica}, volume = {152}, number = {1}, pages = {}, pmid = {42414528}, issn = {1432-0533}, support = {T32AG000255/NH/NIH HHS/United States ; P30AG072979/NH/NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Annexins/metabolism/genetics ; *Neurodegenerative Diseases/pathology/metabolism/genetics ; Animals ; TDP-43 Proteinopathies/pathology/metabolism ; }, abstract = {Annexin A11 (ANXA11) is a Ca[2][+]-dependent phospholipid-binding protein that has recently emerged as a key player in neurodegeneration. Rare pathogenic ANXA11 variants were initially identified in cases of amyotrophic lateral sclerosis (ALS). Since then, ANXA11 has been linked to a broader spectrum of related neurodegenerative diseases. Two independent studies demonstrated that ANXA11 co-aggregates with TDP-43 in all cases of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C, with cryo-EM revealing heteromeric ANXA11-TDP-43 filaments. These discoveries support the direct pathological interaction between the two proteins as an important feature of FTLD-TDP type C. We also described secondary ANXA11 pathology in related neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE), and more rarely in ALS and FTLD-TDP types A and B. ANXA11 and TDP-43 co-aggregates are also a feature of a FTLD-TDP associated with primary lateral sclerosis. These advances have renewed interest in ANXA11 as a major player in ALS/FTLD pathogenesis in both genetic and sporadic neurodegenerative diseases. In this review, we summarize ANXA11 pathology across genetic and sporadic cases, highlighting its heterogeneous overlap with TDP-43 pathology. We synthesize current knowledge of ANXA11's physiological roles in phase separation, membrane repair, and RNA granule dynamics, integrating emerging evidence on how disruption of these processes may promote pathological aggregation and toxicity. Finally, we outline priorities for future research, with particular emphasis on elucidating ANXA11's mechanistic connection to TDP-43.}, }
@article {pmid42414791, year = {2026}, author = {Gray, C and Hou, CG and Brayton, CE and Shepardson, RL and Leung, LB}, title = {Optimization of Virtual and In-Person Care Coordination Between VA Primary Care and Mental Health Teams: A Qualitative Study.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11606-026-10617-x}, pmid = {42414791}, issn = {1525-1497}, support = {I01 HX003635/HX/HSRD VA/United States ; I21 HX003593/HX/HSRD VA/United States ; IK2 HX002867/HX/HSRD VA/United States ; }, abstract = {BACKGROUND: In the Veterans Health Administration (VA), primary care teams include embedded specialists to facilitate timely access to effective mental health treatments, including same-day warm handoffs from primary care clinicians/staff to integrated mental health specialists.<br><br>OBJECTIVE: Understand the impact of the post-COVID-19 shift to virtual care on depression assessment and treatment and explore clinician-identified ways to optimize hybrid (virtual/in-person) integrated care for primary care patients with depression.<br><br>DESIGN: Semi-structured interviews across three geographically diverse VA healthcare systems.<br><br>PARTICIPANTS: Forty-seven primary care clinicians/staff and integrated mental health specialists.<br><br>APPROACH: Interview questions were based on Fortney et al.'s Reconceptualized (Digital) Access Framework. Transcripts were coded using a qualitative descriptive approach with constant comparison.<br><br>KEY RESULTS: Participants indicated that post-pandemic use of virtual care helped increase access to depression treatment. Particularly, they cited a model where integrated mental health clinicians/staff cover clinics across a healthcare system by offering telephone or video visits to patients at multiple sites. Primary care and mental health coordination appeared to work well; nevertheless, some primary care clinicians/staff preferred in-person warm handoffs. When asked about the optimal mix of in-person and virtual depression care, primary care clinicians/staff thought the initial assessment should be done in person, especially for patients presenting complicated cases. Ongoing care, namely cognitive behavioral therapy and medication management, was thought to be ideal for virtual delivery. Participants emphasized the need for offering Veteran-centric care, or care that "meets the Veterans where they are" and encourages them to continue engagement in mental healthcare.<br><br>CONCLUSIONS: Clinicians generally deferred to patients on their preferred care modality, but some indicated certain situations (e.g., initial assessment, complicated cases) may be better suited for in-person over virtual care. Further research should examine quality of virtual and in-person primary care-based mental healthcare, and patient satisfaction and experiences with these care modalities.}, }
@article {pmid42414949, year = {2026}, author = {Njohjam, MN and Ngoule, MO and Niakam, TF}, title = {Biological sex differences in neurodegenerative diseases in Africa: a scoping review of evidence and research gaps.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-05123-w}, pmid = {42414949}, issn = {1471-2377}, abstract = {BACKGROUND: Biological sex is a well-established determinant of risk, progression, and therapeutic response in neurodegenerative diseases (NDs). However, current evidence on sex differences in NDs is from high-income Western populations. This review aims to map and synthesize evidence on biological sex differences in NDs in Africa, and to identify key research gaps.<br><br>METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute methodology and reported in accordance with the PRISMA-ScR guidelines. A literature search was conducted on PubMed, African Journals Online, Sabinet Journals, ScienceDirect, and Google Scholar. We included studies conducted in African countries that reported sex disaggregated data or examined biological sex differences in at least one ND. Data were synthesized descriptively.<br><br>RESULTS: All included studies reported sex distribution, but most (about 84%) did so only descriptively. Approximately 17% conducted sex-stratified analyses beyond prevalence. Similar to global epidemiological trends, several studies suggested a higher prevalence or odds of dementia and multiple sclerosis among females, while male predominance was observed in Parkinson's disease and Amyotrophic lateral sclerosis studies. An earlier onset and a higher mutation frequency in LRRK2-G2019S were reported in females with Parkinson's disease in some studies, while another study reported a higher mortality rate in females with dementia. No study evaluated sex specific biomarker profiles, disease progression, or treatment response.<br><br>CONCLUSIONS: Evidence on biological sex differences in NDs in Africa remains limited and is largely descriptive. Mechanistic, longitudinal, and biomarker-based investigations are largely absent.}, }
@article {pmid42417277, year = {2026}, author = {Wamkpah, NS and Pepper, JP}, title = {Invited Commentary on: Lu et al.'s "Functional and Aesthetic Considerations for Selective Facial Neurectomy with Simultaneous Deep Plane Facelift and Structural Neck Contouring for Facial Paralysis with Synkinesis".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261465163}, doi = {10.1177/26893614261465163}, pmid = {42417277}, issn = {2689-3622}, }
@article {pmid42417282, year = {2026}, author = {Yver, CM and Hadlock, TA}, title = {Invited Commentary on: Lu et al.'s "Functional and Aesthetic Considerations for Selective Facial Neurectomy with Simultaneous Deep Plane Facelift and Structural Neck Contouring for Facial Paralysis with Synkinesis".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261465165}, doi = {10.1177/26893614261465165}, pmid = {42417282}, issn = {2689-3622}, }
@article {pmid42417572, year = {2026}, author = {Cooper, BR and Cena, S and Rasul, T and Blalock, TW and Chavez, AE}, title = {Response to Cooper et al.'s "Reflected Surgical Lighting Exposure at the Mohs Surgeon's Eye Level: Quantifying Effects of Working Distance, Drape Color, and Lamp Positioning".}, journal = {Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]}, volume = {}, number = {}, pages = {}, pmid = {42417572}, issn = {1524-4725}, }
@article {pmid42418280, year = {2026}, author = {Zhang, C and Chen, S and Zhao, H and Wang, Y and Zhou, L and Fan, H and Sun, Y}, title = {Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).}, journal = {Annals of the New York Academy of Sciences}, volume = {1561}, number = {1}, pages = {e70311}, pmid = {42418280}, issn = {1749-6632}, support = {#82371153//National Natural Science Foundation of China/ ; #82571317//National Natural Science Foundation of China/ ; #ZR2022QH073//Natural Science Foundation of Shandong Province/ ; #ZR2025MS1188//Natural Science Foundation of Shandong Province/ ; #ZR2025LZ044//Natural Science Foundation of Yantai/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Phase Separation ; *Protein Aggregation, Pathological/metabolism/pathology ; *Bibliometrics ; Animals ; DNA-Binding Proteins/metabolism ; }, abstract = {Liquid-liquid phase separation (LLPS), a biophysical driver of membraneless organelle assembly, is central to pathological aggregation in neurodegenerative diseases. Initially linked to amyotrophic lateral sclerosis (ALS), LLPS dysregulation has now been implicated in Alzheimer's, Parkinson's, and frontotemporal dementia, where aberrant transitions convert dynamic condensates into insoluble fibrils. To systematically map this landscape, we employed CiteSpace-based bibliometrics to analyze 784 Web of Science articles from 2009 to 2024. Our analyses reveal dominant contributions from the United States, China, and Germany, with collaborative networks focusing on protein dynamics. Key hotspots include LLPS-driven aggregation of TARDBP (TDP-43), FUS, and α-synuclein, alongside stress granule dysfunction and nucleocytoplasmic transport defects. Emerging frontiers highlight therapeutic strategies targeting pathological condensates utilizing small-molecule chaperones and posttranslational modification modulators to restore cellular homeostasis. Our findings underscore LLPS as a critical axis bridging molecular pathology and translational innovation. The field is rapidly shifting from mechanistic exploration to therapeutic applications, emphasizing interventions to halt or reverse aggregation. By delineating global trends and changing priorities, our study highlights the transformative potential of phase-targeted interventions and provides a roadmap of groundbreaking interdisciplinary research into neurodegenerative disorders.}, }
@article {pmid42418533, year = {2026}, author = {Hsu, YW and Lu, YN and Liu, M and Wang, J}, title = {Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration.}, journal = {PLoS genetics}, volume = {22}, number = {7}, pages = {e1012225}, doi = {10.1371/journal.pgen.1012225}, pmid = {42418533}, issn = {1553-7404}, abstract = {Neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) remain largely unsolved, with complex etiology yet to be fully elucidated. The most common genetic cause of ALS in both familial and sporadic cases is the expansion of a hexanucleotide repeat in the C9orf72 gene. To systemically dissect the molecular landscape of ALS, we performed integrative transcriptomic analyses across multiple central nervous system regions from ALS patients carrying pathological C9orf72 repeat expansions (ALS-C9) and those without the mutation (ALS-non-C9). In parallel, we performed transcriptome-wide cell-type deconvolution to assess the cellular composition of neuronal and non-neuronal populations. We identified a set of dysregulated molecular pathways that were consistently altered in both ALS-C9 and ALS-non-C9 patients, suggesting shared pathogenic mechanisms. Distinct gene-specific alterations also pointed to divergent subtype-dependent molecular trajectories. Gene-specific alterations were also associated with short clinical duration in ALS-non-C9, highlighting a sex-dependent immunological contribution to disease outcome. Our cross-regional integrative transcriptomic analyses reveal both convergent and divergent molecular and cellular features between ALS-C9 and ALS-non-C9 subgroups, underscoring the clinical heterogeneity of ALS and providing a framework for subtype- and sex-specific therapeutic stratifications.}, }
@article {pmid42418847, year = {2026}, author = {de La Seiglière, H and Letourneur, &#xc6; and Ichas, F and De Giorgi, F}, title = {Phase separation and protein aggregation in neurodegenerative diseases.}, journal = {Biophysical chemistry}, volume = {338}, number = {}, pages = {107678}, doi = {10.1016/j.bpc.2026.107678}, pmid = {42418847}, issn = {1873-4200}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, frontotemporal dementia, and ALS are characterized by amyloid protein aggregation involving intrinsically disordered proteins that are also capable of liquid-liquid phase separation (LLPS). LLPS, known to drive the formation of dynamic membraneless organelles essential for cellular functions, can play a role in limiting fibrillation process or aberrantly transition into solid aggregates under pathological conditions. Here we review how mutations, post-translational modifications, and environmental factors can modulate LLPS of proteins like Tau, TDP-43, FUS, and α-synuclein, potentially regulating amyloid aggregation. We also examine the interplay of these proteins exploring how LLPS and condensate maturation could impinge on the emergence of co-pathologies contributing to disease progression. Finally we discuss emerging therapeutic strategies, aimed at modulating phase separation dynamics.}, }
@article {pmid42419281, year = {2026}, author = {Kournoutis, A and Stenmark, H}, title = {Sealing and healing: A two-step model for plasma membrane repair.}, journal = {Developmental cell}, volume = {61}, number = {7}, pages = {1345-1346}, doi = {10.1016/j.devcel.2026.06.011}, pmid = {42419281}, issn = {1878-1551}, mesh = {*Cell Membrane/metabolism ; Animals ; Humans ; Models, Biological ; *Annexins/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Mutation ; }, abstract = {Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.}, }
@article {pmid42419491, year = {2026}, author = {Ellappan, S and Kujur, PP and Mondal, AC}, title = {The Autophagy-Senescence-Inflammasome Axis: A Novel Triad in Neurodegenerative Diseases?.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103248}, doi = {10.1016/j.arr.2026.103248}, pmid = {42419491}, issn = {1872-9649}, abstract = {Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.}, }
@article {pmid42419740, year = {2026}, author = {Varga, D and Ráduly, Z and Boros-Oláh, B and Nagy, &#xc9; and Karányi, Z and Halász, L and Bálint, BL and Vámosi, G and Tóth, E and Bai, P and Santangelo, S and Bossolasco, P and Ratti, A and Géli, V and Pommier, Y and Székvölgyi, L}, title = {TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70649}, pmid = {42419740}, issn = {1742-4658}, support = {//Thematic Excellence Programme/ ; 142137//NKFIH/ ; 130913//NKFIH/ ; 135107//NKFIH/ ; K146028//NKFIH/ ; K124141//NKFIH/ ; K152259//NKFIH/ ; TKP2021-EGA-19//NKFIH/ ; TKP2021-EGA-20//NKFIH/ ; //HUN-REN Hungarian Research Network/ ; //National Research, Development and Innovation Fund of Hungary/ ; }, abstract = {Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.}, }
@article {pmid42420066, year = {2026}, author = {Tien-Smith, AZ and Absar, S and Rogowski, CB and Phillips, V and Andersen, ZJ and Bredell, C and Fung, KW and Hong, L and Szybka, M and Woodcock, J and Brayne, C and Khreis, H and Navaratnam, AMD}, title = {Association of long-term outdoor air pollution exposure with incidence of Parkinson's disease, multiple sclerosis and motor neuron diseases: a systematic review and meta-analysis.}, journal = {Environment international}, volume = {}, number = {}, pages = {110377}, doi = {10.1016/j.envint.2026.110377}, pmid = {42420066}, issn = {1873-6750}, abstract = {BACKGROUND: Parkinson's disease (PD), multiple sclerosis (MS) and motor neurone disease (MND) are progressive and debilitating diseases that are increasing in prevalence globally. Some primary studies show an increased risk from long-term outdoor air pollution exposure, while others contradict this association.<br><br>METHODS: A systematic review and meta-analysis were undertaken to assess the associations of long-term (&#x2265;1 year) outdoor air pollution exposure with PD, MS and MND incidence. We searched eight databases for publications up to July 2025. Primary case-control, cohort, cross-sectional or ecological studies investigating the association between long-term air pollution exposure and adult (>18&#xa0;years old) PD, MS, or MND incidence were included. Meta-analyses were carried out using random-effects models with assessment of heterogeneity, meta-bias and shape of the exposure-response functions. PROSPERO (CRD42023417961).<br><br>RESULTS: Of 42 papers included, 26, 3 and 3 were meta-analysed for PD, MS, and MND outcomes, respectively. 19 studies from North America, 12 from Europe and 10 from Asia were meta-analysed. For every 5&#xa0;&#x3bc;g/m[3] and 15&#xa0;&#x3bc;g/m[3] increase of Particulate Matter 2.5 (PM2.5) and PM10 concentration, estimated (95% Confidence Interval) PD risk was 10% (1.10; 1.03-1.19) and 18% (1.18; 1.01-1.38), respectively but effects varied across settings (Prediction Interval: 0.80-1.52 for PM2.5 and 0.41-3.36 for PM10), with the largest estimated risk for PM2.5 in Asia (1.19; 1.01-1.41). There was no clear evidence that PM2.5 (1.01; 0.77-1.32) or nitrogen dioxide (NO2, 0.98, 95% CI: 0.95-1.01) were associated with MS risk or PM2.5 with MND risk (1.07, 95% CI: 0.86-1.33).<br><br>CONCLUSION: This systematic review reports increased PD risk from long-term PM2.5 and PM10 exposure. No association was observed for MS and MND from a very limited evidence base. The neurodegenerative diseases investigated here are rare and therefore alternatives to insufficiently powered cohort studies are needed to strengthen the evidence on risk.}, }
@article {pmid42404433, year = {2026}, author = {Corti, S and Alberti, C and Ottoboni, L and Magni, G and Gagliardi, D and Marcotti, F and Zanotti, S and Moggio, M and Comi, GP}, title = {Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag241}, pmid = {42404433}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by accumulation of the 43-kDa TAR DNA-binding protein (TDP-43). This neuropathological signature has been well documented within the CNS; however, recent findings indicate that the phosphorylated TDP-43 additionally deposits in peripheral tissues, including skeletal muscle and intramuscular nerves. These data warrant a change of view from a neurocentric perspective of amyotrophic lateral sclerosis pathogenesis towards a broader concept of TDP-43 proteinopathy extending both within and beyond the nervous system. In this review, we focus on current evidence supporting the presence of TDP-43 pathology in amyotrophic lateral sclerosis skeletal muscle, examining its topographic distribution, molecular characteristics and associations with intramuscular nerve bundles. We also discuss the susceptibility of intrinsic muscle cells, disrupted axonal transport and impairment in protein quality control. Phosphorylated TDP-43 pathology in muscle biopsies from amyotrophic lateral sclerosis patients has emerged as a promising tool in the early diagnosis of the disease. Moreover, we discuss the relevance of these findings to amyotrophic lateral sclerosis pathogenesis and potential therapeutic implications.}, }
@article {pmid42404435, year = {2026}, author = {Hobin, F and Das, S and Lambrechts, C and De Rocker, C and Dubin, J and Ombelet, F and De Vocht, J and Lamaire, N and Vanmechelen, E and Poesen, K and Van Damme, P}, title = {Value of synaptic proteins as biomarkers in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag247}, pmid = {42404435}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a heterogeneous and rapidly progressing neurodegenerative disorder with limited treatment options. Therefore, there is a critical need for biomarkers that capture the diverse pathophysiological mechanisms underlying disease onset and progression. Emerging evidence suggests that synaptic dysfunction is an early disease mechanism in amyotrophic lateral sclerosis. Using homebrew immunoassays, we explored a panel of pre- and post-synaptic proteins in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (N = 57) and controls (N = 36). The potential value as a biomarker was explored by correlating cerebrospinal fluid levels with clinical parameters and established biomarkers for amyotrophic lateral sclerosis. Higher levels of Neurogranin (NRGN) (P = 0.003) and Vesicle-associated membrane protein 2 (VAMP2) (P = 0.014) were observed in patients with amyotrophic lateral sclerosis compared with controls. VAMP2, Synaptosome-associated protein 25 kDa (SNAP25) and β-synuclein (SNCB) correlated with individual relative disease stage, but none of the biomarkers correlated with disease progression rate. High levels of SNAP25 predicted worse survival in a univariate and stepwise multivariable analysis, but significance did not persist upon including Neurofilament light chain (NfL) levels. Synaptic proteins did not correlate with cerebrospinal fluid levels of neurofilaments or biomarkers of neuroinflammation, suggesting that they reflect different pathological mechanisms in amyotrophic lateral sclerosis. Our findings warrant further investigation to determine whether increased cerebrospinal fluid levels of synaptic proteins reflect synaptic breakdown or active release of synaptic proteins. This will help elucidate how synaptic dysfunction or damage contributes to elevated levels of synaptic markers in amyotrophic lateral sclerosis, and its underlying value as biomarker.}, }
@article {pmid42404802, year = {2026}, author = {Nieva, G and Vassallu, F and Depino, A and Netti, V and Igaz, LM}, title = {Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies.}, journal = {Discovery immunology}, volume = {5}, number = {1}, pages = {kyag011}, pmid = {42404802}, issn = {2754-2483}, abstract = {INTRODUCTION: Aggregation and cytoplasmic mislocalization of TDP-43 are key features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuroinflammatory processes mediated by glial cells play crucial roles in the pathophysiology of these and other diseases, defined as TDP-43 proteinopathies. Here, we characterized region-specific glial activation in two conditional mouse models: hTDP-43-WT (overexpressing nuclear wild-type human TDP-43) and hTDP-43-ΔNLS (expressing cytoplasmic TDP-43 with altered nuclear localization signal) following 1 month of transgene expression.<br><br>METHODS AND RESULTS: Immunofluorescence analysis revealed distinct patterns of microglial activation across brain regions. hTDP-43-WT mice exhibited significant microgliosis in motor (MC) and somatosensory (SSC) cortices and hippocampal dentate gyrus (DG) with pronounced morphological alterations (i.e. increased soma size). Sholl analysis demonstrated reduced branching length and complexity in MC, SSC, and hippocampal subfields. hTDP-43-&#x394;NLS mice displayed more pronounced microglial activation in hippocampal regions (CA1, DG) compared to cortical areas, with significant increases in microglial density. Additionally, we observed region-specific cortical astrocytosis in both models, suggesting coordinated glial reactivity. hTDP-43-&#x394;NLS mice showed decreased polarization of astrocytic water channel Aquaporin-4 (AQP4) around vascular structures in SSC and hippocampal CA1/DG. The changes in AQP4 localization, which is critical for glymphatic function, support the hypothesis that this waste clearance system for the brain is altered in TDP-43 proteinopathies.<br><br>CONCLUSION: These findings demonstrate that these different animal models of ALS/FTD induce distinct neuroinflammatory signatures, potentially contributing to the region-specific vulnerability observed in these diseases. Our data provide insights into early glial-mediated pathogenic mechanisms that could guide targeted therapeutic strategies for TDP-43 proteinopathies.}, }
@article {pmid42405014, year = {2026}, author = {Farè, M and Comi, C and Ferrero, GS and Sala, G and Cerri, F and Calabresi, L and Tremolizzo, L and Pavanello, C}, title = {Cholesterol in amyotrophic lateral sclerosis: a bystander, a biomarker, or a target?.}, journal = {Atherosclerosis plus}, volume = {65}, number = {}, pages = {100576}, pmid = {42405014}, issn = {2667-0895}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. In addition to the different pathogenic mechanisms, in recent years, increasing attention has been directed toward the role of lipid metabolism in ALS pathogenesis, although the clinical relevance of lipid alterations in ALS may differ from their well-established role in cardiovascular disease. This review critically examines the multifactorial relationship between cholesterol and ALS through three perspectives: (1) as a risk factor for disease onset, (2) as a prognostic biomarker of disease progression, and (3) as a potential therapeutic target. Epidemiological and genetic studies suggest a complex and sometimes contradictory association between lipid profile and ALS risk. Elevated LDL-cholesterol and total cholesterol have been linked to increased disease susceptibility in some cohorts, with Mendelian randomization studies supporting a potential causal role. Conversely, evidence regarding HDL-cholesterol remains conflicting and may be influenced by sex-specific and metabolic factors. As a prognostic biomarker, hyperlipidemia has been variably associated with prolonged survival in ALS patients; however, these findings often lose significance after adjusting for body mass index and nutritional status, suggesting that lipid levels may reflect systemic metabolic reserve rather than directly modulating disease progression. Pharmacological modulation of cholesterol reveals further complexity. While statins are generally not associated with increased ALS risk in clinical studies, preclinical models show divergent effects: some statins accelerate disease progression, while others like lovastatin may be protective. Other lipid-lowering drugs, including fibrates and PCSK9 inhibitors, may also influence ALS-related pathways beyond cholesterol lowering, although their potential role remains to be clarified.}, }
@article {pmid42405987, year = {2026}, author = {Botman, LCM and van Unnik, JWJ and Beelen, A and Bakers, JNE and van der Schoot, ND and Gremmen, MAP and van Helm, S and van den Berg, LH and van Eijk, RPA}, title = {Feasibility and sensitivity of a multimodal digital endpoint panel for amyotrophic lateral sclerosis: a prospective cohort study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2696382}, pmid = {42405987}, issn = {2167-9223}, abstract = {Background: The use of digital technology may improve monitoring of amyotrophic lateral sclerosis (ALS) but a multimodal approach is likely required to capture the full disease phenotype. We evaluated the feasibility of a multimodal home monitoring protocol in ALS. Methods: We conducted a 3-month prospective cohort study at the University Medical Center Utrecht, Netherlands, with monthly home assessments of spirometry, accelerometry, speech, and questionnaires on functioning. The primary outcome was protocol adherence, defined as percentage of completed assessments. Secondary outcomes included acceptability ((totally) agree, neutral, (totally) disagree), and perceived burden, ranging from 0 (no burden) to 10 (extremely burdensome). Exploratory analyses were performed to evaluate changes in digital endpoints using linear mixed-effects models. Findings: Fifty patients with ALS were included (January 2023 - June 2025), of whom 47 (94%) completed the 3-month follow-up. Overall adherence was 83.2% (95% CI 76.9-88.6) and did not differ across modalities (p = 0.75). Adherers did not differ from non-adherers in either demographic or disease characteristics. In month 3, 93.0% to 95.3% of patients considered monthly remote assessments as acceptable, with a mean burden score of 2.0 (95% CI 1.7 to 2.3); burden was highest for speech (2.5) and the lowest for questionnaires (1.5). Digital endpoints showed significant change over 3 months (all p < 0.05). Interpretation: This study demonstrates good adherence and acceptability of a multimodal remote monitoring protocol. Digital endpoints offer an innovative approach to capturing disease progression. Future research should assess its long-term feasibility, added value, and integration alongside established clinical outcomes.}, }
@article {pmid42406382, year = {2026}, author = {Guise, AJ and Sellon, MT and Roemer, SF and Monine, M and Comfort Harris, NT and Bartlett, D and David, E and Xu, S and Jandreski, L and Malek, S and Garafalo, S and Nestorov, I and Ireland, MD and King, A and Bowser, RP and Korobeynikov, V and Ravits, J and Shaw, PJ and Highley, JR and Ferguson, TA and Fradette, S and Graham, DL and Sorenson, EJ and Oskarsson, B and Reichard, RR and Dickson, DW and Paganoni, S and Babu, S and Oakley, DH and Frosch, MP and Miller, TM and Bucelli, RC and Perrin, RJ and Ly, CV and Plowey, ED}, title = {Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {42406382}, issn = {2168-6157}, abstract = {IMPORTANCE: Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1-amyotrophic lateral sclerosis (SOD1-ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues.<br><br>OBJECTIVES: To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues.<br><br>This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1-ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026.<br><br>EXPOSURES: Participants received multiple intrathecal 20- to 100-mg tofersen doses.<br><br>MAIN OUTCOMES AND MEASURES: Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study's recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1-ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays.<br><br>RESULTS: In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1-ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses.<br><br>CONCLUSIONS AND RELEVANCE: This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.}, }
@article {pmid42406818, year = {2026}, author = {Ergün, B and Karakuş, E and Huri, M}, title = {School-Based Occupational Therapy Interventions Through the Lens of the F-Words Framework: A Scoping Review.}, journal = {Child: care, health and development}, volume = {52}, number = {4}, pages = {e70312}, doi = {10.1111/cch.70312}, pmid = {42406818}, issn = {1365-2214}, mesh = {Humans ; *Occupational Therapy/methods/organization &amp; administration ; Child ; *Child Development ; *School Health Services/organization &amp; administration ; Adolescent ; Child, Preschool ; Schools ; }, abstract = {BACKGROUND: School participation plays a critical role in children's development; however, the extent to which school-based occupational therapy (SBOT) interventions align with the 'F-words for Child Development' (Functioning, Family, Fitness, Friendships, Fun, Future) has not been systematically examined.<br><br>OBJECTIVE: This study aims to systematically scope SBOT interventions published between 1990 and 2025 and classify them according to the F-words framework.<br><br>METHODS: The review adopted the Arksey-O'Malley scoping review framework as the foundational methodological structure and incorporated Levac et&#xa0;al.'s refinements to enhance rigour. The review was informed by Joanna Briggs Institute (JBI) guidance for scoping reviews, and reporting followed the PRISMA-ScR checklist. PubMed, Scopus and Web of Science were searched using strategies grounded in the OTPF-4 and MeSH. Eligibility criteria included peer-reviewed intervention studies delivered in schools to students aged 3-18&#x2009;years, published in English between 1990 and 2025.<br><br>RESULTS: Of 2406 records, 35 studies met the inclusion criteria. Most originated from North America and Australia. The distribution of interventions across the F-words domains was uneven: Functioning appeared in 34 studies (97%), Fitness in 29 (83%), Fun in 23 (66%), Family in 18 (51%), Future in 11 (31%) and Friendships in only 7 (20%).<br><br>CONCLUSIONS: SBOT research predominantly emphasizes Functioning and Fitness, while Friendships and Future are comparatively neglected. A more balanced application of the F-words framework would provide a broader understanding of how SBOT interventions are distributed across child development domains.}, }
@article {pmid42407013, year = {2026}, author = {Oliveira Santos, M and Castro, J and Castro, I and Swash, M and de Carvalho, M}, title = {Role of the Upper Motor Neuron in the Generation of Fasciculations in Early Disease Stages of Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {107}, number = {2}, pages = {e218273}, doi = {10.1212/WNL.0000000000218273}, pmid = {42407013}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; *Motor Cortex/physiopathology ; Transcranial Magnetic Stimulation ; Female ; Male ; Aged ; *Fasciculation/physiopathology/etiology ; Middle Aged ; Electromyography ; Muscle, Skeletal/physiopathology ; }, abstract = {BACKGROUND AND OBJECTIVES: The origin of fasciculation potentials (FPs) in the early stages of amyotrophic lateral sclerosis (ALS) remains a subject of debate. We investigated the role of the motor cortex in FP generation by comparing resting FP frequency in the first dorsal interosseous (FDI) muscle before and after motor cortex inhibition induced by continuous theta-burst stimulation (cTBS).<br><br>METHODS: We studied patients with early-stage ALS (G1) and a disease-control group (G2) comprising individuals with chronic lower motor neuron (LMN) disorders or benign fasciculation syndrome without upper motor neuron (UMN) involvement. Inclusion required a right FDI strength of MRC grade 4+ or 5. At baseline, we recorded FP frequency and amplitude in the right FDI (3 replicates) and the motor evoked potential (MEP) amplitude. These measures were repeated immediately after cTBS-induced corticomotor inhibition. Statistical significance was set at p < 0.05.<br><br>RESULTS: Twenty-two patients with ALS (14 men; median age 65.5 years; 72.7% spinal onset) were included, with a median disease duration of 6.4 months and a mean ALSFRS-R score of 44. The control group (G2) consisted of 11 participants. Notably, 50% of the ALS cohort showed no neurogenic features on needle EMG of the right FDI at enrollment. Baseline peripheral and cortical amplitudes and left hemisphere motor thresholds were comparable between groups. After cTBS, MEP amplitudes decreased significantly in both G1 (0.93 vs 0.50 mV, p = 0.02) and G2 (1.23 vs 0.38 mV, p = 0.02). However, a significant reduction in FP frequency (39.5%) occurred only in the ALS group (0.43 vs 0.26 Hz, p < 0.001), whereas no change was observed in G2 (0.60 vs 0.77 Hz, p = 0.14). Patients with ALS with a normal FDI EMG demonstrated an even greater reduction in FP frequency (54.5%). FP amplitudes remained stable across both groups after cTBS.<br><br>DISCUSSION: Our findings indicate that in early ALS, LMN excitability is significantly modulated by descending corticospinal input. The reduction in FP frequency after cortical inhibition suggests that FPs in early ALS are driven by a combination of both UMN and LMN hyperexcitability, distinguishing them from fasciculations in other neurogenic disorders.}, }
@article {pmid42407404, year = {2026}, author = {Gündüz, A and Şirin, NG and Boran, E and Baslo, SA and Baslo, MB and Kuruoğlu, HR and Kocasoy Orhan, E and Öge, AE and Yıldız, FG and Tümer, O and Tütüncü, M and Tan, E and Temuçin, &#xc7;M and Uysal, H and Uzun, N and Cengiz, B}, title = {The contribution of trapezius and sternocleidomastoideus motor evoked potentials in the diagnosis of Amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {190}, number = {}, pages = {2112331}, doi = {10.1016/j.clinph.2026.2112331}, pmid = {42407404}, issn = {1872-8952}, abstract = {OBJECTIVE: We aimed to evaluate the role of corticobulbar motor evoked potentials (MEPs) as an objective electrophysiological measure to support clinical assessment of upper motor neurons in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Seventy-three patients with ALS and 44 healthy individuals with similar age and sex underwent transcranial magnetic stimulation with MEP recordings from the sternocleidomastoideus (SCM), trapezius, and abductor pollicis brevis muscles. Corticobulbar involvement was defined by prolonged cortical MEP latency or central motor conduction time (CMCT) or absence of MEP responses. Awaji-Shima diagnostic categories were evaluated before and after the incorporation of corticobulbar MEP abnormalities.<br><br>RESULTS: Corticobulbar MEP abnormalities were significantly more frequent in patients with ALS than in controls. Prolonged SCM-MEP latency and CMCT were the most sensitive electrophysiological markers of corticobulbar involvement. When interpreted alongside clinical upper motor neuron signs, corticobulbar MEP abnormalities facilitated upward diagnostic reclassification within the Awaji-Shima framework. One-fifth of patients who were initially classified as possible or probable ALS were reclassified as probable ALS and definite ALS, respectively, following inclusion of SCM- and trapezius-MEP abnormalities.<br><br>CONCLUSIONS: Corticobulbar MEP assessment provides objective electrophysiological support for upper motor neuron dysfunction and enhances diagnostic sensitivity when used in conjunction with the Awaji-Shima diagnostic framework.<br><br>SIGNIFICANCE: This study demonstrates that electrophysiological assessment of the corticobulbar pathway using SCM- and trapezius-MEPs provides objective evidence of upper motor neuron dysfunction in ALS.}, }
@article {pmid42409373, year = {2026}, author = {Kida, H and Kanai, T and Morita, M and Hasegawa, T}, title = {Bedside muscle ultrasonography to detect fasciculations and support diagnosis of amyotrophic lateral sclerosis in a mechanically ventilated intensive care unit patient.}, journal = {Acute and critical care}, volume = {}, number = {}, pages = {}, doi = {10.4266/acc.002080}, pmid = {42409373}, issn = {2586-6060}, }
@article {pmid42410102, year = {2026}, author = {Binet, M and Jewett, G and Breiner, A and Chum, M and Genge, A and Schellenberg, K and Shoesmith, C and Pfeffer, G and Salmon, K}, title = {A changed landscape: five-year retrospective on the paradigm shift in genetic testing practices for ALS in Canada.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42410102}, issn = {1476-5438}, abstract = {Offering genetic testing is increasingly recommended for all individuals with amyotrophic lateral sclerosis (ALS), particularly following the development of gene-targeted therapies, such as tofersen for SOD1-ALS. Historically, testing was routinely offered to those with familial ALS (fALS), but inconsistently to those with sporadic ALS (sALS). We evaluated changes in genetic testing and counseling practices among Canadian ALS physicians over a five-year period spanning pivotal clinical trial results and regulatory approval of tofersen. Members of the Canadian ALS Research Network were surveyed in 2020, 2022, and 2025 about genetic testing practices for symptomatic and asymptomatic individuals, gene panel composition, access to genetic counseling, and perceived drivers of change. Clinics offering genetic testing for sALS increased from 33% of clinics in 2020 and 57% in 2022 to 100% of respondents in 2025. Genetic testing for patients with a family history (fALS) was near-universal across all timepoints. Broader use of multi-gene panel testing increased over time, coinciding with sponsored testing availability. 61% of respondents reported that Health Canada approval of tofersen directly influenced their practice. Predictive testing offerings increased from 37% in 2020 to 61% in 2025. Genetic testing practices in Canada shifted substantially during late-stage clinical development and following regulatory approval of a gene-targeted therapy (tofersen). Proactive planning during the clinical trial phase facilitated rapid, nationwide adoption. This study captures a key turning point in ALS care, illustrating how therapeutic breakthroughs can redefine national clinical standards.}, }
@article {pmid42410908, year = {2026}, author = {Matsuo, T and Imamura, R}, title = {Nocturia Beyond the Bladder: Editorial Comment on Kira et al.'s Nationwide JaCS 2023 Analysis.}, journal = {International journal of urology : official journal of the Japanese Urological Association}, volume = {33}, number = {7}, pages = {e70564}, doi = {10.1111/iju.70564}, pmid = {42410908}, issn = {1442-2042}, }
@article {pmid42411077, year = {2026}, author = {Singh, P and Bhardwaj, S and Nagarajan, K}, title = {A Review on the Mechanisms of Neurodegeneration and the Potential of Plant Bioactives in Managing Neurological Conditions.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098388719251206111338}, pmid = {42411077}, issn = {1874-6128}, abstract = {Neurodegenerative disorders encompass a wide range of debilitating neurological conditions characterized by the progressive loss of specific neuronal populations in the central and/or peripheral nervous systems. This disease often leads to a gradual decline in cognitive, motor, and sensory abilities. This review explores the role of various lifestyle factors, such as age, sex, poor diet, depression, etc., which contribute to the onset and progression of NDDs. Various diseases are included in the neurodegenerative disorder, like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Lewy body disease, which are chronic conditions that significantly impact cognitive and motor functions. A literature search was conducted in the scientific database using the keywords "neurodegenerative disorders, phytoconstituents, and herbals". This review includes a collection of reports from ScienceDirect, Scholar Google, and PubMed, all searched up to 2024. The results were assessed, gathered, and reported in this paper. A total of 241 articles were included, with exponential growth in publication numbers from 1985 to 2024. Effective management and control of NDDs require addressing these risk factors, alongside exploring therapeutic interventions. Some plants and herbs used to treat neurodegenerative diseases, such as curcumin, ashwagandha, ginkgo biloba, epigallocatechin-3-gallate, quercetin, ginseng, and resveratrol, have shown potential to improve neuronal health and mitigate disease progression. This review highlights the dual role of natural compounds in promoting improvements and upregulating brain function while potentially reducing degradation. The phytopharmaceuticals show the potential for treating neurological conditions with better efficacy and safer profiles. The review suggested that future research should focus on integrating lifestyle modifications and natural therapies to enhance the quality of life for individuals at risk or suffering from neurodegenerative diseases.}, }
@article {pmid42411482, year = {2026}, author = {Yang, EJ}, title = {Amyotrophic Lateral Sclerosis as a Systemic Disease: Why Integrative and Microbiome-Focused Approaches Deserve Re-Evaluation.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {6}, pages = {52497}, doi = {10.31083/FBL52497}, pmid = {42411482}, issn = {2768-6698}, support = {KSN2225011//KIOM/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology/physiopathology ; *Complementary Therapies/methods ; *Gastrointestinal Microbiome ; Animals ; Dysbiosis/microbiology ; }, abstract = {Despite decades of intensive research, therapeutic advances in amyotrophic lateral sclerosis (ALS) remain limited. Increasing evidence suggests that ALS is a multisystem disorder involving motor neuron degeneration, immune dysregulation, skeletal muscle pathology, and gastrointestinal dysfunction, thereby challenging the adequacy of current therapeutic strategies. Complementary and alternative medicine (CAM) approaches are widely used by patients with ALS. However, their efficacy remains controversial owing to limited clinical evidence and methodological limitations. The multicomponent herbal medicine and system-level characteristics of CAM conceptually align with the emerging view of ALS as a multisystemic disease. The involvement of gut microbiome dysbiosis in the pathophysiology of ALS has provided a unifying biological framework linking the peripheral, metabolic, and neuroinflammatory processes. These findings suggest that the combination of CAM and conventional therapy may serve as a potential integrative approach to target gut-brain-muscle interactions and systemic disease pathways. This article highlights critical gaps in the existing evidence and proposes that microbiome-focused, biomarker-driven clinical trials are essential to thoroughly evaluate CAM-based interventions in ALS. Embracing a system-oriented therapeutic framework may help address the complexity of ALS beyond traditional neuron-centered approaches.}, }
@article {pmid42411953, year = {2026}, author = {Adachi, T and Nakano, T and Yoshida, K and Suzuki, Y and Sakuwa, M and Hasegawa, M and Jannah, AR and Hara, N and Miyashita, A and Ikeuchi, T and Hanajima, R}, title = {Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70091}, doi = {10.1111/nan.70091}, pmid = {42411953}, issn = {1365-2990}, support = {24K10643//Japan Society for the Promotion of Science/ ; JP25dk0207060//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Autophagy-Related Proteins ; Adaptor Proteins, Signal Transducing ; *Cell Cycle Proteins/genetics/metabolism ; Mutation ; DNA-Binding Proteins/metabolism ; Autopsy ; Male ; Female ; *Ubiquitins/genetics ; Brain/pathology/metabolism ; Middle Aged ; }, abstract = {We report the clinicopathological and biochemical findings of ALS associated with a UBQLN2 P494L mutation. Autopsy revealed widespread TDP-43 pathology and UBQLN2-positive inclusions. Immunoblot analysis demonstrated a marked reduction of soluble UBQLN2, supporting functional UBQLN2 insufficiency as a pathogenic mechanism underlying TDP-43 aggregation.}, }
@article {pmid42412610, year = {2026}, author = {Pasniceanu, IS and Atwal, MS and Santos Souza, CD and Moll, T and King, M and Treanor, C and Cabezas de la Fuente, D and West, RJH and Ferraiuolo, L and Livesey, MR}, title = {Striatal neuron dysfunction in C9ORF72-FTD/ALS is driven by AIS and potassium channel dysregulation.}, journal = {Cell reports}, volume = {45}, number = {7}, pages = {117672}, doi = {10.1016/j.celrep.2026.117672}, pmid = {42412610}, issn = {2211-1247}, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) form a neurodegenerative spectrum characterized by progressive cognitive, behavioral, and motor decline, yet the contribution of the striatum to disease pathophysiology remains poorly understood. Here, we generate inhibitory striatal medium spiny neurons (MSNs) from human induced pluripotent stem cells carrying the C9ORF72 repeat expansion, the most common genetic cause of FTD/ALS, and compare them with isogenic-corrected, control, and patient-derived motor neurons. Using whole-cell electrophysiology, pharmacological manipulation, and high-resolution imaging, we identify a vulnerability of C9ORF72 MSNs to develop intrinsic hypoexcitability with linked synaptic dysfunction. These abnormalities are associated with axon initial segment shortening and altered voltage-gated potassium channel function relative to control and isogenic-corrected neurons. Pharmacological modulation partially restores action potential waveform properties, indicating that key electrophysiological abnormalities are reversible. These findings identify the striatum as a critical site of dysfunction in FTD/ALS and highlight striatal excitability as a potential therapeutic target.}, }
@article {pmid42401978, year = {2026}, author = {Alsina, R and Riba, M and Sartorio, M and Romera, C and Riu, J and Vilaplana, G and Aldecoa, I and Compta, Y and Sánchez-Valle, R and Del Valle, J and Pelegrí, C and Molina-Porcel, L and Vilaplana, J}, title = {Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02362-3}, pmid = {42401978}, issn = {2051-5960}, support = {FPU//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; Margarita Salas//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; FPI//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; PID2020-115475GB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; 2021 SGR 00288 625//Generalitat de Catalunya/ ; }, abstract = {The glymphatic system plays a key role in clearing waste products from the brain and is essential for maintaining brain homeostasis. When dysfunctional, it appears to contribute to pathological changes that exacerbate brain disorders, including neurodegenerative diseases. Additionally, wasteosomes, also known as corpora amylacea, are structures that function as waste containers and are thought to increase in response to chronic glymphatic insufficiency. Hence, in this study, we evaluated whether the accumulation and distribution of wasteosomes are compatible with both the potential role of wasteosomes as a hallmark of the chronic glymphatic insufficiency and the presence of this insufficiency in certain neurodegenerative diseases. Accordingly, brain tissue from 185 donors was analysed, including cases of Alzheimer's disease, amyotrophic lateral sclerosis with TDP-43 proteinopathy, frontotemporal lobar degeneration with TDP-43 or tau proteinopathy, and non-diseased controls. Wasteosomes were examined across 28 brain regions comprised within 5 major brain areas, using region-specific scoring systems. Analysis was conducted through variance and covariance analyses, along with decision tree procedures. The findings reveal that wasteosomes are consistently found in specific critical regions, with a higher burden in donors with neurodegenerative diseases compared with controls. These regions are independent of the regional distribution of the underlying proteinopathy, and are potentially associated with glymphatic drainage pathways. From an integrated perspective, although further studies are required, the increased presence of wasteosomes in these critical regions across all diseased groups is consistent with the potential presence of chronic glymphatic insufficiency in these diseases.}, }
@article {pmid42402806, year = {2026}, author = {O'Sullivan, S and Tadjine, Y and Palma, GR and Suleyman, N and Woods, E and Fasano, A and Walsh, C and Awiszus, F and Hardiman, O and Carson, RG and McMackin, R}, title = {Very low-amplitude muscle activity increases probability of motor evoked potentials in healthy individuals and in amyotrophic lateral sclerosis.}, journal = {Experimental physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/EP093429}, pmid = {42402806}, issn = {1469-445X}, support = {GOIPG/2017/1014//Irish Research Council (IrishResearch)/ ; McMackin/Oct20/972-799//Motor Neurone Disease Association (MNDA)/ ; MRCG-2018-02//Research Motor Neurone/ ; 23-PPG-674-1//ALS Association (ALSA)/ ; 20-IIA-546//ALS Association (ALSA)/ ; 23-PPG-674-1//ALS Finding A Cure/ ; MRCG-2018-02//Health Research Board (HRB)/ ; SS-2023-039//Health Research Board (HRB)/ ; }, abstract = {Muscle contraction increases motor evoked potential (MEP) amplitude, decreasing motor threshold (MT). Correspondingly, trials where baseline EMG amplitude exceeds a specified threshold are often rejected. We aimed to investigate the influence of motor activity below such a threshold of MEP amplitude. We retrospectively analysed TMS-EMG data collected during resting MT (RMT) measurement in 45 healthy control subjects (1794 data points) and 35 people with amyotrophic lateral sclerosis (ALS; 1229 data points). Trials with de-meaned root mean squared (RMS) EMG amplitude of >10 µV throughout the 200 ms prior to stimulation were rejected. Generalised linear mixed-effects models assessed effects of muscle activity below this rejection threshold on the probability of evoking an MEP with peak-to-peak amplitude of ≥50 µV. Greater sub-rejection-threshold activity significantly increases MEP probability in control subjects and people with ALS. Models predicted a 38%-43% increase in MEP probability when baseline RMS-EMG amplitude increased from 1 $\hskip.001pt 1$ to 9 µV. Sub-rejection-threshold baseline activity was significantly greater in ALS than control subjects. Below a typical rejection threshold, greater baseline RMS-EMG amplitudes markedly increase the probability of evoking MEPs with peak-to-peak amplitude of ≥50 µV. Effects of sub-rejection-threshold muscle activity should be accounted for when comparing RMT measures, particularly between cohorts where such activity differs, such as ALS and control subjects.}, }
@article {pmid42403529, year = {2026}, author = {Wilson, E and Turner, N and Macdonald, G and Faull, C}, title = {Paid homecare worker support for people living with motor neurone disease: A secondary analysis of people living with motor neurone disease and family member perspectives.}, journal = {Palliative care and social practice}, volume = {20}, number = {}, pages = {26323524261452739}, pmid = {42403529}, issn = {2632-3524}, abstract = {BACKGROUND: People living with motor neurone disease (MND) increasingly receive complex, life-sustaining interventions at home, including ventilation, tube feeding, and cough assist support. These demands place substantial strain on family carers and often require input from paid homecare workers. Despite their essential role, little is known about how homecare workers contribute to complex MND care, how they integrate within multidisciplinary teams, or how families experience their involvement.<br><br>OBJECTIVES: To examine people living with MND and family members' perspectives of homecare worker roles, responsibilities, relationships when complex interventions are required.<br><br>DESIGN: A qualitative secondary analysis of data from two prior studies exploring home ventilation and tracheostomy ventilation in MND.<br><br>METHODS: Seven relevant NVivo nodes and 33 sub-nodes from interviews with 68 participants were re-coded using a deductive framework. Fourteen new nodes and 11 sub-nodes were generated and organised into three themes: care commissioning and provision; relationships; and the home environment.<br><br>RESULTS: Participants described fragmented and inconsistent care commissioning, requiring families to advocate persistently for adequate support. Challenges included funding barriers, high staff turnover, and limited MND-specific knowledge, which undermined trust and compromised safe, effective care. Relationships with homecare workers ranged from highly valued, stable partnerships to strained interactions shaped by competence concerns, emotional labour, and mismatched expectations. The presence of homecare workers and medical equipment transformed the home into a quasi-clinical space, reducing privacy, disrupting routines, and requiring households to adapt around care provision. Yet strong relationships with homecare workers could enhance quality of life.<br><br>CONCLUSION: Homecare workers play a critical role in delivering complex home-based MND care, yet quality is inconsistent. Improving training, stabilising staffing, supporting care coordination, and preparing families for the relational and environmental impact of homecare are essential for fostering sustainable, trusted care relationships, and improving outcomes for people living with MND and their families.}, }
@article {pmid42404161, year = {2026}, author = {Riva, N and Finotto, E and Schito, P and Donzelli, G and Russo, T and Domi, T and Pozzi, L and Tettamanti, A and Riboldi, E and Lopez, ID and Quattrini, A and Cremona, G and Comola, M and Filippi, M}, title = {Perspective and quality of life in amyotrophic lateral sclerosis patients undergoing percutaneous endoscopic gastrostomy.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1756642}, pmid = {42404161}, issn = {2296-861X}, abstract = {INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is commonly used to manage dysphagia and nutritional failure, which are among the most frequent and severe complications of amyotrophic lateral sclerosis (ALS). While several studies assessed PEG indications, outcomes, and prognostic factors, there is no evidence regarding ALS patients' perspectives and health-related quality of life (HRQoL) associated with PEG.<br><br>METHODS: This study included 48 consecutive ALS patients. At the 1-month follow-up after PEG, patients and their caregivers completed a PEG satisfaction questionnaire regarding their decision to proceed with the PEG-tube placement. HRQoL was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and the Short Form-36 (SF-36).<br><br>RESULTS: In total, 77.1% of patients and 88.9% of caregivers confirmed that they would prefer to have a PEG tube placed again if required (p&#x202f;>&#x202f;0.001); 93.8% of patients felt that PEG made feeding easier, exerting a positive effect on overall wellbeing (83.3%) and increasing survival rates (93.8%) (p&#x202f;>&#x202f;0.001); 54.2% felt that PEG was cosmetically acceptable. Consistent positive rates were reported by caregivers. The GIQLI digestion subscale values significantly improved from baseline (28.3; SD&#x202f;=&#x202f;6.6) to discharge (30.97, SD&#x202f;=&#x202f;5.84) and were maintained at 1-month follow-up (30.21, SD&#x202f;=&#x202f;6.7; p&#x202f;=&#x202f;0.014). Conversely, in follow-up assessments, we observed a significant reduction in the SF-36 physical component summary (PCS) subscale (baseline&#x202f;=&#x202f;33.3; 1-month follow-up&#x202f;=&#x202f;28.61; p&#x202f;=&#x202f;0.032), which was accompanied by a significant worsening in the GIQLI physical dimension subscale (baseline&#x202f;=&#x202f;9.63; 1-month follow-up&#x202f;=&#x202f;7.38; p&#x202f;=&#x202f;0.044).<br><br>DISCUSSION: This study provides preliminary evidence that ALS patients have a positive perspective on PEG positioning, which may also have a beneficial effect on HRQoL related to gastrointestinal function.}, }
@article {pmid42404323, year = {2026}, author = {Chigudu, D}, title = {Climate Variability, Communal Violence, and Population Health in Africa's Arc of Instability: A Scoping Review of Evidence and Gaps.}, journal = {Annals of global health}, volume = {92}, number = {1}, pages = {62}, pmid = {42404323}, issn = {2214-9996}, mesh = {Humans ; Evidence Gaps ; *Violence ; Africa/epidemiology ; *Population Health ; *Climate Change ; }, abstract = {Background: Africa's arc of instability - a band of countries stretching from Mauritania through the Sahel to the Horn of Africa - experiences a convergence of climate variability, communal violence, and fragile health systems. Evidence on their joint operation remains fragmented across disciplines, limiting policy-relevant synthesis. Objectives: This scoping review maps the published and grey literature on the joint operation of climate variability, communal violence, and population health in the arc of instability between January 2010 and March 2025; it identifies dominant pathways, populations, and methods, and articulates research gaps. Methods: Following Arksey and O'Malley's framework with Levac et al.'s refinements and reporting against the PRISMA-ScR checklist, five electronic databases (PubMed, Scopus, Web of Science, CINAHL, and Africa Wide Information) and grey literature from UN agencies, humanitarian organisations, and conflict and vulnerability databases were searched. Studies addressing at least two of the three domains in the arc, published in English or French, were included and synthesised narratively. Findings: Of 1623 records screened, 47 studies met the inclusion criteria. Four dominant pathways were identified: (i) resource scarcity, communal violence, displacement, and infectious disease; (ii) drought, food insecurity, and child malnutrition and mortality; (iii) heat extremes, weather events, mental health, and service disruption; and (iv) state fragility, health-system disruption, and maternal and child health deterioration. Pastoralist communities, internally displaced persons, women, and children were the most affected populations. Gaps include scarce longitudinal data, limited mental health surveillance in conflict zones, and under-representation of locally-led research among others. Conclusions: Evidence on the joint operation of climate variability, communal violence, and health in the arc of instability is accruing but remains thin, descriptive, and geographically uneven. A locally-led, transdisciplinary research agenda is needed to inform climate-resilient health systems and humanitarian responses, prioritising primary data collection, mental health surveillance, and longitudinal cohort studies.}, }
@article {pmid42396719, year = {2026}, author = {Bjorklund, DF}, title = {Shared intentionality and attachment theories in WILD and WEIRD contexts.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e261}, doi = {10.1017/S0140525X25104019}, pmid = {42396719}, issn = {1469-1825}, mesh = {Humans ; *Object Attachment ; *Intention ; *Social Cognition ; *Social Behavior ; *Psychological Theory ; }, abstract = {Barr et al.'s WILD approach to social-cognitive development appropriately identifies sampling shortcomings in Shared Intentionality and Attachment Theories. I argue these theories reflect evolved social-cognitive mechanisms that are expressed differently in different rearing environments and remain conceptual anchors for understanding important aspects of human social-cognitive development that should gain even more explanatory power with the addition of WILD data.}, }
@article {pmid42397263, year = {2026}, author = {Chen, H and Wang, H and Lu, YN and Chen, P and Zheng, Z and Zhang, T and Wang, J}, title = {Non-canonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42397263}, issn = {2050-084X}, support = {NS110098/NH/NIH HHS/United States ; NS074324/NH/NIH HHS/United States ; NS089616/NH/NIH HHS/United States ; NS128494/NH/NIH HHS/United States ; https://ror.org/042fhmq33//Walder Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry/analysis ; Humans ; *Staining and Labeling/methods ; Animals ; *Stress Granules/metabolism/chemistry ; *Amino Acids/metabolism/chemistry ; *DNA Helicases/metabolism ; *Poly-ADP-Ribose Binding Proteins/metabolism ; *RNA Recognition Motif Proteins/metabolism ; *RNA Helicases/metabolism ; Neurons/metabolism ; Mice ; }, abstract = {We report a minimally disruptive labeling strategy for stress granule protein, G3BP Stress Granule Assembly Factor 1 (G3BP1), and ALS-linked protein, TAR DNA-binding protein 43 (TDP-43), using the fluorescent non-canonical amino acid Anap. By integrating the genetic code expansion (GCE) with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags, and enabling physiologically relevant visualization of protein pathobiology.}, }
@article {pmid42397462, year = {2026}, author = {Xie, X and Jiao, X and Yang, K and Zhang, Q}, title = {A case study of comprehensive association analysis and risk prediction of amyotrophic lateral sclerosis in a Chinese population.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42397462}, issn = {1573-4978}, support = {Grant Number: 32302711//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Polymorphism, Single Nucleotide/genetics ; Genetic Predisposition to Disease/genetics ; Asian People/genetics ; Genetic Risk Score ; Male ; Gene Frequency/genetics ; Female ; Genome-Wide Association Study/methods ; Middle Aged ; China/epidemiology ; Genetic Association Studies/methods ; Multifactorial Inheritance/genetics ; Adult ; Whole Genome Sequencing/methods ; Case-Control Studies ; Aged ; East Asian People ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with significant genetic heterogeneity. While large-scale studies have characterized its genetic architecture in European populations, the genetic basis of ALS in the Chinese population remains under-explored.<br><br>METHODS AND RESULTS: To address this gap, we conducted a comprehensive genetic analysis on a cohort of 40 Chinese individuals (32 ALS patients and 8 controls) using whole genome sequencing. We employed the Phenotype-Covariate Genetic Correlation method to estimate SNP-based heritability on the liability scale and utilized LDAK-KVIK for gene-based association analysis. Our analysis revealed a SNP-based heritability (h[2]SNP) of approximately 25.1% in this Chinese cohort, with a positive correlation between minor allele frequency and heritability, highlighting the substantial contribution of common variants. Gene-based analysis prioritized candidate risk genes, including MIB1, TMED2, and DOC2B, which implicate ubiquitin-mediated protein degradation and intracellular vesicle trafficking in ALS pathogenesis. In risk prediction models, the BOLT-LMM approach achieved a robust mean Area Under the Curve (AUC) of 0.883.<br><br>CONCLUSIONS: This study provides the first comprehensive estimate of SNP-based heritability in a sequenced Chinese ALS cohort and supports the "polygenic background" hypothesis. The identification of candidate risk genes and the preliminary validation of polygenic risk scoring highlight the potential for future genetic stratification in Chinese patients.}, }
@article {pmid42398690, year = {2026}, author = {Sun, Y and Wang, Y and He, Q and Zhao, M and Guo, J and Xu, C and Yan, Q and Chen, Y and Zhang, B and Du, H and Huo, J and Zhang, Y and Zhang, H and Guan, Y and He, Q}, title = {Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress-neuroinflammation crosstalk.}, journal = {Acta biomaterialia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.actbio.2026.07.004}, pmid = {42398690}, issn = {1878-7568}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of ·OH and a hydrogenation catalyst for H2 scavenging reactive oxygen species. To enhance the bioavailability of H2, we develop an orally administered Mg2Si nanosheets based feed for sustained release of high-amount H2. On an ALS model of hSOD1[G93A] transgenic mice, Mg2Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg2Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H2-mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. STATEMENT OF SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H2) exhibits promising neuroprotective potential, conventional H2 therapy is severely limited by unstable and transient H2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg2Si nanosheets that enable sustained H2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo. Mechanistically, Mg2Si-derived H2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg2Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg2Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders.}, }
@article {pmid42399082, year = {2026}, author = {Varela-Cerdeira, M and Nieto, LU and Mendieta, MAG and Recuerda, AS and Benito, YM and Gullon, PC and Alonso-Babarro, A}, title = {Radiologically inserted gastrostomy in advanced amyotrophic lateral sclerosis: clinical outcomes.}, journal = {BMJ supportive &amp; palliative care}, volume = {}, number = {}, pages = {}, doi = {10.1136/spcare-2026-006126}, pmid = {42399082}, issn = {2045-4368}, abstract = {OBJECTIVES: To evaluate survival and clinical outcomes in patients with amyotrophic lateral sclerosis (ALS) undergoing radiologically inserted gastrostomy (RIG) and to describe outcomes in patients in whom gastrostomy was indicated but not performed.<br><br>METHODS: This retrospective observational cohort study included patients with ALS followed by a multidisciplinary palliative care team between 2018 and 2020. Patients were classified according to gastrostomy status (RIG vs no RIG). Clinical data, respiratory support, nutritional status and survival outcomes were collected from medical records. Survival was analysed from gastrostomy indication using Kaplan-Meier curves stratified by baseline non-invasive ventilation (NIV) use.<br><br>RESULTS: Among 155 patients with ALS, RIG was indicated in 53 and performed in 45; eight patients died before the procedure. 65 patients did not undergo gastrostomy. Median survival after RIG was 14.7 months, compared with 8 months in non-RIG patients who died. Baseline NIV use was associated with longer survival. No major safety concerns were identified.<br><br>CONCLUSIONS: RIG appears to be a safe and feasible option in advanced ALS. Multidisciplinary care with integrated palliative involvement may facilitate referral, optimise nutritional support and support shared decision-making aligned with patients' goals of care. Further prospective studies are needed to confirm benefits and identify intervention timing.}, }
@article {pmid42399099, year = {2026}, author = {Liu, RY and Su, WM and Duan, QQ and Wen, XJ and He, SY and Zhang, N and Cao, B and Chen, YP}, title = {Global epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2026-338675}, pmid = {42399099}, issn = {1468-330X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with the global epidemiological profile remaining incompletely understood. While previous systematic reviews existed, an updated comprehensive synthesis is needed to delineate the disease burden.<br><br>METHODS: We searched PubMed, Embase, Scopus, Web of Science and Cochrane databases from inception to 18 February 2025, for studies reporting the incidence, prevalence or mortality of ALS in the general population. Pooled estimates with 95% CIs were calculated, and subgroup analyses were performed.<br><br>RESULTS: Of 29&#x2009;110 articles initially screened, 142 were included. Global pooled incidence was 1.65 per 100&#x2009;000 person-years (95% CI 1.43 to 1.91), prevalence was 5.05 per 100&#x2009;000 population (95%&#x2009;CI 4.26 to 5.99) and mortality was 1.26 per 100&#x2009;000 person-years (95%&#x2009;CI 0.94 to 1.69). Both incidence rate ratio (IRR=0.74) and prevalence rate ratio (PRR=0.69) indicated significantly lower disease burden in females than in males. The burden of disease exhibited a marked age-dependent pattern, peaking at ages 70-79. Temporal trend analyses revealed a consistent increase in prevalence from 1963 to 1999&#x2009;onwards, while incidence peaked in 2014-2017. Geographically, incidence and prevalence were highest in Europe, North America and Oceania and lowest in Asia and South America. The disease burden was significantly higher in high-income countries compared with both upper-middle-income and lower-middle-income countries.<br><br>CONCLUSION: This systematic review provides updated global ALS burden estimates, showing variations by sex, age, time and geography and underscoring the complex interplay of genetic, environmental and socioeconomic factors, with implications for health planning, resource allocation and etiological research.}, }
@article {pmid42399152, year = {2026}, author = {Demeret, R and Vieles Marais, D and Treiner, E and Acket, B and Fabry, V and Levade, T and Nogueira, L and Pages, JC and Cintas, P}, title = {Macrophage inclusions in patients undergoing antisense oligonucleotide therapy for ALS or SMA: A retrospective and transversal study.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2026.05.005}, pmid = {42399152}, issn = {0035-3787}, abstract = {BACKGROUND: Intrathecal antisense oligonucleotides (ASOs) have revolutionized the management of genetic motor neuron diseases. Nusinersen is approved for spinal muscular atrophy (SMA) caused by SMN1 mutations, and tofersen for amyotrophic lateral sclerosis (ALS) linked to SOD1 mutations. Since their approval, some studies reported the presence of macrophagic inclusions in cerebrospinal fluid (CSF) of patients treated with ASOs, first in nusinersen-treated patients and more recently in those receiving tofersen. These findings remain poorly characterized, and their clinical significance is unclear.<br><br>METHODS: We first conducted a retrospective study in 21 patients (132 CSF samples): six treated with tofersen (every 4 weeks) and 15 with nusinersen (every 4 months). CSF samples were analyzed for macrophagic inclusions, their time of onset, and persistence over time. To assess clinical and inflammatory correlates of macrophagic inclusions, we then performed an analysis of CSF inflammatory biomarkers and serum ferritin and neurofilament light chain tests in 18 of these patients still under treatment.<br><br>RESULTS: In tofersen-treated patients, macrophagic inclusions were consistently observed and persisted over time, except in one case. In nusinersen-treated patients, inclusions were rare and transient. An inflammatory CSF profile was associated with the presence of inclusions, but their cellular nature remained undetermined. Notably, tofersen-treated patients with "tofersenophages" exhibited favorable clinical responses.<br><br>DISCUSSION: Macrophagic inclusions appear more frequent in the CSF of tofersen-treated patients than previously reported. While their origin remains unclear, they seem linked to CSF inflammation without precluding a beneficial therapeutic response.}, }
@article {pmid42399370, year = {2026}, author = {Gao, J and Shukla, D and Ding, M and Qin, S and Tang, F and Guerrero, E and Vicuna, L and Xu, J and Li, H and Miyagi, M and Li, PP and Liang, J and Wang, X}, title = {Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.}, journal = {Nature aging}, volume = {}, number = {}, pages = {}, pmid = {42399370}, issn = {2662-8465}, support = {R01AG087952//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065342//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG056320//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AARG-22-923849/ALZ/Alzheimer's Association/United States ; 23-06539//Flinn Foundation/ ; }, abstract = {Autosomal dominant mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is a hallmark of multiple aging-associated neurodegenerative diseases. Despite its pathological role, effective therapies remain limited by the lack of safe, potent molecules targeting TDP-43 neurotoxicity. Here we show that the conserved α-helical region spanning residues 320-340 (conserved region or CR) is a therapeutically actionable target for TDP-43 neurotoxicity. Deletion of CR markedly suppressed TDP-43-induced neuronal death. Structure-based virtual screening identified XL20, a brain-penetrant small molecule that engages CR and confers neuroprotection without affecting TDP-43 splicing activity. XL20 alleviated motor neuron loss, extended survival in TDP-43 p.Ala315Thr ALS mice and enhanced neuronal function in p.Gln331Lys induced pluripotent stem cell-derived human ALS motor neurons. Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid-liquid phase separation. Our findings highlight CR as a therapeutic target for TDP-43-associated neurodegeneration and support CR-binding small molecules as therapeutic candidates.}, }
@article {pmid42399593, year = {2026}, author = {Yuan, Y and Ling, C and Wang, Z and Yuan, Y and Zhang, W and Zhao, Y}, title = {Early and severe masticatory muscle involvement in SOD1-ALS: a case report with biomarker-clinical dissociation.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {8}, pages = {}, pmid = {42399593}, issn = {1590-3478}, }
@article {pmid42399818, year = {2026}, author = {Rizwan Qayyum, R}, title = {Letter to the editor regarding clinical characteristics and factors associated with in-hospital post-surgical mortality in COVID-19 patients at a tertiary care center in Karachi, Pakistan.}, journal = {BMC infectious diseases}, volume = {26}, number = {1}, pages = {}, pmid = {42399818}, issn = {1471-2334}, mesh = {Humans ; *COVID-19/mortality ; Pakistan/epidemiology ; Tertiary Care Centers ; SARS-CoV-2 ; *Hospital Mortality ; Female ; Pandemics ; Betacoronavirus ; Risk Factors ; }, abstract = {A comment on Wagley et al.'s study of post-surgical outcomes in COVID-19 patients in Karachi, highlighting the importance of incorporating COVID-19 severity, timing of surgery, and maternal/fetal outcomes. These considerations can improve perioperative risk assessment and inform resource allocation in low- and middle-income countries.}, }
@article {pmid42400371, year = {2026}, author = {Harrington, EA and Dratch, L and Jones, TA and Fong, JC and Kinnamon, DD and Goldman, J and Uhlmann, WR and Roggenbuck, J}, title = {Reduced penetrance in genetic ALS/FTD spectrum disorders: implications for genetic counseling, predictive testing and treatment.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2696378}, pmid = {42400371}, issn = {2167-9223}, abstract = {As the offer of genetic testing for people with ALS/FTD becomes standard of care, clinicians and affected individuals should have accurate and balanced information regarding the clinical and familial implications of test results, including the penetrance of identified variants. Published estimates of the penetrance of specific ALS/FTD variants, including the C9orf72 repeat expansion, have varied widely. However, it is now apparent that most pathogenic variants identified in clinical testing exhibit reduced penetrance. Although data on the disease risk of many variants is limited and likely to evolve in the coming years, the challenges of estimating penetrance should not preclude transparent discussion of these issues with affected individuals and their families. Here, we review published penetrance data and highlight genetic counseling considerations to support the clinician in discussing disease risk and facilitating decision-making in genetic testing and patient care.}, }
@article {pmid42400523, year = {2026}, author = {Li, ZZ and Chen, ZR and Guo, SP}, title = {Nonlinear Optical-Active NaAlP2S6 Synthesized by the MOBQ Method: Synthesis, Structure, and Optical Properties.}, journal = {Inorganic chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.inorgchem.6c02918}, pmid = {42400523}, issn = {1520-510X}, abstract = {Group 13 metal chalcogenides have been extensively studied as infrared nonlinear optical (NLO) crystals and are considered promising candidates for well-balanced overall performances; however, the subgroup of group 13 metal chalcophosphates remains largely unexplored, particularly Al-based ones. Here, a quaternary thiophosphate NaAlP2S6 was synthesized via reactive flux NaCl-assisted metal oxide-boron-chalcogen (MOBQ) solid-state method. It crystallizes in the orthorhombic noncentrosymmetric Fdd2 structure, and the structure features {[AlP2S6][-]}∞ three-dimentional framework constructed by AlS6 octahedra and ethane-like P2S6 dimers. Notably, because of the strong ionicity and high bond energy of Al-S bonds in AlS6 octahedra, NaAlP2S6 exhibits a wide bandgap (3.72 eV), a moderate SHG response (0.25 × AgGaS2), and an ultrahigh LIDT (14.7 × AgGaS2). Theoretical calculations reveal that the SHG response is mainly contributed by the P2S6 dimers. This work suggests the potential of Al-based functional motifs for NLO applications.}, }
@article {pmid42400730, year = {2026}, author = {Shahsavari, K and Yazarlu, O and Ahmadnia, H and Ardakani, MT and Khanavi, M and Esfahani, HM and Abdollahzadeh, R and Sajedi, A and Kazemizadeh, H and Hasanpour, M}, title = {Neuroprotective potential of resveratrol in Parkinson, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis: a comprehensive review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42400730}, issn = {1573-4978}, mesh = {*Resveratrol/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Multiple Sclerosis/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Huntington Disease/drug therapy/metabolism ; Mitochondria/drug effects/metabolism ; Sirtuin 1/metabolism ; }, abstract = {Resveratrol shows neuroprotective effects in preclinical studies across a number of neurodegenerative illnesses, including Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's disease (HD), and it enhances mitochondrial function through stimulation of the AMPK/SIRT1/PGC-1α pathway, thereby improving mitochondrial oxidative capacity and ATP generation. The natural polyphenol lowers α-synuclein accumulation and affects autophagy; both markers of PD. Combining nano‑resveratrol formulations with L‑DOPA has shown greater therapeutic efficacy in animal models (MPTP mouse), while co‑administration with EGCG has shown synergistic neuroprotection in vitro (SH‑SY5Y cells). These combination strategies offer potential advantages in neuroprotection and symptom alleviation while minimizing adverse drug effects. Resveratrol activates SIRT1 and AMPK signaling in preclinical models, enhancing mitochondrial biogenesis, lowering apoptosis, and restoring cellular resilience. The effectiveness of various models and dosages varies. The primary mechanism by which resveratrol promotes neuronal survival and remyelination in multiple sclerosis is through SIRT1 activation, which does not directly reduce inflammation. As innovative delivery systems, intranasal nanoparticles and exosomes produced from macrophages have shown improved CNS targeting accuracy. Resveratrol slows down neurodegeneration and improves the prognosis of HD by improving motor function and stimulating mitochondrial biogenesis in addition to activating neuroprotective ERK signaling. All of these results point to resveratrol's several pathways as a strong contender for neurodegenerative disease adjunctive treatment. The current evidence base is insufficient to support clinical use of resveratrol for any of the four diseases. Further rigorous preclinical studies (including TDP-43 models for ALS, SIRT1 knockout studies, and human-feasible dosing) and well-designed clinical trials with pharmacokinetic endpoints are required before any clinical recommendations can be made.}, }
@article {pmid42401196, year = {2026}, author = {Polyzogopoulou, E and Tabakovic, S and Harris, T and Horn, R and Connolly, JA and Hoffmann, B and Osterwalder, J}, title = {The Core Compendium of the European Society of Emergency Medicine Ultrasound Curriculum.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2852-6050}, pmid = {42401196}, issn = {1438-8782}, abstract = {The diversity of healthcare systems across Europe has predictably resulted in significant variations in point-of-care ultrasound (PoCUS) training and practice for emergency medicine (EM). To encourage a more synchronized approach and address these inconsistencies, the European Society of Emergency Medicine (EUSEM) chartered its ultrasound section to develop a comprehensive curriculum compendium that should serve as a foundational guide for European Emergency Medicine PoCUS clinical and educational guidelines and policies. Under the leadership of a dedicated task force, the EUSEM ultrasound section developed this compendium to provide a structured, tiered framework designed to meet the needs of physicians at every skill level, from novice to advanced users. The compendium emphasizes applications that are currently practiced in different and diverse emergency departments in Europe, including a broad range of topics. An important goal was allowing flexibility to accommodate the unique resources and challenges of different healthcare environments, so that EM physicians can achieve PoCUS competencies matching their local circumstances and needs. To achieve this goal, good educational and clinical stewardship throughout this process is a key part to the success of advancing PoCUS in European EM. This compendium is intended as a resource for creating standardized yet adaptable training pathways. It represents a major step toward harmonizing and advancing PoCUS practice in European EM. Die Vielfalt der verschiedenen Gesundheitssysteme in Europa hat dazu geführt, dass grosse Unterschiede in der Ausbildung und Anwendung des Point-of-Care-Ultraschalls (PoCUS) in der Notfallmedizin bestehen. Um einen stärker synchronisierten Ansatz zu fördern und diesen Unterschieden zu begegnen, hat die Europäische Gesellschaft für Notfallmedizin (EUSEM) ihre Ultraschallsektion damit beauftragt, ein umfassendes Curriculum-Kompendium zu entwickeln. Dieses soll als ein Leitfaden für Europäische Richtlinien und Standards für PoCUS in der klinischen Ausbildung in der Notfallmedizin dienen. Unter der Leitung einer Task Force hat die Ultraschallsektion der EUSEM dieses Kompendium erarbeitet, um Rahmenbedingungen zu schaffen, die den Bedürfnissen von Ärztinnen und Ärzten auf jedem Kompetenzniveau - vom Einsteiger bis zum fortgeschrittenen Anwender - gerecht werden. Das Kompendium beinhaltet Ultraschallanwendungen, die in derzeit sehr diversen Notfallstationen in ganz Europa praktiziert werden, und deckt daher ein breites Spektrum PoCUS-Anwendungen in der Notfallmedizin ab. Ein zentrales Ziel dieser Arbeit war es, Flexibilität zu ermöglichen, um die spezifischen Merkmale wie auch Ressourcen der jeweiligen Gesundheitssysteme zu berücksichtigen, sodass Notfallmediziner:innen PoCUS-Kompetenzen erwerben können, die ihren lokalen Gegebenheiten und Anforderungen entsprechen. Um das Ziel der Weiterentwicklung von PoCUS in der europäischen Notfallmedizin zu erreichen, ist ein entscheidender Erfolgsfaktor eine gute Begleitung sowohl in der klinischen Anwendung, wie auch in der Ausbildung. Dieses Kompendium soll als Grundlage zur Entwicklung standardisierter, zugleich aber anpassungsfähiger Ausbildungspfade dienen. Es stellt einen wichtigen Schritt zur Harmonisierung und Weiterentwicklung des PoCUS in der europäischen Notfallmedizin dar.}, }
@article {pmid42396027, year = {2026}, author = {Saidi, C and Debbichi, M and Chaaben, N}, title = {Lead-Free Sr3MCl3 (M = Sb, P) Perovskite Solar Cells: from First-Principles Calculations to Recombination-Aware Device Simulations.}, journal = {ACS omega}, volume = {11}, number = {25}, pages = {37467-37485}, pmid = {42396027}, issn = {2470-1343}, abstract = {In this study, first-principles calculations were performed to explore structural, mechanical, electronic, carrier transport, and optical properties of strontium-based perovskites (Sr3MCl3 (M = Sb, P)) using density functional theory (DFT). These calculations reveal that both materials are thermodynamically and mechanically stable. Employing the GGA-PBE functional, they possess a direct-band-gap semiconductor behavior with an energy of 1.704 eV (Sr3SbCl3) and 1.677 eV (Sr3PCl3). The analysis of the density of states (DOS) further corroborates the semiconducting behavior. Carrier mobility calculations indicate that electron/hole mobilities of 89.15/110.52 cm[2]/V·s are achieved for Sr3SbCl3 and 137.16/100.60 cm[2]/V·s for Sr3PCl3. In the visible region, a light absorption coefficient above 10[5] cm[-1] is reached for both materials, highlighting their suitability as an absorber layer (AL) in perovskite solar cells (PSCs). Considering band-to-band recombination (radiative and Auger), SCAPS-1D was used to conduct an inquiry into the photovoltaic performance of various devices, integrating different electron and hole transport layers (ETL/HTL): Ag/FTO/ETL/uniform-AL/HTL/Ni. Among all configurations examined in this study, the Ag/FTO/IGZO/uniform-AL/Cu2O/Ni architecture achieves the highest photovoltaic performance parameters, upon optimization of AL thickness, AL-doping concentration, AL-bulk and interface defect densities, radiative recombination coefficient, and series/shunt resistances. The Sr3SbCl3-based PSC (Device I) attains a power conversion efficiency (PCE) of ∼25.80%, with an open-circuit voltage (V OC) of 1.31 V, a short-circuit current density (J SC) of 21.82 mA/cm[2], and a fill factor (FF) of 90.27%, whereas the Sr3PCl3-based PSC (Device II) achieves a PCE of approximatively 26.22%, with V OC = 1.28 V, J SC = 22.71 mA/cm[2], and FF = 90.09%. Finally, replacing the single uniform-AL with a graded-Sr3Sb1-x P x Cl3 AL (Device III), adopting linear and parabolic graded physical parameters, does not demonstrate marked improvements in device performance. Consequently, this study positions Sr3MCl3 (M = Sb, P) perovskites as alternatives to lead-based ALs, which can constitute a suitable pathway for real-time experimentation of PSC.}, }
@article {pmid42396333, year = {2026}, author = {Yasui, D and Weatherill, D and Dugom, L and Weiner, S and Gopalakrishnan, L and Tran, H and Oskarsson, B and Nagle, K and Miller, T and Gutierrez, G and Ravits, J and Hoover, B and Harms, M and Shneider, N and Neylon, L and Dailey, W and Ladha, S and Holmes, C and Lee, J and Streicher, N and Nayar, S and Harris, BT and Raisinghani, M and Zetterberg, H and Gobom, J and Easton, A and Bowser, R and Ly, CV}, title = {The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.13.26355379}, pmid = {42396333}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.}, }
@article {pmid42396678, year = {2026}, author = {Gernsbacher, MA and Akhtar, N and Dinishak, J}, title = {An inclusive developmental science requires attention to neurodiversity.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e268}, doi = {10.1017/S0140525X25104020}, pmid = {42396678}, issn = {1469-1825}, mesh = {Humans ; *Cultural Diversity ; Individuality ; }, abstract = {Bard et al.'s WILD framework calls for cultural inclusivity in developmental science. We argue for extending this framework to neurodiversity, emphasizing equifinality and individual differences. Including neurodivergent populations enriches developmental theory and avoids harm caused by neurotypical benchmarks. A truly inclusive science must recognize developmental pathways that vary by culture and neurotype as valid and meaningful.}, }
@article {pmid42396689, year = {2026}, author = {Ding, X and Kong, X}, title = {Rethinking "local" and "in situ" in WILD among migrant children.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e266}, doi = {10.1017/S0140525X25104032}, pmid = {42396689}, issn = {1469-1825}, mesh = {Humans ; *Transients and Migrants/psychology ; Child ; *Child Development ; }, abstract = {While Bard et al.'s WILD framework commendably calls for broader inclusivity in developmental science, it underestimates the challenges posed by migration. Migrant children's lives complicate the constructs of local and in situ, demanding their reconceptualization as fluid and multi-sited. Recognizing this complexity is important for advancing culturally robust developmental theories.}, }
@article {pmid42396711, year = {2026}, author = {Sanches de Oliveira, G and Baggs, E}, title = {Ethnographic methods can help psychology overcome its WEIRD problems.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e276}, doi = {10.1017/S0140525X25104007}, pmid = {42396711}, issn = {1469-1825}, mesh = {Humans ; Anthropology, Cultural/methods ; *Psychology/methods ; }, abstract = {We are persuaded by Bard et al.'s argument that cross-cultural work in psychology requires not only a greater diversity of participants but also a greater diversity of theories. We encourage the authors to consider that the solution lies not only in improving experimentally oriented theories but also in adopting non-experimental methods, including purely ethnographic methods.}, }
@article {pmid42386387, year = {2026}, author = {Salmon, K and Ilieva, H and Kelly, D}, title = {NMES-Facilitated Mandibular Rehabilitation for Spasticity-Related Trismus in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70332}, pmid = {42386387}, issn = {1097-4598}, support = {//Salus University through an Internal Faculty Research/ ; }, }
@article {pmid42386657, year = {2026}, author = {Shimakura, K and Oka, A and Yudahira, H and Hama, Y and Otomo, A and Hadano, S}, title = {The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.}, journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms}, volume = {31}, number = {4}, pages = {e70134}, pmid = {42386657}, issn = {1365-2443}, support = {26290018//Japanese Society for Promotion of Science/ ; 24650189//Japanese Society for Promotion of Science/ ; 19H03551//Japanese Society for Promotion of Science/ ; //Tokai University School of Medicine Research Aid/ ; }, mesh = {*Sequestosome-1 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Autophagy ; Microtubule-Associated Proteins/metabolism ; *Ubiquitin/metabolism ; Mutation, Missense ; Lysosomes/metabolism ; Animals ; }, abstract = {SQSTM1 is one of the causative genes of neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The SQSTM1 protein regulates the degradation of polyubiquitinated proteins and autophagosome formation through its interaction with microtubule-associated protein light chain 3 (MAP1LC3/LC3). However, the molecular mechanisms by which SQSTM1-LC3 binding regulates the autophagy-endolysosomal system (APELS) remain unclear. To elucidate the spatiotemporal role of SQSTM1, we transiently expressed wild-type SQSTM1 or missense mutants carrying mutations in the LC3-interacting region (LIR), fused with the photoconvertible fluorescent protein Dendra2. Live-cell fluorescence imaging and co-localization analyses with markers of the APELS were then performed. Particle analysis of photoconverted or non-photoconverted SQSTM1-positive structures in live cells revealed that the pathogenic L341V variant formed larger structures than the wild-type. Co-localization analyses further showed that both the L341V and artificial LIR3A mutants accumulated in large ubiquitin-positive structures, likely due to impaired localization to autophagosomes. These results suggest that mutations within the LIR differentially affect autophagosome formation and cargo degradation within APELS-related compartments, highlighting the importance of SQSTM1 structural integrity in ALS/FTD pathogenesis.}, }
@article {pmid42387528, year = {2026}, author = {Chau, LW and Murphy, JK and Nguyen, VC and Tran, HN and Minas, H and Lam, RW and Hayashi, K and Nguyen, TTX and Krebs, E and O'Neil, J}, title = {Fidelity in the context of adapting a digital intervention for depression from an evidence-based in-person format in Vietnam.}, journal = {BMC health services research}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12913-026-15031-x}, pmid = {42387528}, issn = {1472-6963}, support = {R-TTS-2205-52454//Grand Challenges Canada/ ; 178156/CAPMC/CIHR/Canada ; }, abstract = {BACKGROUND: Digital interventions have emerged as a promising way to better meet growing population mental health needs. Our team developed a digital depression intervention (VMood; smartphone app) in Vietnam. VMood is adapted from an evidence-based in-person intervention (SSM) developed in Canada and uses cognitive behaviour therapy (CBT) principles with remote coaching by non-specialist providers. Fidelity-adaptation is a major tension in implementation science. Fidelity is the degree an intervention is designed and delivered as intended. Conversely, adaptations are sometimes made for specific contexts. This paper aims to identify key elements of fidelity-adaptation - the degree VMood is consistent theoretically with the SSM intervention and practically with implementing digitally in the Vietnamese setting.<br><br>METHODS: This study uses Perez et al.'s modified version of Carroll et al.'s Implementation Fidelity Framework, focusing on Objective 1: Conceptualizing what intervention fidelity means in this specific context (across modes and cultures) and Objective 2: Conducting fidelity testing to identify key elements along the fidelity-adaptation continuum. Ethnographic data from team meetings explored essential components that must remain intact and necessary adaptations. Non-specialist providers and app users from Vietnam tested VMood. Experts familiar with CBT provided theoretical feedback. Interviews or focus groups were conducted with all participants to gain insights into the adaptive intervention. Qualitative data were analyzed using thematic content analysis.<br><br>RESULTS: Participants agreed that VMood captures the essential theoretical components from SSM, noting certain elements of SSM (e.g., change in human contact to online) could not be replicated digitally. Participants also presented adaptation suggestions unique for the digital format to strengthen VMood's acceptability, including keeping the app simple by reducing the amount of text; incorporating more dynamic content (e.g., animations) to increase engagement; and including more culturally appropriate scenarios. Finally, key potential moderators to fidelity reported included quality of program delivery and participant responsiveness.<br><br>CONCLUSIONS: Findings identified intervention specific elements of fidelity-adaptation and showed that VMood retained essential components of SSM while incorporating adaptations to support implementation within the Vietnamese context. With the global increase in digital health services adapted from in-person delivery, understanding how to balance fidelity with necessary adaptations is important both theoretically and practically.}, }
@article {pmid42387584, year = {2026}, author = {He, M and Wu, C and Hu, M and Shi, X and Liu, R and Tong, Y and Wang, H and Hu, H and Liao, H}, title = {SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03925-w}, pmid = {42387584}, issn = {1742-2094}, support = {82372577; 82073831//National Natural Science Foundation of China/ ; }, abstract = {Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1[G93A] mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, sgk1 knockout in SOD1[G93A] mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1[G93A] mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1[G93A] mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.}, }
@article {pmid42387593, year = {2026}, author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF}, title = {Safety, feasibility and preliminary effects of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis: a prospective ABA pilot study.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12984-026-02046-y}, pmid = {42387593}, issn = {1743-0003}, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), progressive weakness makes walking practice increasingly unsafe and difficult, accelerating loss of mobility and autonomy. Lower-limb exoskeletons could preserve task-specific stepping in a controlled setting, but evidence in ALS remains scarce. This study evaluated the safety of an intensive Atalante exoskeleton gait-training program and explored its effects on walking and related clinical outcomes.<br><br>METHODS: In this prospective, monocentric ABA pilot study, 10 ambulatory persons with ALS underwent three consecutive 6-week phases over 18 weeks: A1 (baseline, usual care), B (intervention: Atalante exoskeleton gait training added to usual care; 18 sessions, 3 times/week), and A2 (withdrawal, usual care), with repeated assessments every 3 weeks. The primary endpoint was safety, assessed by adverse events (AE). Secondary endpoints included ALS Functional Rating Scale-Revised, forced vital capacity, standardized walking tests (6-minute walk test, 10-meter walk test, Timed Up and Go test), Berg Balance Scale, postural control on a force platform, lower-limb strength with dynamometry, spasticity with isokinetic dynamometer, Fatigue Severity Scale, Modified Fatigue Impact Scale, ALS Assessment Questionnaire-40, and Hospital Anxiety and Depression Scale. Exoskeleton-specific patient-reported outcomes (PROs) included intrinsic motivation, participants' attitudes toward the intervention, perceived subjective impact of the training, perceived efficacy and interactivity of the exoskeleton. The results were analyzed with linear mixed-effects models.<br><br>RESULTS: No serious AE occurred, and one mild AE was certainly related to the intervention. No outcome showed significant phase-specific slopes or slope contrasts, although several measures displayed directionally consistent trends compatible with attenuated decline during phase B and a return toward a less favorable trajectory after withdrawal. Exoskeleton-specific PROs indicated high intrinsic motivation and acceptability (usefulness for standing, perceived safety, ease of participation, and ease of installation/uninstallation rated very highly), with perceived gait-training efficacy generally positive. Participants frequently reported reduced immobility and increased accomplishment (80% each) and postural improvement (70%), and the Net Promoter Score of recommendation was +&#x2009;40.<br><br>CONCLUSIONS: Atalante exoskeleton gait training was safe and feasible in ambulatory ALS. These pilot data can guide the optimization of future studies to test whether it preserves function. Trial registration ClinicalTrials.gov, NCT06199284. Registered on 29/12/2023.}, }
@article {pmid42387809, year = {2026}, author = {Jensen, SM and Vergoossen, DLE and Huijbers, MG}, title = {Muscle-Specific Kinase Signaling and Its Therapeutic Potential.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70129}, pmid = {42387809}, issn = {1097-4598}, abstract = {The function of the neuromuscular junction (NMJ) is compromised in many neuromuscular diseases (NMDs) such as autoimmune or congenital myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies. The NMJ contains muscle-specific kinase (MuSK), which is a critical regulator of NMJ integrity and function. Activating the MuSK signaling cascade may have therapeutic potential in several of these NMDs that are characterized by impaired neuromuscular communication. The MuSK signaling cascade consists of different components and can be activated with interventions at different levels. In the past years, different therapeutic strategies using an engineered recombinant agrin comprised of the C-terminal fragment of the protein (mini-agrin), gene therapy of key proteins in this pathway, agonist MuSK antibodies, and SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitors have been further developed for this purpose. Each of these strategies engages distinct signaling components: mini-agrin, both as recombinant protein and gene therapy, enhances agrin-Lrp4-MuSK interaction; Dok7 gene therapy amplifies MuSK phosphorylation; Lrp4 gene therapy enhances agrin responsiveness; MuSK agonist antibodies bypass upstream defects and promote downstream signaling; SHP2 inhibitors prolong the duration of active MuSK signaling. These therapeutic strategies have ameliorated NMJ integrity and function in several preclinical models of MG, motor neuron diseases, and muscular dystrophies. In this review, we highlight MuSK signaling as a possible therapeutic target, describe the therapeutic efficacy of intervention in MuSK signaling in different NMDs, and present an outlook on future clinical development.}, }
@article {pmid42388323, year = {2026}, author = {Almeida, S and Song, Y and Marques, F and Sharma, N}, title = {Editorial: Emerging mechanisms in neurodegenerative disease pathogenesis: vertebrate and invertebrate model organisms.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1891031}, doi = {10.3389/fnmol.2026.1891031}, pmid = {42388323}, issn = {1662-5099}, }
@article {pmid42388560, year = {2026}, author = {L'habitant, SF and Schenk, A and Thudium, M and Coburn, M and Lechleuthner, A and Piekarski, F}, title = {Influence of team size on the efficiency of time-critical ALS interventions in prehospital cardiac arrest - A prospective randomised multicentre simulation study.}, journal = {Resuscitation plus}, volume = {30}, number = {}, pages = {101384}, pmid = {42388560}, issn = {2666-5204}, abstract = {OBJECTIVE: To determine whether increasing emergency medical service (EMS) team size improves the efficiency of time-critical invasive procedures during advanced life support (ALS) for out-of-hospital cardiac arrest (OHCA).<br><br>DESIGN: Randomised prospective multicentre simulation study with a parallel-group comparison of four predefined team sizes.<br><br>SETTING: Three accredited EMS training centres in North Rhine-Westphalia, Germany.<br><br>PARTICIPANTS: 210 ALS-trained paramedic students allocated to 59 teams of two to five members.<br><br>INTERVENTIONS: Teams managed a standardised adult ALS scenario (persistent ventricular fibrillation) requiring five invasive procedures: manual defibrillation, supraglottic airway insertion, intravenous access, preparation of amiodarone (300&#xa0;mg), and preparation of epinephrine (1&#xa0;mg).<br><br>MEASUREMENTS AND MAIN RESULTS: The primary endpoint was total scenario time from start to completion of the final procedure. Secondary endpoints were start and completion times for each intervention. Mean total times (mm:ss) decreased progressively with team size: two-person 6:33&#xa0;&#xb1;&#xa0;0:33&#xa0;min, three-person 4:13&#xa0;&#xb1;&#xa0;0:40&#xa0;min, four-person 2:54&#xa0;&#xb1;&#xa0;0:24&#xa0;min, and five-person 2:14&#xa0;&#xb1;&#xa0;0:19&#xa0;min (ANOVA, p&#xa0;<&#xa0;0.001). All pairwise differences were statistically significant (Bonferroni-corrected p adj&#xa0;<&#xa0;0.01). Earlier initiation of intravenous access and drug preparation accounted for most time savings. All teams completed every task successfully.<br><br>CONCLUSIONS: Larger EMS teams performed time-critical ALS procedures significantly faster, with optimal efficiency observed in four- to five-member crews. These findings highlight the operational importance of team composition for prehospital resuscitation performance and may inform staffing policies and simulation-based training.}, }
@article {pmid42389275, year = {2026}, author = {Zhang, P and Zhuang, YD and Lv, WW and Zhao, Y and Wang, JH and Zhang, JY and Wu, LL}, title = {Role of gut microbiota in melanosis coli: from anthraquinone biotransformation to mucosal homeostasis dysbiosis.}, journal = {Frontiers in pharmacology}, volume = {17}, number = {}, pages = {1791164}, pmid = {42389275}, issn = {1663-9812}, abstract = {Melanosis coli (MC) is a benign and usually reversible condition characterized by brownish-black pigmentation of the colonic mucosa and is commonly associated with chronic exposure to anthraquinone laxatives (ALs). The best-established histopathological sequence involves AL-related epithelial apoptosis, phagocytosis of apoptotic bodies by macrophages, and subsequent lipofuscin deposition. Emerging evidence suggests that the gut microbiota (GM) may contribute to this process by converting pharmacologically inactive anthraquinone glycosides into active anthrone metabolites, including rhein anthrone. This narrative review summarizes available MC-specific findings and clearly distinguishes them from mechanistic hypotheses extrapolated from constipation, intestinal barrier, and microbiome literature. We discuss microbial β-glucosidases and reductases involved in AL biotransformation, reported changes in microbial diversity and SCFA-producing taxa in MC or constipation-associated cohorts, and plausible links with barrier dysfunction, bile-acid metabolism, tryptophan-derived metabolites, and LPS-TLR4 signaling. We therefore present the "Microbiota-Apoptosis Axis" as a proposed framework rather than a validated causal pathway. Finally, we review GM-targeted strategies, including probiotics, synbiotics, and fecal microbiota transplantation, while emphasizing that direct clinical evidence in MC remains limited and that cessation of anthraquinone laxatives remains the primary management strategy.}, }
@article {pmid42389895, year = {2026}, author = {Pickett, D and Purvinsh, Y and Skrehot, JT and Warren, D and Kurouski, D}, title = {Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {}, number = {}, pages = {}, pmid = {42389895}, issn = {1463-9084}, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), limbic predominant age-related TDP-43 encephalopathy (LATE), and Parkinson's disease are associated with an abrupt aggregation of TAR DNA-binding protein 43 (TDP-43). Although molecular mechanisms of this pathological aggregation remain unclear, accumulated evidence suggests that the C-terminus domain (C-terminal domain (CTD)) is the trigger of TDP-43 self-assembly into toxic oligomers and fibrils. While the secondary structure and morphology of protein fibrils have been well documented, very little is known about TDP-43 oligomers. This is primarily because of the transient nature and low concentrations of these protein species. In the current study, we utilize nano-infrared spectroscopy, also known as atomic force microscopy-infrared (AFM-IR) spectroscopy, to investigate the morphology and secondary structure of CTD of TDP-43 oligomers formed at the early and middle stages of protein aggregation. This innovative technique allows us to resolve both morphology and secondary structure of individual protein aggregates. We found that at the early stage of protein aggregation, CTD of TDP-43 formed two morphologically different protein aggregates: donut-like (DO) and round (RO) oligomers. DO yielded fibrillar species, while RO persisted throughout the entire course of CTD TDP-43 self-assembly.}, }
@article {pmid42391298, year = {2026}, author = {Ramgopal, S and Martin-Gill, C}, title = {Characterizing pediatric trauma patients and EMS agencies that are optimal targets for prehospital pediatric blood transfusion programs.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/10903127.2026.2696013}, pmid = {42391298}, issn = {1545-0066}, abstract = {OBJECTIVES: Trauma is a leading cause of death among children the United States. Prehospital blood product administration is a potentially lifesaving measure for injured children. We evaluated how often injured children meet physiological criteria for transfusion, determined the use of prehospital blood products in this sample, and identified agency characteristics that can inform the implementation of additional prehospital transfusion programs.<br><br>METHODS: We conducted a retrospective analysis of the 2021-2024 National Emergency Medical Services Information System (NEMSIS) datasets. We included children (<18 years) with injury. We identified patients who may be eligible for prehospital blood transfusion based on (a) a combination of a systolic blood pressure (SBP) below the 5[th] centile for age and elevated heart rate above the 85[th] centile or (b) a systolic blood pressure below the 1[st] centile. We characterized encounters potentially eligible for prehospital blood transfusion, the use of blood products in this group, and the EMS agencies that cared for these patients.<br><br>RESULTS: Of 2,492,731 encounters, 34,221 (1.37%, 95% confidence interval [CI] 1.36%, 1.39%) were potentially eligible for blood transfusion. Patients meeting these criteria were more frequently adolescents (71.1%) and were involved in falls (23.4%) or motor vehicle collisions (22.6%). Blood products were administered in 669 (0.027%; 95% CI 0.025%, 0.029%) encounters overall and to 1.01% (95% CI 0.91%, 1.13%) of encounters meeting criteria for blood transfusion eligibility. In agency-level analysis, 240/16,848 (1.4%) agencies provided blood products to children, and 84.4% of eligible patients were cared for by agencies whose most common level of service was advanced life support (ALS). In multivariable analysis, agencies caring for pediatric trauma patients meeting physiologic criteria for transfusion were more likely to have higher levels of service (ALS or critical care); rural; mixed volunteer/non-volunteer; and governmental non-fire, hospital, or private, non-hospital (vs fire departments).<br><br>CONCLUSIONS: In a nationally representative prehospital sample, many injured children appeared eligible for transfusion. Prehospital blood product use was uncommon and varied by system factors. Expanding access will require implementation of blood programs among EMS agencies most likely to treat these patients, and consideration for equipment and protocols that allow for administration of blood to children.}, }
@article {pmid42391458, year = {2026}, author = {Philbert, SA and Church, SJ and Unwin, RD and Cooper, GJS}, title = {Elevated urea levels in human frontotemporal dementia and amyotrophic lateral sclerosis post-mortem brain tissue: Evidence of a multi-dementia pathogenic mechanism.}, journal = {Molecular omics}, volume = {}, number = {}, pages = {}, doi = {10.1093/molecular-omics/aaiag019}, pmid = {42391458}, issn = {2515-4184}, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent two neurodegenerative diseases on opposite sides of a movement disorder continuum. However, like many other neurodegenerative diseases, the molecular pathogenesis of FTD and ALS is not fully understood. Our group has previously reported evidence for a pervasive elevation of brain urea levels in five other dementia-causing diseases. However, brain urea levels have yet to be measured in ALS and FTD. Here, we employed ultra-high-performance liquid chromatography-tandem mass spectrometry to characterise brain urea differences between control (n = 14/12) and ALS/FTD (FTD: n = 8/9; ALS: n = 13/14) cases in post-mortem tissue from two brain regions with different levels of neuropathological burden (high versus low). Elevated urea levels were observed in both the frontal cortex (high neuropathological burden) and primary visual cortex (low neuropathological burden) in cases with FTD. Contrastingly, in cases with ALS, elevated urea was observed in the primary motor cortex (high neuropathological burden), but not the dentate nucleus (low neuropathological burden). These results not only suggest that elevated urea levels are also present in ALS and FTD but imply that elevated brain urea is linked to a multi-dementia pathogenic mechanism. In contrast to ALS, the observation of elevated urea in regions of both high and low neuropathological burden in FTD implies that this phenotype is likely widespread and, therefore, may play a larger role in the pathogenesis of disease. Such a mechanism could offer new directions for developing treatments targeting this underlying pathology.}, }
@article {pmid42392626, year = {2026}, author = {Beulen, V and Noben, C and Smits, M and Mertens, H and Paulus, A and Van Mook, W}, title = {Workforce shortages and supported access to medical care for hospital employees: a scoping review.}, journal = {BMJ open}, volume = {16}, number = {7}, pages = {e117423}, doi = {10.1136/bmjopen-2026-117423}, pmid = {42392626}, issn = {2044-6055}, mesh = {Humans ; *Health Services Accessibility ; COVID-19 ; SARS-CoV-2 ; *Personnel, Hospital ; Pandemics ; }, abstract = {OBJECTIVES: This scoping review synthesises peer-reviewed and grey literature on supported access to medical care for hospital employees with existing physical health complaints to understand how it may reduce sickness absenteeism by promoting sustainable employability and to identify gaps and opportunities to inform the design and implementation of organisational supported care frameworks.<br><br>DESIGN: We conducted this scoping review following the Arksey and O'Malley framework and Levac et al's methodological recommendations, reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extensions for Scoping Reviews (PRISMA-ScR).<br><br>DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), CINAHL (EBSCO) and Web of Science were searched from database inception to 8 November 2024. The search was updated on 18 May 2026. This was supplemented by forward and backward citation tracking of included peer-reviewed articles and targeted hand searching of Dutch grey literature in Medisch Contact , a leading Dutch professional journal for the medical profession, focusing on clinical practice, medical policy and professional issues.<br><br>ELIGIBILITY: English-language or Dutch-language peer-reviewed publications and well-argued opinion pieces on healthcare workers' access to care (COVID-19 and beyond) in hospital or transferable settings were included. Sources focused on mental health or health promotion, financial aspects, personal protective equipment, patient access or healthcare worker utilisation, as well as non-English/Dutch sources, webpages and papers without full text, were excluded.<br><br>DATA EXTRACTION: ASReview was used for title and abstract screening following the SAFE procedure and full-text screening was conducted with team consensus.<br><br>RESULTS: 27 publications were included from 36&#x2009;685 identified records. The literature was predominantly qualitative in nature and COVID-19-focused, yielding four themes (ethical considerations, multilevel challenges, target groups and strategies and outcomes). It also highlighted limited evidence on evaluated supported-access interventions and workforce outcomes beyond crises.<br><br>CONCLUSIONS: Although supported access to medical care for hospital employees appears a promising multilevel, system-embedded strategy to reduce sickness absenteeism and promote sustainable employability in general, the evidence to substantiate and justify such strategies beyond acute crises is limited. Moreover, current literature lacks clear conceptualisation, operationalisation as well as robust implementation and evaluation frameworks. Addressing these gaps is a priority for future research to scientifically scaffold policies and frameworks to sustain a healthy and stable future hospital workforce.}, }
@article {pmid42392979, year = {2026}, author = {Pant, DC and Lone, MA and Parameswaran, J and Ma, F and Ziak, N and Dutta, P and Wang, Z and Pun, D and Verma, S and Hornemann, T and Jiang, J}, title = {Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes.}, journal = {Life science alliance}, volume = {9}, number = {9}, pages = {}, doi = {10.26508/lsa.202503605}, pmid = {42392979}, issn = {2575-1077}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Exons/genetics ; Mice ; Heterozygote ; Homozygote ; Disease Models, Animal ; Humans ; *Sequence Deletion/genetics ; Mutation ; Genes, Lethal ; CRISPR-Cas Systems ; Male ; Gene Knock-In Techniques ; }, abstract = {Mutations in the human SPTLC1 gene have recently been linked to early-onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2, and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel knock-in mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings provide valuable insights into SPTLC1 exon 2 biology and serve as a useful resource for future mechanistic studies.}, }
@article {pmid42393685, year = {2026}, author = {Luan, J and Yun, Y and Jiao, Y and Wang, Y and Ma, M and Shan, D and Wang, H and Ji, X and Tang, Y and Li, J and Zhan, Z and Sun, X and Gao, N and Lin, P and Yan, C and Yu, D and Liu, S and Liu, F}, title = {Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04932-7}, pmid = {42393685}, issn = {1741-7015}, support = {2025M782111//the China Postdoctoral Science Foundation/ ; 2025CXPT133//the Key R&amp;D Program of Shandong Province/ ; 2022ZLGX03//the Key R&amp;D Program of Shandong Province/ ; ZR2023ZD14//the Shandong Provincial Natural Science Foundation Major Basic Research Project/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; 20201125//Qilu Young Schorship of Shandong University/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) involves widespread brain network dysfunction, yet the molecular mechanisms linked to these alterations remain poorly understood. We investigated macroscopic structural-functional coupling abnormalities in early-stage ALS (ALS-ES) and their underlying transcriptomic signatures.<br><br>METHODS: We analyzed multimodal MRI data from 73 patients with sporadic ALS-ES and 74 age- and sex-matched healthy controls. Structural-functional (SC-FC) coupling was quantified using diffusion tensor imaging and resting-state functional MRI. Machine learning models were constructed to distinguish patients from controls based on network features. Coupling alterations were spatially correlated with neurotransmitter receptor maps and gene expression profiles from the Allen Human Brain Atlas. Key transcriptomic findings were validated using independent single-cell RNA sequencing datasets.<br><br>RESULTS: While structural connectivity remained largely preserved, functional connectivity was significantly reduced in the somatomotor network (SMN). This mismatch manifested as significant SC-FC network decoupling, particularly within the SMN (pFDR = 0.001). A gradient boosting machine model accurately classified patients, identifying SC-FC coupling in the left precentral gyrus as a primary statistical contributor to the classification model. Decoupling spatially correlated with 5-HT2A and mGluR5 receptor distributions. Imaging-transcriptomics linked network failure to a gene signature enriched for synaptic pathways and microglial markers. Single-cell analysis identified FMN1 as a candidate gene whose glial expression spatially associates with network decoupling.<br><br>CONCLUSIONS: Early-stage ALS is characterized by significant structural-functional network decoupling, primarily in motor systems. This macroscopic failure is linked to specific microglial dysregulation, particularly FMN1 downregulation, providing a multiscale framework bridges statistical neuroimaging signatures with potential cellular pathology.}, }
@article {pmid42393788, year = {2026}, author = {Marynen, F and van Bijsterveld, MG and Van In, J and Roosen, J and Fieuws, S and Vanhonacker, D and van Mook, WN and van der Horst, ICC and Dewolf, P}, title = {Comparing two post-resuscitation debriefing frameworks: a randomized cross-over simulation study.}, journal = {Advances in simulation (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s41077-026-00460-9}, pmid = {42393788}, issn = {2059-0628}, support = {R-aiders Grant (2023).//BESEDIM/ ; }, abstract = {BACKGROUND: Post-resuscitation debriefing (PRD) enhances individual and team performance in emergency care, thereby improving patient outcomes and provider well-being. Despite support from the European Resuscitation Council and the American Heart Association, the optimal PRD framework remains undefined. This study compares how team members experience PRD when conducted using either the DISCERN or Post-Code Pause (PCP) debriefing framework in pre-hospital cardiac arrest simulations.<br><br>METHODS: In a randomized cross-over study, 40 medical doctors participated in four advanced life support (ALS) simulation scenarios. Participants acted exclusively within their usual roles as team leaders, while the remaining team members performed standardized roles in accordance with the scenario scripts. Each participant experienced two DISCERN and two PCP debriefings, with the order randomized. The primary outcome was the total score on the Debriefing Experience Scale (DES), with item scores as secondary outcomes. Linear models with generalized estimating equations (GEE) were used to account for repeated measures when comparing the mean scores between the debriefing frameworks.<br><br>RESULTS: A total of 158 DES questionnaires were analyzed. Mean total DES scores were 4.15 (4.02; 4.28) for PCP and 4.16 (4.02; 4.29) for DISCERN (p&#x2009;=&#x2009;0.93 for the comparison). These scores indicate a favorable debriefing experience for both frameworks. At the DES item level, no statistically significant differences were observed between frameworks, except for perceived physical comfort in the debriefing environment, which was rated significantly higher for DISCERN (DISCERN&#x2009;=&#x2009;4.44 (4.27; 4.62), PCP&#x2009;=&#x2009;4.13 (3.96; 4.30), p&#x2009;=&#x2009;<&#x2009;0.0001).<br><br>CONCLUSION: DISCERN and PCP provide similarly favorable debriefing experiences following simulated cardiac arrest scenarios, with no significant difference in overall DES scores. These findings suggest that both frameworks can be implemented without compromising perceived debriefing quality. Further research should include more professionally diverse participant samples and assess long-term debriefing outcomes.<br><br>TRIAL REGISTRATION: Clinical Trial Center UZ Leuven, S65846 September 2021.}, }
@article {pmid42393897, year = {2026}, author = {Anachad, O and Taha, W and Saadoune, C and Ezaouine, A and Nouadi, B and Bennis, F and Chegdani, F}, title = {Bioinformatic Identification of Shared Gene Networks Between Weaning- Induced Intestinal Inflammation and Neuroinflammatory-Related Pathways.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249457554260605114916}, pmid = {42393897}, issn = {1875-6166}, abstract = {INTRODUCTION: Weaning is a critical developmental stage that can trigger intestinal inflammation through disruption of microbial homeostasis, immune responses, and epithelial barrier integrity. While numerous studies have explored gene expression changes during weaning in animals, no comparable analyses have been conducted in humans. Given the close physiological and genetic similarity between pigs and humans, piglet data were employed to investigate the molecular mechanisms underlying weaning-induced intestinal inflammation and its potential links to neurological pathways.<br><br>METHODS: A curated set of 117 differentially expressed genes related to gut inflammation was collected from bibliographic sources. Protein-protein interaction network analysis was performed using NetworkAnalyst and Cytoscape, followed by hub gene selection and functional enrichment using KOBAS, ClusterProfiler, and StringApp.<br><br>RESULTS: Among the identified hub genes, SOD1, CAT, TNF, CXCR4, TLR2, and TGFB1 play key roles in oxidative stress, immune response, glial regulation, and neuroinflammatory signaling. Enrichment analysis revealed significant associations with pathways such as Amyotrophic Lateral Sclerosis, TGF-&#x3b2; signaling, Folate and Vitamin B12 metabolism, and Inflammatory Bowel Disease, as well as biological processes like gliogenesis, hypoxia response, and cytokine signaling.<br><br>DISCUSSION: These findings suggest that intestinal inflammation during weaning may have systemic implications, highlighting shared molecular pathways relevant to neuroinflammatory-related processes.<br><br>CONCLUSION: This study provides new insight into the genetic and molecular landscape of weaning-induced inflammation and its broader systemic effects. The identified shared molecular pathways may provide a foundation for future experimental studies investigating the broader biological implications of early-life intestinal inflammation.}, }
@article {pmid42394053, year = {2026}, author = {Lee, KC and Kushniruk, AW and Borycki, EM}, title = {Use and Usability of Wearable Devices in Assistive Living: A Scoping Review.}, journal = {Studies in health technology and informatics}, volume = {338}, number = {}, pages = {487-491}, doi = {10.3233/SHTI260891}, pmid = {42394053}, issn = {1879-8365}, mesh = {*Wearable Electronic Devices/statistics &amp; numerical data ; *Self-Help Devices/statistics &amp; numerical data ; Humans ; Digital Health ; Aged ; }, abstract = {This paper describes a scoping review that explored the use and usability of wearable devices in assistive living with a focus on barriers to the real-world use of this technology in the home for the elderly. Published research was reviewed from the databases: PubMed, CINAHL, IEEE Xplore, and Web of Science. Using Arksey's et al.'s scoping review methodology relevant studies were identified, resulting in 37 reviewed for thematic analysis. The thematic analysis resulted in specific themes to barriers and facilitators in usability. Themes include privacy and security, technical challenges, providing a sense of safety and continued independence, and knowing connection to support is available if required. Wearable technology can positively contribute to elder care but a number of key issues and barriers remain.}, }
@article {pmid42394165, year = {2026}, author = {Hwang, M and Rist, TM}, title = {Invited Commentary on: Dey et al.'s "Comparing Patient and Casual Observer Perceptions of Complete Facial Paralysis and Facial Synkinesis".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261465155}, doi = {10.1177/26893614261465155}, pmid = {42394165}, issn = {2689-3622}, }
@article {pmid42394299, year = {2026}, author = {Asghar, A and Mustafa, H}, title = {Letter to the Editor in Response to "Age and Nocturnal Polyuria in Nocturia: A Multicenter Voiding Diary Cohort Study".}, journal = {Neurourology and urodynamics}, volume = {}, number = {}, pages = {}, doi = {10.1002/nau.70359}, pmid = {42394299}, issn = {1520-6777}, abstract = {Kawase et al.'s recent multicenter cohort study offers significant evidence about the relationship between nocturnal polyuria (NP) in nocturia patients and aging. The study shows that overactive bladder, maximal voided volume, and 24-h urine volume are significant predictors of NP and that both the nocturnal polyuria index and the prevalence of NP rise with age. Although these results significantly advance our knowledge of age-related urinary dysfunction, a number of methodological issues need to be addressed. The reported relationships may have been impacted by the retrospective design, reliance on self-reported voiding diaries, and lack of information on renal function, sleep problems, hydration status, and diuretic use. Furthermore, using a single diagnostic criteria for NP across all age groups might not accurately represent aging-related physiological changes. To better diagnose and treat nocturnal polyuria in older persons, future prospective studies that take these factors into account and assess age-specific diagnostic criteria are required.}, }
@article {pmid42394935, year = {2026}, author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS}, title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1824840}, pmid = {42394935}, issn = {1664-2295}, abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.}, }
@article {pmid42394962, year = {2026}, author = {Tachiyama, K and Nakamori, M and Fujii, Y and Hokkoku, K and Agari, D and Hemmi, S and Nomura, E and Hatanaka, Y and Kurokawa, K and Sonoo, M and Maruyama, H}, title = {Decremental responses following repetitive nerve stimulation in spinal and bulbar muscular atrophy.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {522-527}, pmid = {42394962}, issn = {2467-981X}, abstract = {OBJECTIVE: The presence of decremental responses following repetitive nerve stimulation (RNS) in amyotrophic lateral sclerosis (ALS) is well established. However, in spinal and bulbar muscular atrophy (SBMA), a rare X-linked recessive lower motor neuron disease, the incidence and distribution of decremental responses across different muscles have not been thoroughly investigated.<br><br>METHODS: Patients with SBMA were retrospectively identified in our database. RNS at a frequency of 3&#xa0;Hz was performed on five muscles: the abductor pollicis brevis (APB), abductor digiti minimi (ADM), upper trapezius, deltoid, and facial muscles (frontalis or nasalis).<br><br>RESULTS: A total of forty patients were identified. A significant (> 5%) decremental response in at least one muscle was observed in all patients. It was observed more frequently in proximal muscles than in distal muscles: deltoid (86%), trapezius (70%), facial muscles (44%), APB (37%) and ADM (25%). The magnitude of the decremental response in the deltoid was significantly higher than that in the other muscles.<br><br>CONCLUSIONS: Our results demonstrated that decremental responses were frequently observed in patients with SBMA, with a distribution pattern similar to that in ALS. The fact that the decremental responses are observed in SBMA having an extremely chronic course would be relevant for the pathophysiological mechanism of the decremental response.<br><br>SIGNIFICANCE: The RNS findings provide valuable insights into the pathological mechanisms of SBMA and may contribute to the development of future treatments.}, }
@article {pmid42395430, year = {2026}, author = {Moore, S and Julian, DL and Alsop, E and Gittings, LM and Lorenzini, I and McMillan, M and Macklin-Isquierdo, S and Lehmkuhl, E and Kalab, P and de Paula Moreira, D and Hayes, L and Donnelly, C and Barmada, SJ and Zarnescu, DC and Van Keuren-Jensen, K and Sattler, R}, title = {ADAR2-Mediated RNA Editing Promotes TDP-43 Nuclear Export and Alters RNA Binding.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.22.730622}, pmid = {42395430}, issn = {2692-8205}, abstract = {BACKGROUND: TAR DNA binding protein - 43 (TDP-43) nuclear loss is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related neurodegenerative disorders. While the consequences of TDP-43 dysfunction have been well-characterized, the mechanisms driving TDP-43 mislocalization remain poorly understood. Previous observations of altered localization and function of the adenosine-to-inosine (A-to-I) RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) in ALS/FTD tissue prompted us to investigate whether dysregulated RNA editing contributes to pathological TDP-43 nucleocytoplasmic trafficking.<br><br>METHODS: TDP-43 cytoplasmic mislocalization was assessed following ADAR2 and TDP-43 co-overexpression in HEK293T cells and a Drosophila model co-overexpressing human TDP-43 and dADAR in motor neurons. We further evaluated TDP-43 mislocalization through both HeLa cell assays and interspecies heterokaryon assays. Next, we assessed TDP-43 binding to A-to-I edited RNA oligomers through electrophoretic mobility shift assays (EMSAs), and investigated inosine-containing RNAs in vivo via TDP-43 RNA immunoprecipitation followed by sequencing (RIP-seq) datasets from human TDP-43-expressing Drosophila . Finally, RNAseq and enhanced cross-linking and immunoprecipitation (eCLIP-seq) were performed in SH-SY5Y cells overexpressing three ADAR2 variants with differing editing activity to identify editing-related transcriptional alterations and RNAs differentially bound to TDP-43.<br><br>RESULTS: ADAR2 overexpression reduced the nucleocytoplasmic (N:C) ratio of TDP-43 in HEK293T cells in a ADAR2 catalytic activity- and TDP-43 RNA-binding capacity-dependent manner. Drosophila motor neurons overexpressing dADAR also exhibited decreased nuclear TDP-43. Interspecies heterokaryons and permeabilized HeLa cell assays demonstrated that catalytically active ADAR2 and synthetic inosine-containing RNA oligomers, respectively, enhance nuclear export of endogenous TDP-43. EMSAs revealed preferential binding of TDP-43 to inosine-containing RNAs relative to unedited RNAs, and analysis of Drosophila RIP-seq datasets demonstrated enrichment of edited transcripts within TDP-43-bound RNAs. Finally, RNAseq and eCLIP-seq analyses identified editing-dependent alterations in gene expression and TDP-43 RNA-binding profiles in SH-SY5Y cells overexpressing active ADAR2 variants.<br><br>CONCLUSIONS: Together, our findings identify A-to-I RNA editing as a previously unrecognized regulator of TDP-43 localization and RNA interactions. These results support a model where altered RNA editing modifies TDP-43-RNA interactions, promoting increased nuclear export of TDP-43. Broadly, our work highlights RNA editing dysregulation as a potential contributor to early pathogenic mechanisms underlying TDP-43 proteinopathies.}, }
@article {pmid42395866, year = {2026}, author = {Sidharth, A and Shin, D}, title = {The role of SUMOylation in regulating proteins that drive neuronal disease progression.}, journal = {Biochemistry and biophysics reports}, volume = {47}, number = {}, pages = {102687}, pmid = {42395866}, issn = {2405-5808}, abstract = {SUMOylation is a post-translational modification in which a Small Ubiquitin-like Modifier (SUMO) protein is reversibly attached to a lysine residue on a target protein in an ATP-dependent process. This modification can affect the function of target proteins by enhancing their stability or changing cellular translocation, thereby making SUMOylation a critical regulator in the pathogenesis of multiple diseases. The functional consequences of SUMOylation, however, are highly context dependent. In Alzheimer's disease, SUMOylation stabilizes proteins that drive disease progression and enhances neurotoxicity, thereby exacerbating these conditions. Similarly, in Progressive Supranuclear Palsy, SUMO-1 conjugation stabilizes truncated tau and blocks its ubiquitination, whereas SUMO-2/3 conjugation promotes Tau clearance and recovery from neuroinflammation, illustrating how distinct SUMO paralogues can exert opposing effects within the same disease. Conversely, increased SUMOylation can be neuroprotective in cerebral ischemia and Parkinson's disease by promoting autophagic clearance of pathogenic proteins. Beyond alterations in protein stability, aberrant SUMOylation can also lead to mis-localization of target proteins, which has been identified as a pathogenic mechanism in disorders such as Huntington's disease and Amyotrophic Lateral Sclerosis that results in impaired clearance and pathogenic buildup, which results in neuronal death. From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders.}, }
@article {pmid42381982, year = {2026}, author = {Deng, Z and Zhang, R and Zhu, Y and Xu, C and Yang, M and Li, L and Cheng, Y and Shi, H and Dou, C and Zhang, M and Xia, Y and Fan, K}, title = {Antioxidant Nanozymes: From Rational Design to Biomedical Applications.}, journal = {Research (Washington, D.C.)}, volume = {9}, number = {}, pages = {1318}, pmid = {42381982}, issn = {2639-5274}, abstract = {Antioxidant nanozymes regulate reactive oxygen species homeostasis by mimicking the core catalytic functions of natural antioxidant enzymes, including superoxide dismutase-, catalase-, and glutathione peroxidase-like activities. The clinical translation of natural antioxidant enzymes has long been hampered by inherent limitations: short in vivo half-life, susceptibility to inactivation under physiological conditions, cumbersome purification processes, high production costs, non-negligible immunogenicity, and limited targeting capacity. In contrast, antioxidant nanozymes can overcome these bottlenecks with superior structural stability, tunable catalytic activity, low preparation cost, and flexible multifunctional modification. Guided by the catalytic mechanisms of natural enzymes, researchers have established rational design strategies for antioxidant nanozymes. To date, a diverse array of antioxidant nanozymes have been developed, with promising applications in multiple biomedical fields, including inflammatory diseases, ischemia-reperfusion injury, neurodegenerative disorders, and cancer adjuvant therapy. Notably, landmark clinical progress has been achieved: The catalytic nanocrystal suspension CNM-Au8, a therapeutic candidate for amyotrophic lateral sclerosis, has advanced to phase II clinical trials. This review systematically summarizes the core catalytic mechanisms of antioxidant nanozymes, clarifies the structure-activity relationships between rational material design and catalytic performance, reviews the latest advances in their biomedical applications, and dissects the key bottlenecks restricting preclinical research and clinical translation. It aims to provide rational design principles for researchers in this field, reduce empirical trial and error in material development, and provide guidance for the further optimization and clinical translation of antioxidant nanozymes.}, }
@article {pmid42382427, year = {2026}, author = {Sugimoto, T and Tachiyama, K and Hironaka, A and Naito, H and Nakamori, M and Aoki, S and Yamazaki, Y and Maruyama, H}, title = {Simultaneous ultrasound and needle electromyography recording of fasciculations in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {448-452}, pmid = {42382427}, issn = {2467-981X}, abstract = {OBJECTIVE: Fasciculations can be detected using both muscle ultrasonography and needle electromyography, yet the correspondence between ultrasonographically observed fasciculations (U-fas) and needle electromyography-detected fasciculation potentials (N-fas) has not been clarified. This study investigated their correspondence using fully synchronized recordings.<br><br>METHODS: Adult patients showing fasciculation-like contractions on muscle ultrasonography were enrolled; all were subsequently diagnosed with amyotrophic lateral sclerosis. Ultrasound and needle electromyography were recorded simultaneously in up to three muscles per patient, with a recording duration of 3&#xa0;min per muscle. For each ultrasonographically observed fasciculation, the presence of a corresponding electromyographic event and contraction duration assessed by M-mode imaging were evaluated.<br><br>RESULTS: Ten patients with amyotrophic lateral sclerosis were included. A total of 472 focused U-fas events were analyzed. Corresponding N-fas were detected in 437 events, yielding an overall concordance rate of 92.6% (95% confidence interval, 90.2-95.0%). U-fas contraction duration ranged from 343 to 971&#xa0;ms, whereas N-fas duration ranged from 10.9 to 76.4&#xa0;ms. The number of phases of N-fas observed during U-fas events ranged from 1 to 10.<br><br>CONCLUSIONS: Most ultrasonographically observed fasciculations corresponded to electromyography-detected events on simultaneous recording.<br><br>SIGNIFICANCE: Ultrasonographically detected fasciculations may serve as a supplementary indicator of lower motor neuron involvement in amyotrophic lateral sclerosis.}, }
@article {pmid42383056, year = {2026}, author = {Liu, DZ and Cheng, GL and Hu, CF and Li, RY and Yang, CC and Chen, NC and Li, X and Jiang, DY and Chang, JY}, title = {Alternative splicing-based therapeutics for neurodegenerative diseases: a dual-database bibliometric and NLP-driven analysis (2000-2025).}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1849726}, pmid = {42383056}, issn = {2296-858X}, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are driven by complex molecular dysregulation, among which aberrant alternative splicing (AS) has emerged as a critical pathogenic mechanism. Despite the rapid development of splicing-targeted therapeutics, including antisense oligonucleotides (ASOs) and small molecules, comprehensive big-data syntheses mapping this translational landscape remain scarce. This study systematically analyzes the global research trends, conceptual frameworks, and clinical evolution of AS-based therapeutics for NDDs using an integrated bibliometric and natural language processing (NLP) approach.<br><br>METHODS: A dual-database retrieval strategy utilized the Web of Science Core Collection (WoSCC) and PubMed. The analysis targeted literature published between January 1, 2000, and December 31, 2025. A primary dataset of 620 records was extracted from WoSCC for comprehensive bibliometric mapping and Latent Dirichlet Allocation (LDA) topic modeling. A parallel analysis incorporated 10 targeted clinical trials and randomized controlled trials (RCTs) from PubMed using CLARA clustering to characterize high-evidence research. Bibliometric analyses, encompassing network topologies, citation bursts, and keyword evolution, were visualized using VOSviewer, CiteSpace, SCImago, and R.<br><br>RESULTS: Publication output exhibited sustained linear growth from 2000 to 2025. The United States and Western Europe emerged as the dominant collaborative hubs, while China exhibited high productivity but limited international integration. LDA topic modeling identified three core conceptual axes: molecular mechanisms, disease-specific pathological models (e.g., ALS, Alzheimer's, and SMA), and translational methodological frameworks. Keyword trajectories delineated a transition from fundamental in vitro exploration to in vivo models, culminating in clinical "drug discovery" and "RNA" therapeutics. CLARA clustering of clinical trials demonstrated a stark concentration of splicing-modifying interventions in pediatric spinal muscular atrophy (SMA), revealing a dual-track paradigm of supportive care and molecular interventions.<br><br>CONCLUSION: This multi-database bibliometric and NLP-driven study delineates the structural landscape of AS-based therapeutics for NDDs. It identifies a definitive paradigm shift from descriptive molecular biology to clinically actionable splicing interventions. These insights highlight the necessity to expand targeted RNA platforms beyond SMA into adult neurodegenerative populations, providing a strategic roadmap for future translational research.}, }
@article {pmid42383305, year = {2026}, author = {Christoforidou, E and McFagan, E and McLaughlin, M and Hafezparast, M}, title = {TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.}, journal = {Biochemical Society transactions}, volume = {54}, number = {7}, pages = {901-913}, doi = {10.1042/BST20260896}, pmid = {42383305}, issn = {1470-8752}, support = {Hafezparast/Apr21/880-791//Motor Neurone Disease Association (MNDA)/ ; //LifeArc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/genetics/pathology ; Biomarkers/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *TDP-43 Proteinopathies/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.}, }
@article {pmid42383366, year = {2026}, author = {Serag, RM and El-Gazar, HE and AbdElgayed, MH and Gouda, RA and Berdida, DJE and Mohamed, AA}, title = {Response to Yu et al.'s Commentary on Effectiveness of Oral Care Intervention and Safe Swallowing Education on Post-Extubation Dysphagia in ICU Patients: A Nurse-Led Quasi-Experimental Study.}, journal = {Nursing in critical care}, volume = {31}, number = {4}, pages = {e70557}, doi = {10.1111/nicc.70557}, pmid = {42383366}, issn = {1478-5153}, }
@article {pmid42383392, year = {2026}, author = {Sabouri, E and Shahmoradi, T and Keshvari, NZ and Khodaee, P and Saleki, K and Rezaei, N}, title = {Role of Toll-like receptors and oral-gut-brain axis in neurodegenerative and neuropsychiatric disorders.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {42383392}, issn = {2191-0200}, abstract = {The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.}, }
@article {pmid42383500, year = {2026}, author = {Carlo, C and Giovanni, C}, title = {On the clinical anatomy of technological cognition.}, journal = {Cognitive neuroscience}, volume = {17}, number = {3}, pages = {136-138}, doi = {10.1080/17588928.2025.2573257}, pmid = {42383500}, issn = {1758-8936}, mesh = {Humans ; *White Matter/diagnostic imaging/physiology ; Diffusion Tensor Imaging ; *Cognition/physiology ; *Brain/physiology/diagnostic imaging ; Neural Pathways/physiology/diagnostic imaging ; Digital Media ; *Nerve Net/diagnostic imaging ; }, abstract = {This commentary emphasizes the critical role of white matter tracts in technological cognition, complementing Federico et al.'s (2025) hub-and-processor model focused on cortical regions. Diffusion tensor imaging highlights white matter pathways as essential for integrating visuospatial, semantic, and motor information, underpinning complex tool use and technological interaction. The disconnectionist perspective reveals that cognitive deficits often arise from disrupted white matter connectivity. Additionally, the emerging concept of "digital dementia" underscores the impact of excessive digital exposure on brain networks. Integrating white matter connectivity advances clinical understanding and informs rehabilitation strategies for technological cognition deficits.}, }
@article {pmid42384233, year = {2026}, author = {Kotambail, A and Arunachal, G and Keerthipriya, MS and Mahima, R and Sukrutha, R and Ramyashree, MB and Deekshitha, M and Rao, BM and Biswas, P and Polavarapu, K and Preethish-Kumar, V and Reddy, P and Gray, O and Wasik, KA and Emde, AK and Angadi, S and Bhattacharya, B and Zacharia, M and Jeevitha, KV and Kumar, KD and Masaraddi, NH and Nashi, S and Chetan, GK and Vengalil, S and Nalini, A}, title = {Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {7}, pages = {}, pmid = {42384233}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; India ; Female ; Male ; Superoxide Dismutase-1/genetics ; Adult ; C9orf72 Protein/genetics ; Middle Aged ; Cell Cycle Proteins/genetics ; Transcription Factor TFIIIA/genetics ; Genome-Wide Association Study ; Aged ; Ataxin-2/genetics ; Exome Sequencing ; Genetic Variation/genetics ; Young Adult ; Genetic Predisposition to Disease ; Membrane Transport Proteins ; Janus Kinase 2 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (C9orf72, ATXN2, NOTCH2NLC, NOP56) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). SOD1 dominated familial cases (53.85%), while OPTN, SOD1 and FIG4 were prevalent in sporadic cases. Homozygous SOD1 variants in six patients correlated with juvenile/young onset (< 30 years). C9orf72 expansions (4%) and ATXN2 repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified JAK2 as a novel genome-wide significant signal (FDR = 3.5 × 10[-5]). This first large-scale genomic survey of Indian ALS patients showed SOD1 being the predominant cause of fALS, while OPTN, FIG4, and other genes drive disease amidst low C9orf72 frequency. The novel JAK2 association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.}, }
@article {pmid42385017, year = {2026}, author = {Huynh, A and Cranley, L and Barnett-Tapia, C and Abrahao, A and Zinman, L and Yunusova, Y}, title = {Understanding patients' experiences and needs around decision-making for bulbar symptom management at a multidisciplinary ALS clinic.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/09638288.2026.2693395}, pmid = {42385017}, issn = {1464-5165}, abstract = {PURPOSE: This study explored the decision-making experiences of people living with amyotrophic lateral sclerosis (ALS) for managing bulbar symptoms and their perceived needs for decision-making support from healthcare professionals.<br><br>METHODS: An interpretive, descriptive qualitative study was conducted. We recruited adult patients with ALS with and without any bulbar symptoms from a multidisciplinary ALS clinic in Central Canada. Patients were interviewed using a semi-structured guide. Reflexive thematic analysis was used to analyze study data. Recruitment ceased when information power was reached.<br><br>RESULTS: Twelve participants were interviewed. Three themes were identified for patient's decision-making experiences and needs: (1) Disease uncertainty hinders decision-making; (2) Quality information triggers decision-making; and (3) Personal values and beliefs inform decision-making.<br><br>CONCLUSIONS: To reduce psychological consequences of disease uncertainty and complexity on bulbar-related decision-making, patients emphasized the need for specific and contextualized information and healthcare professional supports aligned with their decision-making styles and approaches, highlighting the importance of a person- and family-centred approach to ALS care.}, }
@article {pmid42385702, year = {2026}, author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Ramesh, N and Bae, M and Caplin, A and Shao, DD and Sahile, B and Essuman, K and Goodman, E and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2026.06.013}, pmid = {42385702}, issn = {1097-4172}, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.}, }
@article {pmid42385894, year = {2026}, author = {Guo, B and Zhang, X}, title = {Response to Huang et al.'s "Real-world efficacy and safety of tofacitinib on the progression of skin sclerosis in patients with systemic sclerosis: an analysis of national multicenter data from the CRDC.".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.06.122}, pmid = {42385894}, issn = {1097-6787}, }
@article {pmid42385897, year = {2026}, author = {Yuan, L and Huang, H and Hui, M and Xu, S and Xu, D}, title = {Response to Guo et al., "Response to Huang et al.'s 'Real-world efficacy and safety of tofacitinib on the progression of skin sclerosis in patients with systemic sclerosis: an analysis of national multicenter data from the CRDC.'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.06.121}, pmid = {42385897}, issn = {1097-6787}, }
@article {pmid42373582, year = {2026}, author = {Granger, SM and Staniforth, RA and Snorradottir, AO and Cooper-Knock, J and De Vos, KJ and Highley, JR}, title = {Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70083}, pmid = {42373582}, issn = {1365-2990}, support = {/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Cystatin C/metabolism ; Animals ; *Inclusion Bodies/pathology/metabolism ; *Motor Neurons/pathology/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43-positive inclusion and the cystatin C-positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co-occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti-amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post-mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.}, }
@article {pmid42373784, year = {2026}, author = {Li, Y and Ulrich, JD and Holtzman, DM}, title = {Adaptive immunity in the pathogenesis of neurodegeneration.}, journal = {Nature immunology}, volume = {27}, number = {7}, pages = {1375-1389}, pmid = {42373784}, issn = {1529-2916}, support = {AG085374//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG069701//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG078106//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG083977//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; NS090934//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Adaptive Immunity/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; Animals ; Microglia/immunology ; *Central Nervous System/immunology/pathology ; Astrocytes/immunology ; Immunity, Innate ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression. Advances in genetic, neuropathological and experimental studies also underscore the potential role of the adaptive immune system in disease pathogenesis. Here we summarize the current understanding of how adaptive immunity can shape the progression of neurodegenerative diseases and highlight cross-disease parallels and potentially shared mechanisms. We also examine cellular events leading to the recruitment of peripheral immune cells to the CNS, as well as candidate antigens driving the adaptive immune response. Last, we discuss potential therapeutic strategies to treat neurodegeneration via the manipulation of adaptive immune cells.}, }
@article {pmid42373786, year = {2026}, author = {Guo, AX and Fisher, TM and Comandante-Lou, N and De Jager, PL and Liddelow, SA}, title = {Innate immune signaling and functions in astrocytes.}, journal = {Nature immunology}, volume = {27}, number = {7}, pages = {1364-1374}, pmid = {42373786}, issn = {1529-2916}, support = {AARF-24-1313800/ALZ/Alzheimer's Association/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; }, mesh = {*Astrocytes/immunology/metabolism ; Humans ; *Immunity, Innate/immunology ; Animals ; *Signal Transduction/immunology ; Toll-Like Receptors/metabolism/immunology ; Innate Immunity Recognition ; Inflammasomes/metabolism/immunology ; }, abstract = {Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.}, }
@article {pmid42374626, year = {2026}, author = {Walton, EI and Sun, J}, title = {Microbiome and metabolites impact enteric and central nervous systems in ALS.}, journal = {Gut microbes}, volume = {18}, number = {1}, pages = {2692737}, doi = {10.1080/19490976.2026.2692737}, pmid = {42374626}, issn = {1949-0984}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/physiopathology ; Humans ; *Central Nervous System/metabolism/microbiology/physiopathology ; *Enteric Nervous System/metabolism/physiopathology/microbiology ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis/microbiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to gastrointestinal symptoms and alterations in the gut microbiota. The enteric nervous system (ENS) coordinates intestinal function and sits at the host-microbe interface. The mechanisms by which luminal changes relay to the central nervous system (CNS), where motor neurons reside, have yet to be completely defined. In this narrative review, we first present evidence from ALS patient cohorts and preclinical models alongside mechanistic studies of infection, dysbiosis, and related neurodegenerative diseases to discuss how the microbiota and its metabolites may affect the ENS and CNS in ALS. Next, we propose a plausible mechanism of ALS pathogenesis through the gut-microbiome-brain axis. We further offer a summary of clinical trials that have studied the impacts of the microbiota on human ALS. Finally, we discuss future directions for studies of microbiota-ENS-CNS interactions in ALS. Better understanding of the dynamic interactions among the microbiota, microbial metabolites, neuroactive metabolites, and inflammation through the ENS/CNS in ALS will provide innovative insights into ALS prevention and treatment.}, }
@article {pmid42375068, year = {2026}, author = {Siddik, SH and Miah, MBA and Alam, SKM and Sumaiya, TS and Debnath, D and Haque, SMA}, title = {Distal Motor Latency in Amyotrophic Lateral Sclerosis: A Robust and Reliable Prognostic Marker.}, journal = {Mymensingh medical journal : MMJ}, volume = {35}, number = {3}, pages = {924-931}, pmid = {42375068}, issn = {2408-8757}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Prognosis ; Female ; Male ; Longitudinal Studies ; Middle Aged ; Adult ; }, abstract = {An electrophysiological test is routinely done to confirm Amyotrophic Lateral Sclerosis (ALS) and rule out differentials. Distal Motor Latency (DML) is a simple electrophysiological measure that is always done in a primary setting. It can be used as an excellent prognostic marker for ALS so that we can know ALS better and formulate precise management plans. This longitudinal study was conducted in the Neurology Department of Bangladesh Medical University (BMU), Dhaka, Bangladesh from April 2022 to October 2023. In this study a total of 34 subjects, 17 ALS patients with normal DML and 17 ALS patients with prolonged DML, were enrolled. Severity was assessed by the ALS functional rating scale-revised (ALSFRS-R). The study's endpoints were determined as death during this 6-month follow-up or reaching an advanced stage (ALSFRS-R <20). Then, an electrophysiological test was used to measure DML in all four commonly tested nerves. ALSFRS-R was significantly reduced (p<0.025) at 6 months in ALS patients with prolonged DML than normal DML. It was found that having a higher odd (p<0.012, OR=20.718), prolonged DML had a significant impact on the outcome of ALS patients than that of normal DML. In multivariate analysis, lower ALSFRS-R at diagnosis (B= -0.124, p<0.001, HR=0.883) and prolonged DML (B=1.412, p<0.031, HR=4.104) were associated with poor outcomes. ALS patients with prolonged DML also had a poorer prognosis than patients with normal DML (log-rank test, p<0.045). In this study, patients with prolonged DML had a significant functional decline, rapid disease progression and poor prognosis than patients with normal DML. So, prolonged DML can be used as a robust prognostic marker for patients with ALS.}, }
@article {pmid42375130, year = {2026}, author = {Bozkurt, H and Reid, KR and Newton, J and Gill, J and Chau, I and Parker, C and Kurucu King, H and Tam, J and Ng, D and Stavrou, M and Baxter, P and Marland, O and Burr, K and Heslegrave, A and Veleva, E and Swann, OJ and Zetterberg, H and Hunt, DPJ and Thangaraj Selvaraj, B and Chandran, S and Pal, S}, title = {Blood-based biomarker discovery in motor neuron disease using nucleic acid-linked immuno-sandwich assay.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag180}, pmid = {42375130}, issn = {2632-1297}, abstract = {Motor neuron disease (MND) presents with phenotypic heterogeneity, is diagnostically challenging, and has poor prognosis. The absence of accessible blood-based biomarkers has hampered progress towards precision medicine. Highly sensitive immunoassays offer considerable promise for identifying blood-based biomarkers informing underlying pathophysiology and enabling accurate diagnosis and monitoring. We report findings on parallel use of the ultra-sensitive multiplexed NUcleic Acid-Linked Immuno-Sandwich Assay (NULISA) and single molecule array (Simoa), to interrogate serum from people with MND. Sera (48 MND, 38 controls) were analysed using a NULISAseq targeted neurodegenerative panel and a Simoa neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP) duplex assay. Neurofilament light and heavy chain, total tau (t-tau), phosphorylated tau (pTau)-181, pTau-217, pTau-231, fatty acid binding protein 3, amyloid beta (Aβ) 38 and Aβ40 levels were significantly elevated in MND (P < 0.05). Simoa and NULISAseq assays demonstrated strong correlations for NfL and GFAP (r > 0.90). Use of the multiplexed NULISAseq panel confirmed a well-established NfL elevation in MND, and replicated findings for other proteins from recent studies. Results add confidence in the validity and reproducibility of biomarkers identified using NULISAseq, while offering insights into the underlying pathophysiology and heterogeneity of MND.}, }
@article {pmid42375131, year = {2026}, author = {Thomas, EV and Pant, DC}, title = {Beyond neurofilaments: a multidimensional blood signature for amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag231}, pmid = {42375131}, issn = {2632-1297}, abstract = {This scientific commentary refers to 'Blood-based biomarker discovery in motor neuron disease using nucleic acid-linked immuno-sandwich assay', by Bozkurt et al. (https://doi.org/10.1093/braincomms/fcag180).}, }
@article {pmid42375239, year = {2026}, author = {Koçer, AM and Acar, A}, title = {Letter to the Editor: Comment on Gümüş et al.'s "Toluene-Related Toxic Optic Neuropathy: A Case Report".}, journal = {Neuro-ophthalmology (Aeolus Press)}, volume = {50}, number = {4}, pages = {397-398}, pmid = {42375239}, issn = {0165-8107}, abstract = {We highlight key diagnostic gaps in a reported case of toluene-related toxic optic neuropathy, including the absence of anion gap calculation, lack of explicit methanol exclusion, and incomplete temporal characterization of visual symptoms. A comprehensive toxicological workup - including serum methanol levels, osmolar gap, and metabolic profiling - is essential to distinguish toluene from methanol or mixed solvent toxicity in cases of acute bilateral visual loss.}, }
@article {pmid42376391, year = {2026}, author = {Ali, MA and Al-Ezzy, AIA}, title = {Investigating the human-animal interface: Clinical and molecular features of oral Candida spp. in cat owners.}, journal = {Open veterinary journal}, volume = {16}, number = {2}, pages = {1012-1026}, pmid = {42376391}, issn = {2218-6050}, mesh = {Animals ; Cats ; Humans ; *Cat Diseases/microbiology/epidemiology ; Male ; Female ; *Mouth/microbiology ; *Candida/isolation &amp; purification/genetics ; *Candidiasis, Oral/veterinary/microbiology/epidemiology ; Candida albicans/isolation &amp; purification/genetics ; Risk Factors ; }, abstract = {BACKGROUND: Candida albicans is a ubiquitous commensal fungus and is capable of transitioning from commensalism to infection.<br><br>AIM: To isolate and identify Candida spp. from oral swabs of domestic cats. Detection of virulence factors, agglutinin-like sequence agglutinin-like sequence 1 (ALS), and Candidalysin (ECE1) genes exploration of the possible relationship between Candida and potential risk factors in cat owners.<br><br>METHODS: A total of 119 oral swabs were collected from cat owners and streaked directly on Sabouraud's dextrose and chrome agars. Confirmation was performed by testing the isolates using the Vitek 2 compact system and conventional polymerase chain reaction (PCR) using primers specific to the ITS4 and ITS5 regions. ALS and ECE1 genes were detected using conventional PCR.<br><br>RESULTS: The total number of Candida spp. isolated from the oral cavity of cat owners was 10/119 (8.40%). Correlations were reported between the isolation of Candida from the oral cavity and age group; use of oral antibiotic drops; diabetes mellitus; oral lesions; and vitamin D3 deficiency (p value < 0.001). No significant correlation was reported between sex, season, smoking habit, denture wearing, steroid inhalation, immune suppression, and Candida isolation from the oral cavity of cat owners. ASL1 and ECE1 were detected in 100% of C. albicans isolated from the oral cavity of cat owners.<br><br>CONCLUSION: This study reveals a low prevalence but high pathogenic potential of oral C. albicans in domestic cat owners, as evidenced by the universal presence of major virulence genes (ALS1, ECE1). Older age, antibiotic drops, Diabetes miletus, oral lesions, and vitamin D3 deficiency were associated with the risk of colonization. The commonly suspected risk factors showed no association. The universal presence of ALS1 and ECE1 highlights the pathogenic threat posed by these yeasts.}, }
@article {pmid42376656, year = {2026}, author = {Baik, J and Hughes, N and Ferrer, V}, title = {Afferent loop syndrome secondary to recurrent pancreatic adenocarcinoma post-Whipple procedure: case report.}, journal = {Frontiers in oncology}, volume = {16}, number = {}, pages = {1838218}, pmid = {42376656}, issn = {2234-943X}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare but serious complication following pancreaticoduodenectomy, most often due to recurrent malignancy.<br><br>CASE PRESENTATION: A 62-year-old male patient with stage IIb pancreatic ductal adenocarcinoma status post-Whipple procedure presented with acute abdominal pain, bowel obstruction, and sepsis after months of persistent watery diarrhea. Imaging demonstrated recurrent pancreatic malignancy causing obstruction of the pancreaticobiliary limb consistent with ALS. Blood cultures grew Klebsiella pneumoniae, confirming sepsis secondary to obstruction. Endoscopy revealed a severe non-traversable afferent limb stricture, and palliative decompression with uncovered metal stent placement resulted in rapid clinical improvement.<br><br>DISCUSSION/CONCLUSION: This case highlights the need for a high degree of suspicion for ALS in post-Whipple patients with nonspecific gastrointestinal symptoms, particularly in the setting of recurrent malignancy. The prolonged refractory diarrhea preceding acute obstruction illustrates an atypical presentation that may delay diagnosis. Early imaging and minimally invasive endoscopic intervention can provide effective palliation and prevent severe complications.}, }
@article {pmid42377311, year = {2026}, author = {Price, TR and Chang, CY and Skinner, K and Dinneny, M and Nafezi, P and Kuramoto, L and De Vera, MA and Cashman, NR and Cragg, JJ}, title = {Could anticholinergics accelerate ALS progression? A critical perspective on drug safety and disease vulnerability.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/14740338.2026.2687628}, pmid = {42377311}, issn = {1744-764X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited treatment options and diverse symptoms necessitating active management. Anticholinergic medications are frequently used in ALS care, particularly for sialorrhea and mood disturbances. Their cumulative effects, termed anticholinergic burden, may pose underrecognized risks in this neurologically vulnerable population. This review highlights a plausible safety signal and outlines priorities for future research.<br><br>AREAS COVERED: This narrative review synthesizes evidence from non-ALS populations reporting associations between higher anticholinergic burden and cognitive decline, respiratory complications, functional deterioration, and mortality. Evidence was identified through targeted PubMed/MEDLINE and Embase searches with reference chaining, emphasizing recent and seminal studies. Mechanistic overlap with ALS pathophysiology, including neuromuscular junction disruption, impaired cholinergic signaling, and neuroinflammation, supports biological plausibility for harm. Current ALS guidelines do not address cumulative anticholinergic exposure, leaving clinicians without a framework for evaluating risk or deprescribing.<br><br>EXPERT OPINION: This article proposes a testable hypothesis that anticholinergic burden may represent a clinically relevant yet unmeasured risk factor in ALS. Emerging pharmacoepidemiologic methods and validated burden tools offer approaches to quantify exposure and evaluate relationships with ALS outcomes, supporting safer symptomatic management. Prioritizing longitudinal studies and integrating burden assessment into multidisciplinary care may help clarify risk.}, }
@article {pmid42377323, year = {2026}, author = {Wei, LC}, title = {Clinical Confidence in Personality Disorder Care Requires Team-Based Formulation.}, journal = {Personality and mental health}, volume = {20}, number = {3}, pages = {e70092}, doi = {10.1002/pmh.70092}, pmid = {42377323}, issn = {1932-863X}, mesh = {Humans ; *Personality Disorders/therapy ; *Patient Care Team ; *Clinical Competence ; Surveys and Questionnaires ; *Psychotherapy, Psychodynamic ; }, abstract = {This letter responds to Pingani et al.'s validation of a questionnaire on clinical confidence and psychodynamic skills in personality disorder care. It argues that confidence should be interpreted at the team level, where formulation, boundaries, risk communication, and emotional containment shape the patient's experience of care.}, }
@article {pmid42378369, year = {2026}, author = {Kim, J and Lee, H and Lim, J and Oh, J and Shin, SS and Yoon, M}, title = {RETRACTED: Kim et al. The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease Through Regulating the Visceral Adipose-Tissue Function. Int. J. Mol. Sci. 2017, 18, 846.}, journal = {International journal of molecular sciences}, volume = {27}, number = {13}, pages = {}, pmid = {42378369}, issn = {1422-0067}, abstract = {The journal retracts the article titled "The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Regulating the Visceral Adipose-Tissue Function" [...].}, }
@article {pmid42379746, year = {2026}, author = {Farsang, Z and Pánczél, Z and Jaskó, R and Kiss, E and Altorjay, &#xc1;G and Szigeti, M and Rüll, M and Szilágyi, A and Altorjay, &#xc1; and Vereczkei, A}, title = {Navigating Unanticipated Non-recurrent Laryngeal Nerves in Thyroid Surgery: Strategies for Preservation and Anticipation.}, journal = {In vivo (Athens, Greece)}, volume = {40}, number = {4}, pages = {2150-2156}, doi = {10.21873/invivo.14368}, pmid = {42379746}, issn = {1791-7549}, mesh = {Humans ; Female ; Male ; *Thyroid Gland/surgery ; *Thyroidectomy/adverse effects/methods ; *Recurrent Laryngeal Nerve/surgery ; Middle Aged ; Adult ; *Laryngeal Nerves/surgery ; Aged ; Ultrasonography ; Adolescent ; }, abstract = {BACKGROUND/AIM: This study aimed to investigate the incidence, anatomical characteristics, and clinical implications of non-recurrent laryngeal nerves (NRLNs) discovered during thyroid surgeries and autopsies.<br><br>PATIENTS AND METHODS: A total of 2,215 thyroid surgeries and 194 autopsies were reviewed, identifying 17 and 1 case of NRLN, respectively. Data regarding nerve anatomy, associated vascular anomalies, and patient medical history were collected and analyzed. Neck ultrasound examinations were subsequently performed on the 17 living patients, 5 months to 19 years post-surgery, by three radiologists specializing in head and neck soft-tissue imaging. Two radiologists were blinded to the specific nerve anatomy, while one was unblinded.<br><br>RESULTS: Vascular anomalies of the aortic arch were described only by the unblinded radiologist. Among the 17 NRLN cases, three (16.7%) exhibited normal vascular anatomy. According to Toniato et al.'s classification, one case each was categorized as 2a, 2b, and one case involved a coexisting right NRLN and right RLN. No definitive recurrent paresis was observed, with only one patient experiencing transient palsy lasting 5 weeks. Histological evaluation revealed no structural differences between NRLN and RLN variants, although their epineurium and adventitia were notably thinner than those of the vagal nerve.<br><br>CONCLUSION: Achieving blood-free conditions for meticulous dissection and preserving sympathetic nerve branches are essential for optimal functional outcomes in thyroid surgeries involving NRLNs.}, }
@article {pmid42381214, year = {2026}, author = {Suer, IE and Tursun, N}, title = {Effects of elevated CO2 and temperature on cocklebur (Xanthium strumarium L.) and its herbicide response.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71064}, pmid = {42381214}, issn = {1526-4998}, support = {//Tarimsal Ara&#x15f;tirmalar ve Politikalar Genel M&#xfc;d&#xfc;rl&#xfc;&#x11f;&#xfc;, T&#xfc;rkiye Cumhuriyeti Tarim Ve Orman Bakanli&#x11f;i/ ; }, abstract = {BACKGROUND: Climate change, characterized by rising atmospheric CO2 and temperature fluctuations, significantly alters crop-weed interactions and weed management efficacy. This study evaluated the interactive effects of elevated CO2 (400, 600, 800, and 1000 ppm) and temperature regimes (26/16°C and 29/19°C) on the biomass accumulation of Xanthium strumarium and the efficacy of two herbicides with distinct modes of action: trifloxysulfuron-sodium (systemic, ALS inhibitor) and fluometuron (soil-active, PSII inhibitor).<br><br>RESULTS: Elevated CO2 concentration up to 1000&#x2009;ppm at the optimal temperature (26/16&#xb0;C) significantly stimulated the vegetative growth and dry biomass of X. strumarium. Crucially, dose-response analyses revealed that this climate-driven accelerated growth did not induce herbicide resistance; rather, it increased the weed's susceptibility to the systemic herbicide. Elevated CO2 facilitated the translocation of trifloxysulfuron-sodium due to increased plant metabolism, thereby significantly lowering ED50 values. In contrast, the efficacy of the soil-applied fluometuron remained highly stable and unaffected by variations in either CO2 or temperature.<br><br>CONCLUSION: The interaction between climate change variables and chemical weed control is fundamentally driven by the herbicide's mode of action. While elevated CO2 acts as a fertilizer for X. strumarium, the resulting rapid growth paradoxically increases the efficacy of systemic herbicides by accelerating the movement of active ingredients. Meanwhile, soil-active herbicides like fluometuron offer a climate-resilient weed management strategy. Future studies should incorporate molecular approaches to fully elucidate these mode-of-action-specific physiological responses under changing climatic conditions. &#xa9; 2026 The Author(s). Pest Management Science published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.}, }
@article {pmid42381488, year = {2026}, author = {Eigenhuis, KN and Ferrer, RM and Pasterkamp, RJ}, title = {Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {Journal of neurochemistry}, volume = {170}, number = {7}, pages = {e70513}, doi = {10.1111/jnc.70513}, pmid = {42381488}, issn = {1471-4159}, support = {//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Organoids/pathology/metabolism ; *Induced Pluripotent Stem Cells/pathology/metabolism ; Animals ; *Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning and TDP-43 pathology, extend into frontal, parietal, and temporal areas, pointing to defects across broader cortical regions. The advent of human induced pluripotent stem cell (hiPSC) technology has enabled the generation of human-specific brain cell types in vitro. Here, we provide an overview of the three-dimensional (3D) hiPSC-derived neural organoid platforms used to model cortical structures and to study cortical ALS-associated phenotypes. We review which pathological hallmarks have been recapitulated in these organoids and discuss disease phenotypes reported to date. Further, we comprehensively cover different neural organoid models and experimental strategies, including patient-derived hiPSC models and exogenous pathology induction, while addressing current technical challenges. Together, these advances position neural organoids as an emerging tool to study cell-type-specific and circuit-level mechanisms related to cortical changes in ALS.}, }
@article {pmid42368190, year = {2026}, author = {Meng, J and Deng, ZJ and Zhang, J and Yu, W and Wu, X and Lei, P}, title = {Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.}, journal = {Life medicine}, volume = {5}, number = {3}, pages = {lnag016}, pmid = {42368190}, issn = {2755-1733}, abstract = {Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed "tauopathy", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the "atypical" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.}, }
@article {pmid42368206, year = {2026}, author = {Zafarullah, M and Banerjee, R and Singh, A and Ghosh, A and Almeida, S}, title = {Editorial: Neuromuscular disorders: biomarkers, precision diagnosis, and targeted therapeutics.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1878340}, doi = {10.3389/fnins.2026.1878340}, pmid = {42368206}, issn = {1662-4548}, }
@article {pmid42369121, year = {2026}, author = {Cao, G and Yang, X and Wang, X and Shi, X and Yang, L and Wang, P and Tan, H}, title = {Meniscal repair and partial meniscectomy demonstrated similar clinical outcomes with simultaneous combined anterior cruciate ligament and anterolateral structure reconstruction.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1847295}, pmid = {42369121}, issn = {2296-858X}, abstract = {PURPOSE: The clinical outcomes of patients after combined anterior cruciate ligament (ACL) and anterolateral structure (ALS) reconstruction with or without concomitant meniscal treatment were limited. The purpose of this study was to evaluate clinical outcomes and investigate the effect of concomitant treatment of meniscal injury on these outcomes following combined ACL and ALS reconstruction.<br><br>METHODS: A total of 86 patients with combined ACL and ALS reconstruction were eligible for inclusion, from August 2018 to November 2022, with at least 1-year follow-up. The patients were assigned to three groups based on meniscal status, including the no injury group (n&#x202f;=&#x202f;26), the partial meniscectomy group (the meniscus was resected partially, n&#x202f;=&#x202f;24), and the repair group (the meniscus was sutured, n&#x202f;=&#x202f;36). Outcome measurements consisted of function, stability, and safety evaluation. Functional evaluation included Lysholm score, Tegner score, and International Knee Documentation Committee (IKDC) score.<br><br>RESULTS: At the last follow-up, the Lysholm, Tegner, and IKDC scores were significantly improved compared with preoperative status (p&#x202f;<&#x202f;0.05). Functional scores in the no injury group were much higher than those in the partial meniscectomy and repair groups. In addition, the expense was significantly higher in the repair group (43840.9&#x202f;&#xb1;&#x202f;10804.9) than that in the no injury (37767.7&#x202f;&#xb1;&#x202f;4537.4, p&#x202f;=&#x202f;0.003) and partial meniscectomy (37738.7&#x202f;&#xb1;&#x202f;3794.4, p&#x202f;=&#x202f;0.004) groups. The stability and safety indices did not differ significantly among the three groups (p&#x202f;>&#x202f;0.05).<br><br>CONCLUSION: Among patients following simultaneous ACL and ALS reconstruction with concomitant meniscal injury, meniscal repair and partial meniscectomy could demonstrate comparable functional outcomes.}, }
@article {pmid42369228, year = {2026}, author = {Wojtowicz, E and Yous, ML and Baxter, P and Kaasalainen, S}, title = {Talking about the hypothetical future: Serious illness communication for residents living with dementia in long-term care homes - An integrative review.}, journal = {Palliative care and social practice}, volume = {20}, number = {}, pages = {26323524261462628}, pmid = {42369228}, issn = {2632-3524}, abstract = {BACKGROUND: In long-term care (LTC) homes, residents living with dementia frequently experience serious illness communication that is crisis-initiated and oriented to institutional documentation (e.g., transfer and resuscitation orders), rather than iterative, values-based discussions aligned with a palliative approach and substitute decision-making frameworks. Unpaid care partners often make high-stakes decisions with limited preparation, and residents are inconsistently included.<br><br>OBJECTIVES: To explore how serious illness communication occurs with residents living with dementia, unpaid care partners, and healthcare providers in LTC, and to identify practice-relevant communication strategies and contextual factors applicable to clinical practice.<br><br>METHODS: An integrative review following Toronto and Remington's six-stage methodology included 31 high-relevance studies (qualitative, quantitative, mixed methods, reviews, theoretical) published from 2015 to 2025 on serious illness, goals-of-care, or end-of-life communication in LTC dementia care. Directed content analysis was guided by Tarbi et al.'s basic science of communication in serious illness (lexical, non-lexical, contextual elements, and outcomes).<br><br>RESULTS: Serious illness communication was predominantly biomedical and documentation-focused, often occurring at admission or during crises and directed mainly to unpaid care partners, with limited resident involvement. Lexical practices such as clear, jargon-free information, explicit invitations to discuss "what matters most," and early conversations about hypothetical future scenarios enhanced trust, preparedness, and alignment of care with resident values. Non-lexical elements (tone, eye contact, pacing, use of silence) shaped perceived empathy but were seldom explicitly addressed by interventions.<br><br>CONCLUSIONS: For LTC healthcare providers, embedding earlier, iterative serious illness communication, explicitly involving residents where possible, and cultivating both lexical and non-lexical skills are key to achieving relationship-centred, legally compliant, and goal-concordant palliative approaches to care.&#x200b;.}, }
@article {pmid42369360, year = {2026}, author = {Keihani, A and Hassani, M and Sajadi, SS and Modarresi, SA and Khoshkholgh, M and Haresabadi, M and Amani, K and Jourahmad, Z and Ferrarelli, F}, title = {Assessing upper motor neuron dysfunction in ALS: from TMS-EEG and EMG neurophysiology to a combined tFUS-TMS translational framework.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1798525}, pmid = {42369360}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of upper motor neurons (UMNs) and lower motor neurons (LMNs). Despite significant advances in molecular and neuroimaging biomarkers, the initial site of pathology and the causal contribution of UMN dysfunction to disease progression remain undetermined. Accumulating neurophysiological evidence points to cortical hyperexcitability as an early and potentially upstream mechanism, raising the possibility that UMN pathology drives LMN degeneration through an anterograde dying-forward process. In this review, we synthesize findings from noninvasive brain stimulation (NIBS) studies, with particular emphasis on transcranial magnetic stimulation (TMS)-based neurophysiological markers of UMN dysfunction. We review evidence from TMS-electromyography (TMS-EMG) and TMS-electroencephalography (TMS-EEG) paradigms demonstrating cortical disinhibition and excitatory-inhibitory imbalance in ALS, consistent with impaired GABAergic interneuronal dysfunction and supportive of a cortical onset hypothesis. Finally, we propose integrating transcranial focused ultrasound (tFUS) with TMS as a novel experimental and translational framework to directly examine and modulate cortical hyperexcitability and test the causal role of UMN dysfunction in ALS. The combination of targeted neuromodulation with sensitive neurophysiological readouts in controlled experimental designs offers a promising avenue to advance mechanistic insight, refine biomarkers, and inform mechanism-based therapeutic strategies. Together, these approaches position noninvasive neurophysiology as a powerful tool for elucidating UMN dysfunction in ALS.}, }
@article {pmid42369427, year = {2025}, author = {Liu, H and Tang, M and Che, L and Lu, J and Zhang, L}, title = {Investigating the potential mechanism of bisphenols on neurodegeneration through network toxicology and molecular docking.}, journal = {NAM journal}, volume = {1}, number = {}, pages = {100044}, pmid = {42369427}, issn = {3050-6204}, abstract = {This study aims to elucidate the mechanisms underlying bisphenols (BPs)-induced neurodegeneration and their contribution to neurodegenerative diseases. Focusing on four major disorders-Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease-we systematically examined key molecular pathways potentially perturbed by BPs during disease progression. Preliminary toxicological profiling of four representative BPs was conducted using ProTox-3.0, ADMETlab 3.0, and the Xundrug database. Subsequent target identification involved integrated analyses of multiple bioinformatics resources, including CHEMBL and STITCH. Protein-protein interaction networks constructed with STRING and Cytoscape identified core targets such as HSP90AA1, ESR1, BCL2, and PTGS2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses further revealed critical biological processes, including enzyme binding and heme binding, as well as key pathways associated with BPs neurotoxicity, such as chemical carcinogenesis-receptor activation, chemical carcinogenesis-DNA adducts, and arachidonic acid metabolism. Molecular docking studies demonstrated strong binding affinities between BPs and core targets, supported by low free energy values. Molecular dynamics simulations further validated stable binding conformations and dynamic interactions. Additionally, we analyzed regulatory networks of mRNA-miRNA-lncRNA interactions for core targets. In summary, our findings establish a novel multi-target and multi-pathway framework for BPs-induced neurodegeneration, revealing synergistic effects of pathways including carcinogenic signaling activation and metabolic dysregulation. This study advances understanding of environmental neurotoxicity and provides a foundation for developing preventive strategies against neurodegenerative diseases.}, }
@article {pmid42370031, year = {2026}, author = {Head, A and Birkett, M and Fleming, K and Kypridemos, C and O'Flaherty, M}, title = {Exploring theoretical policy options for reducing socioeconomic inequalities in multimorbidity: A microsimulation study in England from 2019-2049.}, journal = {Journal of multimorbidity and comorbidity}, volume = {16}, number = {}, pages = {26335565261441403}, pmid = {42370031}, issn = {2633-5565}, abstract = {BACKGROUND: Projections suggest that the number of adults living with multimorbidity will continue growing in the coming decades. Little is known, however, about the potential impact of prevention policies on multimorbidity.<br><br>METHODS &amp; FINDINGS: We applied a validated microsimulation model of multimorbidity accumulation to simulate theoretical scenarios of health improvement and inequality reduction in England over 30 years (2019-2049), compared to a baseline scenario of continuing patterns in accumulation. Four theoretical scenarios were based on Benach et al.'s typology of health policies: 1) targeted intervention on the worst-off; 2) universal policy + additional focus on the gap; 3) redistributive policy; 4) proportionate universalism; plus an idealistic fifth scenario completely removing socioeconomic inequality in transition times between states. We selected a target of 3% reduction in mortality for scenarios 1-4, based on reductions seen from tobacco control policies. Outputs compared were: difference in 2049 projected prevalence and numbers compared to baseline, total cases prevented/postponed compared to baseline, and expected years lived without multimorbidity at age 30. Our results suggest that gains in levelling socioeconomic inequalities in health would prevent/postpone multimorbidity cases and reduce relative health inequalities among those aged <65. However, this would also likely lead to increased absolute numbers living with multimorbidity overall.<br><br>CONCLUSIONS: Our theoretical modelling suggests effective and equitable policies have potential to reduce the population-level burden of multimorbidity, postponing a substantial number of multimorbidity cases, particularly before age 65. This is, however, likely to lead to greater absolute numbers of multimorbidity cases as individuals live for longer.}, }
@article {pmid42370313, year = {2026}, author = {Alkorom, S and Chong, MC and Che Seman, NH and Aqtam, I}, title = {Resilience-Building Interventions and Advanced Life Support Competency for Emergency Nurses in Palestinian Hospitals: A Scoping Review.}, journal = {SAGE open nursing}, volume = {12}, number = {}, pages = {23779608261464872}, pmid = {42370313}, issn = {2377-9608}, abstract = {BACKGROUND: Emergency nurses in Palestinian hospitals operate under chronic stress related to political instability, resource constraints, and high trauma exposure. These conditions may affect both psychological resilience and Advanced Life Support (ALS) competency, yet the evidence base remains unclear. This scoping review sought to map the available body of literature about psychological resilience and ALS competency among emergency nurses in Palestine, identify gaps in research, and determine the relationship between psychological resilience and ALS competency, which is the core focus of this review.<br><br>METHODS: Following PRISMA-ScR guidelines and JBI scoping review methodology, a comprehensive search of seven electronic databases and grey literature was conducted for studies published between January 2000 and January 2026. Two reviewers independently screened studies and extracted data using a standardized, pilot-tested charting form. Findings were synthesized descriptively using narrative synthesis organized around the review objectives.<br><br>RESULTS: From 1,292 records identified, 18 studies met inclusion criteria. Most studies were descriptive or correlational (94.4%). Burnout prevalence among emergency nurses ranged from 64% to 72.9%, and substantial gaps in ALS/BLS knowledge were reported, including low accuracy in resuscitation sequence identification (26.6%). Only one intervention study was identified, evaluating simulation-based BLS training. No studies were found that assessed resilience-based or comprehensive programs which address psychological wellbeing and clinical competency issues. There were no studies that specifically analyzed the connection between psychological resilience and competency in ALS.<br><br>CONCLUSION: The existing literature on Palestinian emergency nurses is dominated by descriptive studies, with a marked absence of intervention research. Despite documented psychological distress and clinical competency gaps, no studies have evaluated psychological resilience-focused or integrated interventions. This review highlights critical evidence gaps and provides a foundation for future intervention-oriented research.}, }
@article {pmid42371053, year = {2026}, author = {Stipa, G and Colosimo, C and Vanacore, N}, title = {Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42371053}, issn = {1435-1463}, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are among the most well-known and prevalent neurodegenerative disorders. These diseases result from an interaction between the environment and genetically predisposed individuals. This review examines the evidence available in the literature underlying this multifaceted interaction, focusing on various chemical substances such as metals, fertilizers, and herbicides, as well as toxic agents of microbiological origin, including cyanobacteria and their neurotoxins. In addition, the pathways through which toxic substances can enter the human body are discussed, such as air and water, which may lead to absorption through the lungs, the gastrointestinal tract, the skin, and mucosae. The routes by which neurotoxic substances gain access to the human body may help explain the increased risk of developing neurodegenerative diseases observed in sports played on soil and grass surfaces, such as soccer, American football, and golf.}, }
@article {pmid42371122, year = {2026}, author = {Gremmler, PA and von der Gablentz, J and Meyer, J and Ilse, B and Farahi Ghasraboonasr, B and Dalbert, S and Buchholz, IJ and Grosskreutz, J and Steinbach, R}, title = {Quantification of amyotrophic lateral sclerosis (ALS) disease accumulation with T1-weighted high-resolution magnetic resonance imaging: validation in an independent cohort.}, journal = {Journal of neurology}, volume = {273}, number = {7}, pages = {}, pmid = {42371122}, issn = {1432-1459}, support = {EXC 2167//Deutsche Forschungsgemeinschaft/ ; 413668513//Deutsche Forschungsgemeinschaft/ ; 583362031//Deutsche Forschungsgemeinschaft/ ; ACSP 14//Interdisciplinary Centre of Clinical Research of the Medical Faculty Jena/ ; PROMO-2025-01//Interdisciplinary Centre of Clinical Research of the Medical Faculty Jena/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Female ; Male ; Cohort Studies ; Middle Aged ; Aged ; Disease Progression ; *Gray Matter/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; Image Processing, Computer-Assisted ; Adult ; Case-Control Studies ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease with multifaceted phenotypic presentation thus obstructing objective disease staging. The D50 disease progression model is a framework to comprehensively dissect biomarker-signals towards their relevance regarding disease accumulation/phase (rD50), or disease aggressiveness (D50). Based on previous findings using 1.5-Tesla Magnetic-Resonance-Imaging (MRI), this study hypothesized that high-resolution MRI markers of Grey-Matter (GM) structural integrity would enable quantification of disease accumulation, independent of aggressiveness.<br><br>METHODS: A separate cohort of 75 patients with ALS and 73 Healthy Controls (HC) underwent T1-weighted 3-Tesla MRI. Voxel-Based-Morphometry measured GM and White-Matter (WM) density and Surface-Based-Morphometry assessed Cortical Thickness (CT). Non-parametric Threshold-Free-Cluster-Enhancement with 5000 permutations was applied for inter-group and regression contrasts, whilst correcting for possibly interfering co-variates and applying Family-Wise-Error-adjustment.<br><br>RESULTS: Compared with HC, the ALS cohort showed widespread decreases of CT and GM/WM density (p&#x2009;<&#x2009;0.001). These case-control effects were driven by patients scanned during rD50-defined disease Phase 2 (p&#x2009;<&#x2009;0.001). Within the ALS-cohort, direct Phase 2 versus Phase 1 contrasts revealed spatially-distributed decreases, reflecting higher disease accumulation (p&#x2009;<&#x2009;0.05). These were independent of disease aggressiveness (and onset-region), as corrected for in the models. Accordingly, all contrasts assessing aggressiveness did not yield significant results.<br><br>CONCLUSIONS: These semi-automated analyses of T1-weighted-images captured disease accumulation related GM structural integrity-loss in this cohort scanned with 3-Tesla MRI, independent of the underlying disease aggressiveness. This principle was validated across different scanners and field strengths, supporting its application for objective and non-invasive staging of patients with ALS, whereby true longitudinal studies are necessary.}, }
@article {pmid42372734, year = {2026}, author = {Pena, C and Barker, C and Grossberg, AN and Mian, I and Williams, S and MacAllister, T and Vu, T and Linseman, DA}, title = {An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2694507}, pmid = {42372734}, issn = {2167-9223}, abstract = {OBJECTIVES: The primary objective was to assess the safety of oral fasudil in amyotrophic lateral sclerosis (ALS) patients. Changes in serum neurofilament light (NfL) levels and the ratio of phosphorylated to total AKT (pAKT/tAKT) were exploratory endpoints.<br><br>METHODS: This was a multicenter, open-label study. Two 31-patient cohorts were sequentially enrolled and treated with either 180&#x2009;mg or 300&#x2009;mg per day of oral fasudil for 24&#x2009;weeks. The primary endpoint was safety. Secondary endpoints evaluated changes in the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity, and muscle strength. We also assessed changes in serum NfL and pAKT/tAKT ratios in plasma (neuron-derived) and CSF (total) extracellular vesicles (EVs).<br><br>RESULTS: Eighty-one percent (25/31) and 71% (22/31) of patients completed 24&#x2009;weeks of treatment in the 180 and 300&#x2009;mg cohort, respectively. Fasudil was safe and well tolerated, with predominantly mild drug-related adverse events. Secondary endpoints, though not statistically significant, were directionally consistent with a treatment effect. Exploratory analyses showed a 15.4% reduction in serum NfL at 24&#x2009;weeks (p&#x2009;=&#x2009;0.001) in the 180&#x2009;mg cohort, with no change in the 300&#x2009;mg cohort (-0.4%, p&#x2009;=&#x2009;0.990). The NfL reduction was inversely correlated with ALSFRS-R decline (Spearman&#x2009;=&#x2009;-0.45, p&#x2009;=&#x2009;0.028). Ratios of pAKT/tAKT, a pharmacodynamic marker of rho kinase (ROCK) inhibition, were significantly increased at 24&#x2009;weeks in plasma (neuron-derived) and CSF EVs.<br><br>CONCLUSIONS: Oral fasudil is safe and well-tolerated in ALS patients. The reduction in NfL and demonstration of CNS target engagement, supports studying the 180&#x2009;mg dose in a double-blind placebo-controlled study.}, }
@article {pmid42360043, year = {2026}, author = {Sabetta, E and Rallmann, K and Taba, P and Pfaff, AL and Poudel, BH and Ferrari, D and Locatelli, M and Kõks, S and Bergquist, J}, title = {Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.}, journal = {Journal of neurochemistry}, volume = {170}, number = {6}, pages = {e70508}, pmid = {42360043}, issn = {1471-4159}, support = {//Multiple Sclerosis Society of Western Australia/ ; SA EUS 100a Fund//Perron Institute for Neurological and Translational Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; *Proteomics/methods ; Female ; Male ; Biomarkers/cerebrospinal fluid ; Middle Aged ; Aged ; Adult ; Tandem Mass Spectrometry ; Cerebrospinal Fluid Proteins ; Chromatography, Liquid ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.}, }
@article {pmid42360520, year = {2026}, author = {Jayaswal, RP and Thapliyal, S and Badyal, RK}, title = {Comments on: Predictors of pathologic complete response in early-stage triple-negative breast cancer treated with neoadjuvant chemo-immunotherapy.}, journal = {Breast cancer research and treatment}, volume = {217}, number = {3}, pages = {}, pmid = {42360520}, issn = {1573-7217}, mesh = {Humans ; Neoadjuvant Therapy/methods ; Pathologic Complete Response ; *Triple Negative Breast Neoplasms/pathology/drug therapy/therapy ; Female ; Neoplasm Staging ; *Immunotherapy/methods ; Treatment Outcome ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; }, abstract = {This correspondence comments on LeVee et al.'s real-world study of neoadjuvant chemo-immunotherapy in early-stage triple-negative breast cancer. We highlight diabetes as a potentially modifiable host-state factor influencing pathologic complete response and propose a metabolic immunotherapy-readiness framework integrating glycaemic control, treatment delivery, endocrine monitoring, and equity-focused implementation. This perspective aims to support globally applicable strategies for improving chemo-immunotherapy effectiveness and access.}, }
@article {pmid42360551, year = {2026}, author = {Pramanik, S and Debnath, B and Chakraborty, A and Islam, A and Mullick, S and Chaudhary, P and Nath, R and Chellappan, DK and Mondal, M and Ashique, S}, title = {Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42360551}, issn = {1559-1182}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy/pathology ; *DNA, Mitochondrial/genetics/metabolism ; Animals ; *Mitochondria/genetics/metabolism/pathology ; Gene Editing ; }, abstract = {Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.}, }
@article {pmid42360563, year = {2026}, author = {Ketabforoush, A and Arnold, WD and Ariaei, A and Faghihi, F and Azedi, F and Khalili, M and Gholami, F and Joghataei, MT and Ashtiani, BH}, title = {Characterization of sensory nerve conduction abnormalities at the time of ALS diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {7}, pages = {}, pmid = {42360563}, issn = {1590-3478}, support = {1401-1-20-22913//Iran University of Medical Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Male ; Nerve Conduction Studies ; Middle Aged ; *Neural Conduction/physiology ; Cross-Sectional Studies ; Prospective Studies ; Aged ; Adult ; Sural Nerve/physiopathology ; Ulnar Nerve/physiopathology ; Motor Neurons/physiology ; Median Nerve/physiopathology ; }, abstract = {OBJECTIVES: Although sensory nerve abnormalities have been reported in amyotrophic lateral sclerosis (ALS), their distribution at diagnosis, relative to motor involvement and clinical onset phenotype remains incompletely characterized. We aimed to systematically compare sensory and motor nerve conduction abnormalities at ALS diagnosis and determine whether sensory involvement follows an onset-dependent pattern similar to motor dysfunction.<br><br>METHODS: In this prospective cross-sectional study, 40 newly diagnosed ALS patients enrolled in the Iran University ALS Registry (March 2022-March 2023) underwent standardized motor and sensory nerve conduction studies (NCS). For between-group comparisons, a matched ALS subgroup was compared with matched healthy controls, while the expanded ALS cohort was used for subgroup and correlation analyses.<br><br>RESULTS: SNAP amplitudes of the median, ulnar, and sural nerves were reduced by 45%, 34%, and 43%, respectively, compared with healthy controls, with similar reductions observed across upper- and lower-limb onset phenotypes and no significant onset-dependent differences. In contrast CMAP amplitudes were markedly reduced in ALS patients, most prominently in the peroneal (79%), median (47%), tibial (42%), and ulnar (37%) nerves. Motor abnormalities were most severe in the clinically affected limb but were also detectable in asymptomatic extremities, consistent with early subclinical spread.<br><br>CONCLUSION: At ALS diagnosis, sensory and motor nerve conduction abnormalities exhibited divergent spatial patterns, with asymmetric, onset-related motor involvement and relatively uniform sensory axonal dysfunction. These findings support the presence of measurable sensory nerve conduction abnormalities in a subset of ALS patients, while highlighting the need for cautious interpretation of sensory NCS changes in ALS.}, }
@article {pmid42361455, year = {2026}, author = {Kim, JS and Yu, S and Mitchell, MB and Goss, D and Schumacher, DJ and Chen, JX}, title = {The Implementation of Competency-Based Medical Education in Surgical Training: A Scoping Review.}, journal = {Journal of surgical education}, volume = {83}, number = {9}, pages = {104056}, doi = {10.1016/j.jsurg.2026.104056}, pmid = {42361455}, issn = {1878-7452}, abstract = {BACKGROUND: The pace of implementation of competency-based medical education (CBME) in postgraduate surgical training has varied substantially across settings, due in part to inconsistent definitions of what constitutes CBME in practice. Employing the lens of Van Melle et al.'s 2019 codification of the core components of CBME, this scoping review aims to characterize how CBME has been implemented in surgical residency programs worldwide.<br><br>METHODS: Embase, PubMed, MedEdPortal, and ERIC were searched for English-language articles describing active CBME implementation in surgical residency programs. A scoping review was conducted using Covidence and reported using the PRISMA-ScR guidelines. Research abstracts, systematic/scoping reviews, and studies describing isolated workshops or training supplements were excluded. CBME implementations extracted from included studies were classified as systemic implementations, local innovations, or competency-based assessment instruments. Given substantial redundancy in the literature, not all studies describing the U.S. Accreditation Council for Graduate Medical Education Core Competencies or Milestones were included; 5 exemplary studies from this corpus were included as representative descriptions. All included studies were evaluated against the 5 CBME core components: outcome competencies, sequenced progression, tailored learning experiences, competency-focused instruction, and programmatic assessment.<br><br>RESULTS: Seventy studies published between 2001 and 2023 were included, predominantly from North America and Europe. Outcome competencies were clearly defined across all systemic implementations; however, sequenced progression, competency-focused instruction, and programmatic assessment were more variably incorporated, and were more often satisfied in Canadian and European frameworks. While local innovations and assessment instruments demonstrated novelty and the feasibility of CBME implementation, alignment with all 5 core components was uncommon.<br><br>CONCLUSIONS: CBME implementation in surgical residency remains heterogeneous, with many programs layering components of CBME onto existing curricular structures. These findings suggest that greater emphasis on future systemic educational reform efforts may support more impactful CBME implementation in surgical training programs.}, }
@article {pmid42361623, year = {2026}, author = {Deptuła, P and Chmielewska-Deptuła, S and Spałek, J and Kaliniak, S and Okła, S and Bucki, R}, title = {Decoding the pathogenesis of Candida albicans infection and evaluating the efficacy of antifungal drugs using atomic force microscopy.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {201}, number = {}, pages = {119705}, doi = {10.1016/j.biopha.2026.119705}, pmid = {42361623}, issn = {1950-6007}, abstract = {Atomic force microscopy (AFM) has emerged as a pivotal method enabling multidimensional characterization of Candida albicans (C. albicans) by simultaneously providing topographical imaging, mechanical profiling, and quantitative measurements of adhesion forces under near-physiological conditions. AFM-derived data demonstrate that nanoscale surface alterations, including wrinkling, indentations, increased roughness, and perforations correlate closely with modulation of the Young's modulus and with the reorganization of mannoproteins and adhesins, particularly those of the Als family. The co-occurrence of structural, mechanical, and adhesive changes reflects the dynamic remodeling of the fungal cell wall that governs morphogenesis, virulence, and biofilm formation. AFM offers high resolution insight into the mechanisms of action of antifungal drugs, antimicrobial peptides, nanomaterials, and physical treatments that destabilize the cell wall, reduce its stiffness, or conversely induce compensatory stiffening and adhesin exposure. As a result, the technique enables the identification of critical steps in stress responses and hyperadhesive phenotypes that contribute to fungal invasion and treatment resistance. Integration of AFM with spectroscopic and microfluidic approaches further enhances its potential to reveal new therapeutic targets. Collectively, evidence from numerous studies underscores AFM as a foundational tool in the rational design of modern, multimodal antifungal strategies aimed at the cell wall and biofilm of C. albicans.}, }
@article {pmid42362190, year = {2026}, author = {Lyu, R and Ruff, KM and Palmer, CS and Ramirez, AE and Ormsby, AR and Scott, DJ and Pappu, RV and Stojanovski, D and Stroud, DA and Hatters, DM}, title = {ASAP-ID: Proximity labelling with small tags.}, journal = {Molecular &amp; cellular proteomics : MCP}, volume = {}, number = {}, pages = {101616}, doi = {10.1016/j.mcpro.2026.101616}, pmid = {42362190}, issn = {1535-9484}, abstract = {Biotinylation-based proximity labelling methods are valuable for discovering protein-protein interactions within cellular systems. However, one limitation of these approaches is that most require fusing the target protein with the enzyme that biotinylates nearby proteins (i.e., TurboID or APEX2), which risks sterically disrupting the protein's native function. Here, we present a method designed to reduce the steric impact of these fusions and offer greater flexibility in labelling modalities. The method, Antibody and Small-tag Assembly on Proteins for Interaction Detection (ASAP-ID), involves a bipartite system. Target proteins are fused to a small peptide antigen that recruits TurboID or APEX2 fused to an antibody directed to the antigen. Using two different antigen/antibody systems (SunTag and MoonTag), we show that ASAP-ID can specifically label human Lamin A in cells. The method works when the target protein and nanobody are co-expressed together in cis (ASAP-ID[IC]). We also demonstrate that the approach works when the antibody fusion is added in trans to fixed cells post-expression (ASAP-ID[IT]). ASAP-ID[IT] identified more than 448 known and previously undescribed potential interactors of lamin. We further used ASAP-ID[IT] to study how ALS-mutant profilin 1 affected its interactome. The method identified proteins involved in protein quality control that correlated with aggregation propensity. Moreover, the different mutants showed variation in the cellular location where aggregates formed. ASAP-ID[IT] revealed preferences for mitochondrial proteins for the two profilin mutants that tend to aggregate in the cytoplasm, C71G and M114T, and nuclear proteins for a mutant more prone to nuclear aggregation. These findings position ASAP-ID as a powerful addition to the proximity labelling toolkit, capable of probing subtle differences in interactomes in a less invasive manner.}, }
@article {pmid42362484, year = {2026}, author = {Nakayama, Y and Kume, K and Baba, T and Ayaki, T and Hanada, K and Miyamoto, K and Inoue, N and Kawakami, H and Ito, H}, title = {Neuropathological and Molecular Features Associated With a Heterozygous DNAJC7 Mutation in Amyotrophic Lateral Sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {4}, pages = {e70086}, doi = {10.1111/nan.70086}, pmid = {42362484}, issn = {1365-2990}, support = {18H02743//Japan Society for the Promotion of Science/ ; 25K10801//Japan Society for the Promotion of Science/ ; //Takeda Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Female ; Male ; Middle Aged ; *Molecular Chaperones/genetics ; Mutation ; Aged ; Heterozygote ; Heat-Shock Proteins ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear molecular mechanisms. Heterozygous protein-truncating variants of DNAJC7, which encode a cochaperone involved in Hsp70/90-mediated protein quality control, are potential risk factors for ALS. However, the neuropathological consequences of heterozygous DNAJC7 mutations are unclear. We aimed to clarify the molecular and neuropathological features associated with a heterozygous DNAJC7 mutation in ALS.<br><br>METHODS: We genetically screened 39 Japanese patients with ALS and identified a novel heterozygous frameshift mutation in DNAJC7 (c.157_163del, p.Lys53Ter) in one patient that was neuropathologically diagnosed with Kii ALS. We performed biochemical and neuropathological analyses using postmortem tissues from this patient, from cases of ALS without the mutation and from control cases.<br><br>RESULTS: In the cases of ALS without DNAJC7 mutation, there was elevation of both DNAJC7 mRNA and protein levels compared with controls. The patient with DNAJC7 mutation showed relatively lower DNAJC7 mRNA and protein levels compared with the nonmutated cases of ALS, although mRNA expression remained relatively higher. DNAJC7 may be upregulated as a protective response against ALS pathogenesis, whereas a heterozygous mutation may attenuate this response. Immunohistochemistry and double immunofluorescence demonstrated partial colocalization of DNAJC7 with phospho-TDP-43-positive neuronal cytoplasmic inclusions, which supports a direct role for DNAJC7 in modulating pathological TDP-43 aggregation.<br><br>CONCLUSIONS: These findings provide neuropathological evidence linking heterozygous DNAJC7 mutation to ALS, demonstrating impaired protein expression and suggesting a loss-of-function mechanism that compromises protective responses to TDP-43 pathology. DNAJC7 may represent a key modulator of ALS pathogenesis and potential therapeutic target.}, }
@article {pmid42363583, year = {2026}, author = {Ludwig, TD and Rabelo-Araujo, JVDS and Munhoz Pedroso, R}, title = {Enhanced weed control in flooded rice through diversified pre-emergence programs integrating PROTOX-inhibiting herbicides.}, journal = {Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/03601234.2026.2694270}, pmid = {42363583}, issn = {1532-4109}, abstract = {Rice (Oryza sativa L.) productivity in Brazil is increasingly threatened by herbicide-resistant weeds. We evaluated diversified pre-emergence programs in flooded Clearfield rice (Puitá INTA CL) through two field experiments conducted in southern Brazil during the 2016/2017 season. Programs were based on acetolactate synthase (ALS) inhibitors alone or combined with alternative modes of action, including protoporphyrinogen oxidase (PROTOX) inhibitors (saflufenacil and flumioxazin). Weed control of Aeschynomene spp. and Echinochloa spp. was high (≥80%) at 14 days after application (DAA) and remained satisfactory up to 21 DAA in most programs. Crop injury was treatment-dependent, with higher early phytotoxicity observed in mixtures containing mesotrione, but visual symptoms declined over time and did not compromise grain yield. All herbicide programs significantly increased productivity compared to the untreated control. These findings indicate that integrating PROTOX inhibitors into Clearfield-based pre-emergence programs is a feasible strategy to diversify modes of action while maintaining effective weed control and yield stability under flooded conditions.}, }
@article {pmid42363684, year = {2026}, author = {Majumder, P and Ahsan, A and Bubphachat, P and Akter, K and Huang, JK and Huang, CS}, title = {FMRP-Mediated Proteasome Regulation: A Novel Mechanism in ALS Pathology.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {13}, pages = {e72063}, doi = {10.1096/fj.202600563R}, pmid = {42363684}, issn = {1530-6860}, support = {NSTC 114-2320-B-038-055//National Science and Technology Council (NSTC)/ ; NSTC 110-2320-B-038-067-MY3//National Science and Technology Council (NSTC)/ ; NSTC 110-2320-B-038-090-MY3//National Science and Technology Council (NSTC)/ ; NSTC 113-2320-B-038-061//National Science and Technology Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Proteasome Endopeptidase Complex/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Humans ; *Fragile X Messenger Ribonucleoprotein 1/metabolism/genetics ; Mice ; Mice, Transgenic ; Cytoplasm/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the hallmark cytoplasmic accumulation and aggregation of TAR DNA binding protein 43 (TDP-43), which impairs proteasome activity through its interaction with Tankyrase (TNKS). Using molecular and imaging techniques, we have identified a novel role for the Fragile X Mental Retardation Protein (FMRP) in regulating the TNKS/PI31-mediated proteasome activation mechanism in co-operation with TDP-43. Our results demonstrate that depletion of FMRP causes nuclear translocation of TDP-43, reducing cytoplasmic TNKS/TDP-43 co-localization, thereby releasing TNKS in the cytoplasm. Free TNKS gets associated with proteasome inhibitor of 31 kDa (PI31), reversing PI31-mediated inhibition of proteasome assembly, trafficking, and activity. Thus, FMRP regulates proteasome activity by modulating the subcellular distribution of TDP-43. Interestingly, FMRP expression is elevated in specific brain regions and spinal cords of TDP-43[A315T] transgenic ALS mice that helps more TDP-43 to stay in cytoplasm to sequester more TNKS with it, resulting in proteasome dysfunction in ALS disease system. We have demonstrated for the first time that FMRP can act as a disease modifier for ALS. ALS patients with high FMRP expression in the brain and spinal cord may exhibit more severe protein aggregation due to proteasome dysfunction.}, }
@article {pmid42364760, year = {2026}, author = {Baird, KT}, title = {The impedance mismatch theory: A non-equilibrium thermodynamic framework for a shared energetic stress pathway in neurodegeneration.}, journal = {Bio Systems}, volume = {}, number = {}, pages = {105862}, doi = {10.1016/j.biosystems.2026.105862}, pmid = {42364760}, issn = {1872-8324}, abstract = {Current neurobiological models of Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's Disease (HD) utilize multi-omic interactome analyses to map cascades of proteinopathy. While essential, these approaches often overlook the macroscopic thermodynamic limits of the neural substrate as an information processing system. We propose the Impedance Mismatch Theory, a theoretical biophysical model and quantitative framework for the thermodynamic limits of neural computation, positing that these distinct pathologies converge as a shared energetic stress pathway. We introduce the Neurophysiological Load Index (NLI)-a dimensionless parameter quantifying the mismatch between electrical computational drive, topological network impedance, and the local structural and microvascular dissipation capacity. Drawing on the Pennes Bioheat Transfer Equation and insights from multiplex network theory, we hypothesize that pathology initiates as localized thermal runaway, where resistive metabolic heat exceeds convective blood perfusion and thermal conduction, inducing acute decompensation. We outline cross-translational disease-network mechanisms, address the inverse cancer comorbidity paradox via speculative bioelectric attractor states, and propose falsifiable predictions involving high-resolution in vivo proton magnetic resonance spectroscopy thermometry ([1]H-MRS-t) and phosphorus-31 magnetic resonance spectroscopy ([31]P-MRS).}, }
@article {pmid42365206, year = {2026}, author = {Hammond, RM and Salvalaggio, G and Nykiforuk, CIJ and Hyshka, E}, title = {Navigating the CBD: How Urban Risk Environment Shapes Daily Life for People Who Use Drugs in Edmonton's Central Business District.}, journal = {Journal of urban health : bulletin of the New York Academy of Medicine}, volume = {}, number = {}, pages = {}, pmid = {42365206}, issn = {1468-2869}, support = {Subcontract//Boyle Street Community Services/ ; }, abstract = {Public drug use in urban central business districts (CBDs) presents an urgent public health challenge in Canada. People who use drugs (PWUD) in CBDs navigate intersecting risks related to criminalization, stigma, hostile architecture, urban redevelopment, and limited access to essential services-factors that compound health disparities and increase morbidity and mortality. Yet CBDs also function as sites of informal social networks, mutual aid, and adaptive survival strategies that, while precarious, constitute critical resources for daily safety and belonging. This focused ethnographic study, conducted in Edmonton's CBD between July 2022 and September 2023, draws on 25 semi-structured interviews and over 170 h of embedded field immersion to investigate how intersecting environmental forces shape the daily lives of PWUD. Using Collins et al.'s (2019) intersectional risk environment framework and Duff's (2009) enabling environment concept, we analyzed how physical, social, economic, and policy environments-operating across micro and macro levels-produce differential harms and, simultaneously, generate precarious yet meaningful sites of connection, resourcefulness, and collective care. Findings reveal how displacement, over-policing, and gentrification-driven spatial change coexist with participants' place-based belonging, moral economies of reciprocity, and culturally grounded survival knowledge. We argue that effective interventions must account for this co-production of risk and enabling conditions and that urban governance must center the voices of those most structurally affected.}, }
@article {pmid42365390, year = {2026}, author = {Zheng, H and Luo, H and Lu, Y and Yuan, Y and Zhang, N and Duan, S and Xia, Z and Xu, Y}, title = {Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42365390}, issn = {2047-9158}, support = {82301619//the National Natural Science Foundation of China/ ; 82571514//the National Natural Science Foundation of China/ ; 232102311229//the key scientific and technological breakthrough project in Henan province/ ; 2022M722875//the China Postdoctoral Science Foundation/ ; }, mesh = {Humans ; *Lysosomes/metabolism/pathology ; *Frontotemporal Lobar Degeneration/metabolism/pathology/genetics ; *Autophagy/physiology ; *Annexins/metabolism/genetics ; *Amyloid/metabolism ; Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; }, abstract = {BACKGROUND: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression.<br><br>METHODS: To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent "prion-like" spreading of aggregates.<br><br>RESULTS: The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival.<br><br>CONCLUSIONS: Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.}, }
@article {pmid42366580, year = {2026}, author = {Macklin, EA and Berry, JD and Harkey, BA and Heyd, L and Chase, M and Yu, H and Sherman, AV and Dagostino, D and Kittle, G and Hall, M and Connolly, MR and Drake, K and Giacomelli, E and Scirocco, E and Sharma, S and Babu, S and Benatar, M and Simmons, Z and Young, E and Cudkowicz, ME and Shefner, J and Paganoni, S and , }, title = {At-Home Versus in-Clinic Vital Capacity Measurement: Insights From the HEALEY ALS Platform Trial.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70322}, pmid = {42366580}, issn = {1097-4598}, support = {MDA 1313867//Muscular Dystrophy Association/ ; //Tackle ALS/ ; //ALS Finding a Cure/ ; //ALS Association/ ; //ALS ONE/ ; //The Arthur M. Blank Family Foundation/ ; //The AMG Charitable Foundation/ ; }, abstract = {INTRODUCTION/AIMS: Respiratory weakness, typically monitored as vital capacity (VC), is a central feature of amyotrophic lateral sclerosis (ALS). VC is increasingly measured remotely in participants' homes, although in-clinic assessment remains the standard. We tested concordance between at-home and in-clinic VC to determine trial eligibility, track progression, and predict survival in a large ALS trial.<br><br>METHODS: At-home and in-clinic VC were assessed at baseline and approximately every 8&#x2009;weeks for a year in the first four regimens of the HEALEY ALS Platform Trial. At-home assessments were coached via live videoconference and centrally reviewed. VC measurements, expressed as percent of predicted normal (%PN), were compared cross-sectionally, longitudinally, and for predicting survival time. Data from 233 participants with 3-8 paired at-home and in-clinic VC assessments completed <&#x2009;14&#x2009;days apart were analyzed.<br><br>RESULTS: At-home and in-clinic VC were well correlated (Lin's rc&#x2009;=&#x2009;0.82) with no systematic bias. At-home VC &#x2265;&#x2009;60%PN predicted in-clinic VC &#x2265;&#x2009;60%PN with a positive predictive value of 91% and a negative predictive value of 65%. VC slopes were moderately correlated (rc&#x2009;=&#x2009;0.68). At-home VC progressed 28% faster than in-clinic VC with proportionately less variance (at-home [SE]&#x2009;=&#x2009;-1.882 [0.153] %PN/month, in-clinic&#x2009;=&#x2009;-1.476 [0.131] %PN/month). Slopes of at-home and in-clinic VC explained 15% and 17% of variation in future survival time, respectively.<br><br>DISCUSSION: At-home and in-clinic VC were well correlated cross-sectionally. At-home VC performed well tracking longitudinal change and predicting survival. The reduced participant burden of assessment and concordance with in-clinic measurement support use of at-home monitoring of VC.}, }
@article {pmid42367369, year = {2026}, author = {Morganroth, J and Yasek, J and Harms, M}, title = {Preparing Amyotrophic Lateral Sclerosis Clinics to Provide Longitudinal Care for Individuals Carrying ALS Risk Variants.}, journal = {Neurology. Genetics}, volume = {12}, number = {4}, pages = {e200406}, pmid = {42367369}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Emerging genetic therapies and the expansion of genetic testing are identifying individuals carrying amyotrophic lateral sclerosis (ALS) risk variants who would benefit from surveillance and early intervention. Anticipating the geographic distribution and clinical needs of this population is essential for optimizing care delivery and ensuring readiness as new therapies become available. We estimate the number of individuals in the United States carrying ALS risk variants and project the clinical engagement required to support this population. This is especially timely because ALS clinics are already grappling with rising numbers of patients with symptomatic ALS and deep funding cuts.<br><br>METHODS: We developed a population model to estimate the number of symptomatic individuals with gene-positive ALS and asymptomatic gene carriers across US states over the next decade (year 1: 2026). State-level ALS prevalence and incidence were calculated using 2 approaches: (1) race-adjusted ALS rates from the Atlanta metropolitan study applied to 2023 Census demographics and (2) observed state-level ALS case counts from the National ALS Registry (2011-2018). Gene-positive cases were estimated using published frequencies of SOD1, C9orf72, FUS, and TARDBP pathogenic variants. At-risk relatives were modeled assuming autosomal-dominant inheritance with &#x223c;5 first-degree and &#x223c;7 second-degree living relatives per proband, and broad uptake of cascade genetic testing. Surveillance needs were modeled as 1 annual visit per asymptomatic carrier, which was normalized by the number of ALS centers per state.<br><br>RESULTS: In year 1 (2026), the model estimated 2,704 symptomatic gene-positive ALS carriers. With an average of 4.25 carrier relatives per proband, 10,944 asymptomatic carriers were projected nationwide. Most states required <50 additional visits per clinic annually, with 12 states in the 50-99 range and none exceeding 100. By year 10 (2035), the model projected 7,474 symptomatic and 26,111 asymptomatic carriers. State-level demand shifted substantially: only 6 states remained below 50 visits per clinic annually; 22 reached 50-99; 18 reached 100-199; and 3 exceeded 200.<br><br>DISCUSSION: Gene-targeted testing is projected to substantially increase ALS clinic visits among asymptomatic gene carriers. While current infrastructure may accommodate the initial rise, within a decade, most states will require significant expansion. Anticipating and planning for this growth now is essential to ensure seamless integration of gene-positive individuals into ALS care.}, }
@article {pmid42367645, year = {2025}, author = {Toussirot, E and Tatu, L and Bereau, M}, title = {Occurrence of amyotrophic lateral sclerosis during TNF inhibitor treatment in inflammatory rheumatic disease. What are the relationships?.}, journal = {EULAR rheumatology open}, volume = {1}, number = {4}, pages = {475-477}, pmid = {42367645}, issn = {3050-7081}, abstract = {Neurological adverse events have been reported in patients receiving tumor necrosis factor inhibitors (TNFi) for the treatment of inflammatory rheumatic diseases. The occurrence of amyotrophic lateral sclerosis (ALS) during TNFi therapy is rare but raises the question of a possible relationship. We report 2 cases of ALS diagnosed during TNFi treatment: the first in a patient with spondyloarthritis treated with adalimumab and the second in a patient with seronegative polyarthritis treated with infliximab. Tumor necrosis factor alpha (TNFα) has been implicated in ALS pathogenesis and is considered to exert both neuroprotective and neurotoxic effects, depending on the differential expression of its receptors in distinct regions of the central nervous system. We also review data from pharmacovigilance databases and discuss the potential influence of TNFα inhibition on ALS development.}, }
@article {pmid42367691, year = {2026}, author = {Loser, V and Afanasiev, V and Vicino, A and Théaudin, M}, title = {Chronic Inflammatory Demyelinating Polyradiculoneuropathy-Like Neuropathy in Heterozygous C9orf72 Mutation: A Case Report.}, journal = {Case reports in neurology}, volume = {18}, number = {1}, pages = {260-266}, pmid = {42367691}, issn = {1662-680X}, abstract = {INTRODUCTION: C9orf72 repeat expansion is usually associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS/FTD overlap. We report an atypical neuromuscular presentation of C9orf72 repeat expansion.<br><br>CASE PRESENTATION: A 68-year-old patient developed a sensorimotor polyneuropathy with slow continuous worsening over 3 years. Symptoms started in the left foot and slowly extended to all four limbs. Nerve conduction studies were consistent with a non-length-dependent predominantly axonal sensorimotor polyneuropathy, with some additional demyelinating features (proximal temporal dispersion and F-wave latency prolongation). Electro-clinical presentation fulfilled EAN/PNS 2021 criteria for CIDP, but the patient was not responsive to IVIg. RT-PCR revealed a heterozygous pathogenic expansion of the C9orf72 gene. The patient's father and brother died from ALS. At onset, his brother also had sensorimotor involvement and was misdiagnosed with CIDP.<br><br>CONCLUSION: This case may expand the phenotypic spectrum associated with C9orf72 repeat expansion. The initial phenotype could be a non-length-dependent sensorimotor polyneuropathy with demyelinating features that potentially mimics CIDP.}, }
@article {pmid42359101, year = {2026}, author = {Carder, P and Smith, L and Bunker, JN and Hua, CL and Hsu, EC and Boun, I and Ainsworth, OM and Thomas, KS and Jutkowitz, E}, title = {How do US states define person-centered and family-involved care in assisted living regulations.}, journal = {Frontiers in dementia}, volume = {5}, number = {}, pages = {1824907}, pmid = {42359101}, issn = {2813-3919}, abstract = {INTRODUCTION: A large share of assisted living (AL) residents have a diagnosis of dementia or cognitive impairment, and these individuals can benefit from person-centered care and family-involved care. This study examines whether and how states' AL licenses address these topics.<br><br>METHODS: This research analyzed a national database of 249 unique licensing requirements that govern 35,602 ALs in all states and associated regulations, including those that govern memory care (MC) services. We reviewed each regulation for the presence of person-centered or family involved care and then used content analysis of license requirements with at least one relevant policy to identify key categories and regulatory specificity.<br><br>RESULTS: A larger share of AL with licenses that govern MC services are covered by person-centered care policies (44%) and family-involved policies (62%), compared to AL without MC-specific requirements (20 and 32% respectively). Key categories of person-centered care included staff training, care planning procedures, and social activities; and family-involved care included care planning, direct involvement in providing care, and support for families. Few states' licenses contained highly specific regulations.<br><br>DISCUSSION: This study reveals substantial variation in whether and how states define and regulate person-centered and family-involved care for people living with dementia in AL. MC-specific licenses are roughly twice as likely to require these policies, but fewer than two-thirds of MC-AL communities are covered. State licenses take different approaches to categorizing and specifying these policies. These findings suggest uneven application of core principles of AL associated with quality of life and satisfaction.}, }
@article {pmid42359165, year = {2026}, author = {Morimoto, S and Kato, C and Takahashi, S and Okano, H}, title = {Therapeutic frontiers in ALS: iPSC-based drug discovery, cell therapy, and gene therapy-Advances through 2026.}, journal = {Regenerative therapy}, volume = {33}, number = {}, pages = {101150}, pmid = {42359165}, issn = {2352-3204}, abstract = {Three converging therapeutic paradigms-iPSC-based drug discovery, cell transplantation, and gene therapy-have substantially expanded the therapeutic pipeline for amyotrophic lateral sclerosis (ALS) between 2020 and 2026. The FDA's accelerated approval of tofersen (Qalsody) in April 2023 marked the first treatment targeting a genetic cause of ALS. iPSC-derived drug candidates, including ropinirole and bosutinib, have completed early-phase clinical trials led by Japanese institutions. Cell therapies targeting neuroinflammation through regulatory T cells are being actively explored as immunomodulatory strategies, although efficacy remains to be established in adequately powered trials. Next-generation gene-silencing approaches-including RNA interference (RNAi) therapeutics and AAV-delivered microRNA-entered first-in-human trials in 2024-2025. The identification of STMN2 as a downstream target of TDP-43 dysfunction has opened a potential TDP-43-downstream nucleic acid therapeutic avenue for sporadic ALS, which constitutes approximately 90% of all cases, with company-reported interim data suggesting target engagement in the ongoing Phase 1/2 ANQUR trial (QRL-201). This review synthesizes the latest evidence across all three therapeutic domains, with attention to the hierarchy of evidence, regulatory milestones, and the pioneering contributions of Japanese research groups.}, }
@article {pmid42359357, year = {2026}, author = {Shu, X and Yu, X and Xu, P and Wang, A}, title = {Innate immune crosstalk in ALS/FTD pathogenesis.}, journal = {Cell insight}, volume = {5}, number = {4}, pages = {100340}, pmid = {42359357}, issn = {2772-8927}, abstract = {Marked by protein aggregation, impaired proteostasis, organelle stress, and chronic neuroinflammation, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a clinically, genetically, and pathologically overlapping disease spectrum. Increasing evidence indicates that innate immune activation is not merely a secondary response to neuronal injury, but an active driver of disease progression. In this review, we elaborate on how ALS/FTD-associated genetic lesions and pathogenic protein aggregates, including TDP-43, SOD1, FUS, and C9orf72-derived dipeptide repeat proteins, engage three interconnected innate immune pathways: cGAS-STING, NLRP3 inflammasomes, and TREM2-DAP12 signaling. We further highlight emerging crosstalk among these pathways, in which cGAS-STING and NLRP3 reinforce inflammatory signaling, while NLRP3-driven TREM2 shedding may impair microglial clearance and perpetuate proteostatic failure. Understanding this immune network may help define disease subtypes, identify biomarkers, and guide combinatorial therapeutic strategies that suppress harmful inflammation while preserving protective microglial functions.}, }
@article {pmid42359392, year = {2026}, author = {Imamura, K and Nagahashi, A and Okusa, A and Yamamoto, T and Izumi, Y and Ueda, N and Kawahara, Y and Inoue, H}, title = {Nonlinear combinatorial analysis of blood transcriptomes identifies PRKAR1A as a regulator of TDP-43 pathophysiology in amyotrophic lateral sclerosis.}, journal = {Biology methods &amp; protocols}, volume = {11}, number = {1}, pages = {bpag023}, pmid = {42359392}, issn = {2396-8923}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Accurate and accessible blood-based diagnostics for neurodegenerative diseases, including ALS, are being progressively required. Although blood cell gene expression profiles have potential clinical utility for distinguishing ALS, robust transcriptomic biomarkers for supportive diagnosis have not yet been established. Here, we analyzed publicly available peripheral blood mononuclear cell (PBMC) transcriptomic data from ALS patients using Maximum Mean Discrepancy, a kernel-based method that captures nonlinear distributional differences in a reproducing kernel Hilbert space and enables the extraction of informative gene combinations while minimizing multicollinearity, a common issue in multiple regression models. Using this approach, we identified a nonlinear three-gene combination-PRKAR1A, QPCT, and TMEM71-that distinguished ALS from healthy controls with an area under the curve (AUC) of 0.83 in a public PBMC dataset. This achievement was confirmed in laboratory PBMC samples with an AUC of 0.85, supporting the robustness of the identified gene signature in independent samples. Furthermore, these genes also enabled ALS classification in induced pluripotent stem cell-derived motor neurons with an AUC of 0.79. Knockdown of PRKAR1A, QPCT, or TMEM71 in motor neurons increased the TDP-43 expression levels, and PRKAR1A knockdown induced the mislocalization of TDP-43, accompanied by phosphorylation, suggesting a potential link to ALS-related pathophysiology. These findings suggest that nonlinear gene combinations may provide a useful strategy for identifying blood-based biomarkers and offer insights into ALS pathogenesis. This nonlinear, data-driven analytical framework enabled the transition from unbiased gene discovery to the identification of pathophysiology-associated molecules by in vitro functional validation.}, }
@article {pmid42359947, year = {2026}, author = {Rozman, SI and Hamzaid, NA and Lim, E and Hamzah, N}, title = {Noninvasive assessment of cardiovascular autonomic reflexes in amyotrophic lateral sclerosis: a systematic review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/21678421.2026.2692135}, pmid = {42359947}, issn = {2167-9223}, abstract = {Dysautonomia is gradually recognized in amyotrophic lateral sclerosis (ALS), raising concerns of secondary complications from heightened autonomic burden. Autonomic disturbances, particularly cardiac dysautonomia, significantly impact patient outcomes, contributing to increased cardiovascular risks and mortality rate. While the ALS Functional Rating Score-Revised (ALSFRS-R) measures functional decline as disease progress, it overlooks autonomic criteria - a critical factor in ALS progression. This review aims to analyze noninvasive applications of cardiovascular signal variability for continuous real-time monitoring of autonomic dysfunction in ALS, while addressing gaps in current clinical assessments. A total of 584 literatures were gathered from four databases (WoS, PubMed, Science Direct and MEDLINE EBSCOhost) - published from inception till December 2023. 21 peer-reviewed studies were included in this review after screening and meeting the inclusion criteria. Various cardiovascular signal variability metrics and autonomic protocols were discussed. Key findings highlight cardiac autonomic dysfunction in ALS is marked by reduced heart rate variability, absent blood pressure regulation upon orthostatic stress and circadian changes, prolonged QTc interval and low baroreflex sensitivity. Moreover, increased autonomic burden is associated with a shift from sympathetic to parasympathetic dysregulation as the disease progresses. Evidence highlights the need to integrate noninvasive autonomic biomarkers into digital ALS monitoring frameworks, enabling earlier detection of autonomic involvement and more precise longitudinal monitoring beyond motor decline.}, }
@article {pmid42346159, year = {2026}, author = {Verde, EM and Secco, V and Ghezzi, A and Mandrioli, J and Carra, S}, title = {Correction: Verde et al. Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses. Cells 2025, 14, 680.}, journal = {Cells}, volume = {15}, number = {12}, pages = {}, pmid = {42346159}, issn = {2073-4409}, abstract = {In order to facilitate readers' better understanding, some language descriptions and grammar as well as the layout of some chapters have been modified [...].}, }
@article {pmid42347120, year = {2026}, author = {Alves Ferreira, JM and Tukaiev, S and Giannouli, V}, title = {RNA-Binding Proteins in Ageing and Age-Related Disease.}, journal = {Neurology international}, volume = {18}, number = {6}, pages = {}, doi = {10.3390/neurolint18060112}, pmid = {42347120}, issn = {2035-8385}, abstract = {RNA-binding proteins (RBPs) are essential regulators of all aspects of RNA metabolism, including splicing, stability, localisation, translation, and degradation. Through their ability to recognise specific cis-elements in target transcripts, often via RNA-recognition motifs or other conserved domains, RBPs enable rapid cellular adaptation to stress and maintain proteostasis, particularly in post-mitotic tissues with limited transcriptional flexibility. Accumulating evidence positions RBPs as both modulators and drivers of the molecular hallmarks of ageing, including genomic instability, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and chronic inflammation. This review synthesises peer-reviewed studies on the multifaceted roles of RNA-binding proteins in organismal ageing and age-related diseases. Key themes include the tissue- and age-dependent changes in expression of turnover and translation regulatory RBPs such as HuR (ELAVL1), AUF1 (HNRNPD), TIA-1, and tristetraprolin (ZFP36), which alter the stability of mRNAs encoding cell-cycle regulators, pro-inflammatory cytokines, and stress-response proteins. Systematic downregulation of core splicing factors, including PTBP1 and several heterogeneous nuclear ribonucleoproteins, drives widespread senescence-associated splicing alterations in pathways governing cell division, autophagy, DNA repair, and mitochondrial function, suggesting a causal contribution to the senescent phenotype. Prion-like RBPs such as TDP-43 and FUS exhibit age-dependent mislocalisation, nuclear depletion, and cytoplasmic aggregation, contributing to splicing defects, impaired RNA transport, and neurodegeneration in amyotrophic lateral sclerosis, frontotemporal dementia, and limbic-predominant age-related TDP-43 encephalopathy. Interactions between RBPs and non-coding RNAs, together with disrupted liquid-liquid phase separation dynamics, further exacerbate age-related decline. By integrating mechanistic studies from cellular and animal models with observations in human cohorts, this review underscores RBPs as central nodes linking multiple ageing hallmarks and highlights their potential as biomarkers and therapeutic targets to promote healthy ageing. Limitations of current models and priorities for future translational research are discussed.}, }
@article {pmid42347662, year = {2026}, author = {Breuer, A and Raeder, V and Pernice, HF and Boesl, F and Prüss, H and Audebert, H and Hahn, K and Franke, C}, title = {Fasciculations Following COVID-19 Vaccination-A Case Series of Ten Patients.}, journal = {Vaccines}, volume = {14}, number = {6}, pages = {}, doi = {10.3390/vaccines14060541}, pmid = {42347662}, issn = {2076-393X}, abstract = {Introduction: Vaccination against COVID-19 has been crucial in controlling the pandemic. While side effects are typically mild, rare neurological complications have been reported. This is a case series of ten patients who reported of persistent fasciculations after COVID-19 vaccination. Methods: We describe the clinical presentation and diagnostic work-up of ten patients with new-onset fasciculations in temporal proximity to COVID-19 vaccination. Patients with prior SARS-CoV-2 infection or known alternative causes of fasciculations were excluded. Routine clinical data, including neurological examination, laboratory results, and electrophysiology (electromyography and nerve conduction studies), were analyzed. Results: Ten patients (5 male, 5 female; mean age 42.4 years) reported fasciculations beginning within 6 h to 13 days post-vaccination and persisting for 2-12 months at the time of presentation. Fasciculations were accompanied by additional symptoms such as paresthesia and fatigue. Laboratory results were mostly unremarkable; two patients had positive myositis antibodies without clinical correlates. Electrophysiology was unremarkable in six patients, while fasciculation potentials were detected in four patients. Nine were diagnosed with probable benign fasciculation syndrome (BFS), and one met diagnostic criteria for amyotrophic lateral sclerosis (ALS). Discussion: In this small, retrospective case series, most cases of post-vaccination fasciculations were benign and compatible with BFS. Whether BFS onset was causally linked to vaccination or due to a nocebo effect remains unclear. One patient was diagnosed with ALS, though a causal link remains speculative given the study's limitations and rarity of similar reports. Larger, prospective studies are needed to validate these observations and explore underlying pathophysiological mechanisms.}, }
@article {pmid42347833, year = {2026}, author = {Wesenberg, J and Matthies, P and Schwiecker, K and Bittner, V and Hamzic, S and Vielhaber, S and Radakovic, R}, title = {Validation of the German version of the Dimensional Apathy Scale (G-DAS): Application in amyotrophic lateral sclerosis.}, journal = {Journal of neuropsychology}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnp.70061}, pmid = {42347833}, issn = {1748-6653}, support = {//Center for Behavioral Brain Sciences/ ; }, abstract = {Apathy is a common behavioural impairment in neurodegenerative conditions and is conceptualized within the Dimensional Apathy Framework as comprising Executive, Emotional and Initiation subtypes. The Dimensional Apathy Scale (DAS) is widely used to assess these domains, yet no validated German version has been available. This study aimed to translate and validate the German DAS (G-DAS) in control participants (HC) and to characterize apathy profiles in German-speaking people with amyotrophic lateral sclerosis (pwALS). Seventy-seven HC and 32 pwALS completed self-rated and caregiver-rated measures of apathy, depression, disinhibition and executive dysfunction. The G-DAS was translated using a multi-round back-translation procedure. Psychometric validation was undertaken in the HC cohort. A subsample of HC matched to pwALS on age and sex was used for between-group comparisons and for deriving exploratory reference thresholds. The G-DAS demonstrated good to high internal consistency across subscales (α = .76-.85) and total scores (self-rated: α = .88; caregiver-rated: α = .86). Convergent validity was supported by significant correlations with the Apathy Evaluation Scale and Frontal Systems Behavior subscales, particularly for the Initiation and Executive subscales. Divergent validity was evidenced by the absence of associations with anxiety and depression. PwALS showed significantly higher Executive and Initiation apathy compared with matched HC, whereas Emotional apathy did not differ. Exploratory threshold scores derived from matched HC indicated that up to 47% of pwALS exhibited clinically elevated Initiation apathy. The G-DAS is a reliable and valid German-language measure of multidimensional apathy. It effectively captures the characteristic Executive and Initiation apathy profile in ALS, supporting its clinical and research utility.}, }
@article {pmid42348198, year = {2026}, author = {Walter, KL}, title = {Amyotrophic Lateral Sclerosis.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2026.9755}, pmid = {42348198}, issn = {1538-3598}, }
@article {pmid42349387, year = {2026}, author = {Pusic, MV and Ten Cate, O}, title = {Artificial Intelligence, Cognitive Abundance, and the Multi-Layered Competence of Health Professionals.}, journal = {The Journal of continuing education in the health professions}, volume = {}, number = {}, pages = {}, doi = {10.1097/CEH.0000000000000656}, pmid = {42349387}, issn = {1554-558X}, abstract = {Artificial intelligence (AI) is transforming how health care professionals develop, maintain, and express competence across the span of their careers. Traditional continuing professional development has been shaped by a paradigm of what has been called cognitive scarcity (or informational resource scarcity) where clinicians had limited opportunity to find, read, synthesize, and interpret evidence, and learning systems evolved to deliver knowledge in periodic, curated updates. Emerging AI systems-large language models, multimodal analytic tools, predictive algorithms, and reflective agents-disrupt this scarcity by creating cognitive abundance (or informational resource abundance). These systems generate real-time evidence syntheses, contextual insights, adaptive learning trajectories, and continuous performance feedback. Using ten Cate et al.'s (2024, Medical competence as a multilayered construct. Med Educ, 58, 93) multilayered model of competence-canonical, contextual, and personalized-this paper analyzes how AI can both enhance existing educational processes and fundamentally reshape the developmental landscape. AI shifts clinicians from being knowledge stewards to orchestrators of distributed cognition, from experiential learners to data-informed practitioners, and from using opportunistic continuous personal development to continuous reshaping of professional identity. Continuing professional development must evolve to cultivate AI literacy, hybrid reasoning, interprofessional coherence, and ethical stewardship in work environments where cognition is abundant. The contents of long-term memory of clinicians will shift from a predominance of biomedical facts needed to steer daily clinical work, to new procedural inquiry skills needed to find, select, and evaluate the validity of information for clinical decision making.}, }
@article {pmid42349418, year = {2026}, author = {Heffner, CM and Starling, GP and Straker, LC and Hawes, PC and Isaacs, AM and Carlton, JG}, title = {The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.}, journal = {Developmental cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.devcel.2026.05.014}, pmid = {42349418}, issn = {1878-1551}, abstract = {Maintenance of plasma membrane integrity is essential for compartmentalization of the cytosol and for cellular viability. Upon membrane damage, several factors including endosomal sorting complex required for transport-III (ESCRT-III) proteins, annexins, stress granules, lipids, and membrane fusion proteins are mobilized to orchestrate membrane repair. However, whether these factors operate independently or act together is unclear. Here, using human cell lines, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and annexin proteins to sites of plasma membrane damage. We show that annexin proteins are recruited immediately and form a plug at the damage site, restricting membrane permeability. We find that ESCRT-III assembles later and acts to release plug-containing damaged membranes from the cell. Further, frontotemporal dementia (FTD)- and amyotrophic lateral sclerosis (ALS)-associated mutations in the ESCRT-III protein, CHMP2B, and the annexin protein, ANXA11, compromise plasma membrane repair, suggesting that defects in this process may contribute to these pathologies. These data present an integrated "sealing and healing" model of membrane repair.}, }
@article {pmid42349421, year = {2026}, author = {Aubry, L and Korolchuk, VI and Sarkar, S}, title = {Rewiring ALS by modulating the autophagy receptor SQSTM1.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102976}, doi = {10.1016/j.stemcr.2026.102976}, pmid = {42349421}, issn = {2213-6711}, abstract = {Drug screening for genetic disorders is limited by difficulty identifying disease-relevant phenotypes. In this issue, Roussange et al., show that reverse phenotypic mapping could uncover therapeutic gene expression signatures. Using this approach, they identified prazosin, which increases SQSTM1 expression and rescues disease phenotypes in iPSC-derived motor neurons and zebrafish model of amyotrophic lateral sclerosis with SQSTM1 haploinsufficiency.}, }
@article {pmid42349423, year = {2026}, author = {Roussange, F and Gide, J and Tournois, J and Cailleret, M and Boland, A and Battail, C and Deleuze, JF and Polvèche, H and Auboeuf, D and Brockmann, K and Kabashi, E and Marian, A and El Kassar, L and Blondel, S and Salachas, F and Bruneteau, G and Peschanski, M and Martinat, C and Baghdoyan, S}, title = {Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102977}, doi = {10.1016/j.stemcr.2026.102977}, pmid = {42349423}, issn = {2213-6711}, abstract = {The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific genetic diseases. To remedy this, an alternative approach of reverse phenotypic mapping was tested: Compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in FTD/ALS type 3 models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries.}, }
@article {pmid42350166, year = {2026}, author = {Tikkinen, KAO and Tondroanamag, F and Parpia, S and Guyatt, GH and Violette, PD and , }, title = {Reply to Vallée M, Stangl FP, Wagenlehner F et al's Letter to the Editor re: Tikkinen KAO, Najafabadi BT, Hajebrahimi S, et al. A Multicenter Randomized Controlled Trial of Antimicrobial Prophylaxis to Prevent Urinary Tract Infections After Shockwave Lithotripsy for Urolithiasis: The APPEAL Trial. Eur Urol 2025;88(6):543-51.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.06.008}, pmid = {42350166}, issn = {1873-7560}, }
@article {pmid42350373, year = {2026}, author = {Casterton, R and Martinez-Cotrina, A and Barnard, J and Wycherley, E and Hu, Y and Anderson, R and Janel, S and Byun, J and Houghton, O and Solomon, DA and Alcalde, J and Lafont, F and Ruepp, MD and Hirth, F and Tummers, B and Cho, YY and De Nicola, G and Mizielinska, S and Fanto, M}, title = {Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42350373}, issn = {2041-1723}, support = {ARUK-PG2019B-008//Alzheimer's Research UK (ARUK)/ ; }, mesh = {Proteotoxic Stress ; Animals ; Humans ; Cell Death ; Neurons/metabolism/pathology ; Lamin Type B/metabolism/genetics ; Phosphorylation ; Alzheimer Disease/pathology/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Nuclear Lamina/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Mice ; Frontotemporal Dementia/pathology/metabolism ; Cell Nucleus/metabolism ; }, abstract = {Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.}, }
@article {pmid42350385, year = {2026}, author = {Wan, F and He, J and Ma, H and PiresFerreira, D and Kumanan, V and Lee, JS and Chen, X and He, R and Su, Q and Gallagher, TL and Zhu, S and Cabrera, GT and Zhao, L and Shen, J and Gruntman, A and Brown, RH and Xu, Z and Gao, G and Xie, J}, title = {Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42350385}, issn = {2041-1723}, support = {AL240123//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Dependovirus/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Models, Animal ; *Genetic Vectors/administration &amp; dosage/genetics ; Mice ; Motor Neurons/metabolism/pathology ; *Genetic Therapy/methods ; *Gene Silencing ; Mice, Transgenic ; Administration, Intravenous ; MicroRNAs/genetics ; Neuromuscular Junction/metabolism ; Female ; Gene Therapy Agents ; Male ; }, abstract = {Adeno-associated virus (AAV)-mediated gene silencing offers a promising strategy for achieving durable therapeutic effects with a single administration. Mutations in the human superoxide dismutase 1 (hSOD1) gene, inherited in an autosomal dominant manner, lead to motor neuron degeneration in amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease with no effective treatment. In this study, we employed AAV9 to deliver to the SOD1[G93A] ALS mouse model artificial microRNAs targeting SOD1, embedded in dual miR-33 scaffolds driven by the promoter of the human survival motor neuron 1 (hSMN1) gene. A single intravenous injection achieved widespread and sustained suppression of SOD1, preserved α-motor neurons, maintained neuromuscular junctions (NMJs), and improved muscle function. These benefits are translated into significantly improved respiratory function, motor performance, and survival. Therapeutic efficacy was observed both when the treatment was administered pre-symptomatically and during symptomatic stages. Compared with previous AAV-based interventions, the survival benefit achieved in this IV delivery approach is unprecedented, supporting its potential for clinical translation in SOD1-linked ALS and other central nervous system (CNS) diseases caused by gain-of-toxicity gene mutations.}, }
@article {pmid42351201, year = {2026}, author = {Dominguez, GTY and Alarcan, H and Peralta, V and Labroche, N and Corcia, P and Marcel, P and Blasco, H}, title = {Learning a distance for the clustering of patients with amyotrophic lateral sclerosis.}, journal = {BioData mining}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13040-026-00579-5}, pmid = {42351201}, issn = {1756-0381}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with median survival of 3-5 years. Patient responses to treatments vary widely, highlighting the need for personalized care. Clustering patients based on disease progression could improve prognosis, guide clinical decision-making, and optimize clinical trial design. This study aimed to identify robust ALS patient clusters using ALS Functional Rating Scale-Revised (ALSFRS-R) scores and to determine diagnostic parameters predictive of cluster membership, enabling earlier stratification and targeted management.<br><br>METHODS: Data from the Tours ALS center registry (April 1997-October 2023) were analyzed; after preprocessing, 353 patients monitored every three months between January 2004 and July 2023 with ALSFRS-R, clinical, biological, and demographic data were retained. After preprocessing to handle missing or aberrant data, a weakly supervised approach labeled patient pairs based on their ALSFRS-R sequences. These labels were used to train a classifier to learn a distance for off-the-shelf clustering algorithms. Multiple configurations were tested, varying clustering algorithms, dimensionality reduction method, and number of clusters. Random Forest (RF) model predicted cluster membership from diagnostic parameters. Optimal clustering was selected using silhouette score, validated with Kaplan-Meier survival analysis. Stability and robustness were assessed with the Adjusted Rand Index (ARI) and silhouette score respectively. Predictive performance was evaluated using specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). Diagnostic parameters associated with clusters were identified using Kruskal-Wallis and chi-squared tests for continuous and categorical variables.<br><br>RESULTS: Three clusters (n&#x2009;=&#x2009;139, 121, 93) were identified, demonstrating strong separation (silhouette&#x2009;&#x2248;&#x2009;0.6) and high stability of results (ARI&#x2009;&#x2248;&#x2009;0.7). Survival differed significantly among clusters: over 50% of patients in the third cluster survived beyond 50 months, compared to less than 25% in the other clusters. Thirteen diagnostic parameters-including ALSFRS-R subscores, IgG levels, albumin quotient, and time to diagnosis-were key predictors of cluster membership. Cluster prediction achieved specificity and NPV&#x2009;&#x2248;&#x2009;0.75, with close sensitivity and PPV compared to state-of-the-art methods.<br><br>CONCLUSION: This framework successfully stratifies ALS patients into clinically meaningful clusters, revealing underlying disease heterogeneity and providing strong prognostic insight. Such classification can facilitate personalized care, guide therapeutic decisions, and inform the design of targeted interventions to improve outcomes.<br><br>CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid42351263, year = {2026}, author = {Riggio, F and Fenili, G and Caporossi, D and Paronetto, MP}, title = {Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02356-1}, pmid = {42351263}, issn = {2051-5960}, support = {PNRR-MR1-2022-12376821//Ministero della Salute/ ; }, abstract = {Extracellular vesicles (EVs) are heterogenous lipid bilayer-enclosed particles secreted by virtually all cell types. They encapsulate a diverse array of bioactive molecules, including proteins, lipids, nucleic acids, and metabolites, which can be transferred to recipient cells, thereby modulating their function and phenotype. In recent years, skeletal muscle-derived EVs (SkM-EVs) have emerged as key players in the bidirectional communication between skeletal muscle and motor neurons, contributing to the establishment and maintenance of neuromuscular homeostasis. Disruptions in this intercellular signalling have been implicated in the pathophysiology of motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In these contexts, SkM-EVs may contribute to disease progression by delivering pathogenic cargo, including misfolded proteins and aberrant RNAs, to motor neurons. A comprehensive understanding of SkM-EV biology, particularly their roles in neuromuscular communication, could offer critical insights into disease mechanisms and identify novel opportunities for biomarker discovery and therapeutic intervention. This review synthesizes current knowledge on the functional roles of SkM-EVs in motor neuron health and disease and evaluates their potential as diagnostic tools and therapeutic vectors in the context of MNDs.}, }
@article {pmid42351313, year = {2026}, author = {Brenner, D and Ponomarenko, A and Petrut, I and Beyrle, S and Contardo, M and Loss, I and Radke, C and Frank, J and Zimmer, E and Schlesner, M and Achenbach, P and Scheveneels, W and Aly, A and Nazlican, H and Hesebeck-Brinkmann, J and Oeckl, P and Müller, K and Siebert, R and Böckers, T and van Eijk, K and Veldink, J and Kleger, A and Mulaw, M and Andersen, PM and Forsberg, K and Weishaupt, JH and Loghmani, SB and Grehl, T and van Damme, P and Weis, J and Catanese, A}, title = {A rare missense variant impacting NEK1 kinase function is associated with ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42351313}, issn = {2051-5960}, mesh = {*NIMA-Related Kinase 1/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mutation, Missense/genetics ; Female ; Motor Neurons/pathology/metabolism ; Male ; Pedigree ; Animals ; }, abstract = {Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.}, }
@article {pmid42352309, year = {2026}, author = {Morciano, G and Gorgoglione, R and Porcelli, V and Ahmed, A and Scarcia, P and Vozza, A and Lasorsa, FM and Fiermonte, G and Palmieri, L}, title = {Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.}, journal = {Biomolecules}, volume = {16}, number = {6}, pages = {}, doi = {10.3390/biom16060842}, pmid = {42352309}, issn = {2218-273X}, support = {2020RRJP5L//Ministry of Universities and Research/ ; 2022ZY7ATN//Ministry of Universities and Research/ ; GR-2019-12369862//Italian Ministry of Health/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; *Mitochondrial Dynamics ; *Mitochondria/metabolism ; Animals ; *Mitochondrial Proteins/metabolism ; Energy Metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; }, abstract = {Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.}, }
@article {pmid42352358, year = {2026}, author = {Lee, BC and Hwang, JJ and Tsai, HJ}, title = {Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.}, journal = {Biomolecules}, volume = {16}, number = {6}, pages = {}, doi = {10.3390/biom16060893}, pmid = {42352358}, issn = {2218-273X}, support = {NSTC-114-2313-B-030-001//National Science and Technology Council/ ; F630410//USA FJCU Alumni Foundation/ ; CPL-202508003//Collaborative Research Project between FJUH and FJU/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; *Phosphopyruvate Hydratase/metabolism ; Animals ; *Phosphoglycerate Kinase/metabolism ; *Motor Neurons/metabolism/pathology/drug effects ; *Peptides/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP/p-Pak1-T423/p-P38-T180/pMK2-T334/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1/-2 as promising protein/peptide drugs for ALS treatment.}, }
@article {pmid42352620, year = {2026}, author = {De Luca, E and Saba, A and Bertarini, L and Brusini, A and Artioli, G and Dellafiore, F}, title = {Spiritual Care Needs and Challenges Among Caregivers and Families of People with Neurodegenerative Diseases in Palliative and End-of-Life Care: A Scoping Review.}, journal = {Brain sciences}, volume = {16}, number = {6}, pages = {}, doi = {10.3390/brainsci16060611}, pmid = {42352620}, issn = {2076-3425}, abstract = {Background/Objectives: Spirituality is increasingly recognised as a core dimension of holistic and palliative care. Neurodegenerative diseases such as dementia, amyotrophic lateral sclerosis and Parkinson's disease involve prolonged trajectories of loss, uncertainty and relational change, which may heighten spiritual and existential needs for patients, particularly among those involved in caregiving, such as family caregivers and, to a lesser extent, healthcare professionals. However, evidence on how spirituality is understood, experienced and addressed within neurodegenerative palliative care remains fragmented and conceptually heterogeneous. This scoping review aimed to map the literature on caregivers' spiritual needs and challenges. Methods: A scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews (PRISMA ScR). Searches were conducted across PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), APA PsycINFO, and Scopus, with no date or geographical restrictions. Grey literature was searched through Google Scholar and relevant organisational and policy sources in the field of palliative care and spirituality. Reference list screening of included studies and relevant reviews was also conducted. Quantitative, qualitative, and mixed methods studies published in English or Italian were included. Results: Twenty-four studies published between 2007 and 2025 were included. Findings were organised into three interconnected domains: spiritual needs, spiritual processes and spiritual care. Spirituality emerged as a dynamic, relational and context-dependent dimension of caregiving, encompassing meaning, identity, connection and coping with vulnerability and loss. Spiritual needs and processes were widely described, while spiritual care was inconsistently recognised within healthcare systems. Conceptual ambiguity, under-representation of end-of-life dementia and cultural imbalances were evident. The evidence predominantly focused on family caregivers, with limited representation of healthcare professionals. Conclusions: This scoping review highlights a persistent gap between caregivers' lived spiritual experiences and system-level responses in neurodegenerative palliative care in caregiving contexts globally. The findings support integrated, caregiver-inclusive and culturally responsive approaches to spiritual care.}, }
@article {pmid42352782, year = {2026}, author = {Hümpfer-Gerhards, L and Schwager, S and Benecke, M and Fuhrmann, S and Kunert, J and Knigge, M}, title = {Reducing Barriers in Neurodiverse Schools-schAUT: A Program to Identify and Reduce Barriers for Autistic and All Students.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {16}, number = {6}, pages = {}, doi = {10.3390/bs16060949}, pmid = {42352782}, issn = {2076-328X}, support = {01NV2104//Federal Ministry of Education and Research Germany/ ; }, abstract = {This paper presents results from the project schAUT, a participatory research project initiated by Humboldt University Berlin, Goethe University Frankfurt a.M. and White Unicorn e.V., funded by the German Federal Ministry of Education and Research (BMBF; FKZ: 01NV2104). It aimed to identify and reduce barriers to learning and participation in mainstream schools, with a particular focus on autistic students. This paper introduces a questionnaire and a program to support School Organizational Development (SOD), aiming to provide equitable and accessible learning environments grounded in international frameworks on inclusive education. This study combines qualitative and quantitative approaches to examine the subjective experiences of barriers. We present data obtained through a multi-phase development and validation phase. The results show that neurodivergent participants generally experienced higher subjective barriers, although we observed that barriers affect neurotypical students as well, highlighting a subjective nature. We argue that these findings support neurodiversity as a relevant concept, especially in educational contexts. This supports Larrauri et al.'s Big-Tent approach to neurodiversity, emphasizing individual variability while acknowledging structural biases towards neurotypical norms in educational environments. The study highlights the value of multiperspective approaches in (participatory) research and SOD, to develop strategies for an inclusive educational environment through neurodiversity-informed decision processes and enable equitable learning environments for all students.}, }
@article {pmid42352907, year = {2026}, author = {Scrivo, A and Bernardino, L and Consiglio, A}, title = {The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, doi = {10.3390/ijms27125182}, pmid = {42352907}, issn = {1422-0067}, support = {2023 BP 00242//Ag&#xe8;ncia de Gesti&#xf3; d'Ajuts Universitaris i de Recerca/ ; }, abstract = {Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.}, }
@article {pmid42353064, year = {2026}, author = {Reedich, EJ and Chen, YT and Imhoff-Manuel, R and Li, D and Manuel, M}, title = {Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1[G93A] Mouse Spinal Motoneurons.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, doi = {10.3390/ijms27125342}, pmid = {42353064}, issn = {1422-0067}, support = {1R01NS110953-05/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/drug effects/metabolism/physiology ; *Diazepam/pharmacology ; Mice ; *Homeostasis/drug effects ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism/physiopathology/pathology ; *Spinal Cord/drug effects/metabolism ; *Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Action Potentials/drug effects ; Disease Models, Animal ; Synaptic Transmission/drug effects ; }, abstract = {Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1[G93A] mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild-type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1[G93A] mice modulate excitability differently than wild-type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1[G93A] versus wild-type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1[G93A] motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.}, }
@article {pmid42353079, year = {2026}, author = {Romano, G and Klima, R and Feiguin, F}, title = {Loss of TDP-43 Drives Innate Immune Activation Through Relish in Drosophila.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, doi = {10.3390/ijms27125359}, pmid = {42353079}, issn = {1422-0067}, mesh = {Animals ; *Drosophila Proteins/genetics/metabolism/immunology ; *DNA-Binding Proteins/genetics/metabolism ; *Immunity, Innate/genetics ; *Transcription Factors/genetics/metabolism ; Signal Transduction ; *Drosophila melanogaster/immunology/genetics ; }, abstract = {Inflammatory and immune alterations are increasingly recognized as components of ALS pathology, yet whether they arise as a direct consequence of TDP-43 dysfunction or as a downstream response to neurodegeneration remains unresolved. To address this question, we profiled adult head transcriptomes of Drosophila lacking TBPH, the fly homolog of TDP-43, and identified marked overactivation of the conserved Toll/Imd/NF-κB (Relish) innate immune pathway, including increased expression of antimicrobial effector genes and inflammatory genes. We further found that TDP-43/TBPH regulates the NF-κB homolog Relish by associating with its mRNA and that its loss permits Relish-dependent immune overactivation. Genetic reduction in Relish in TDP-43-deficient flies suppressed inflammatory signaling and ameliorated neurological defects in vivo, indicating that immune dysregulation contributes to TDP-43 loss-associated phenotypes.}, }
@article {pmid42353250, year = {2026}, author = {Sharma, N and An, SSA}, title = {Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, doi = {10.3390/ijms27125537}, pmid = {42353250}, issn = {1422-0067}, support = {RS-2021-NR060117//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Microglia/metabolism/pathology ; Biomarkers/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/therapy ; *Frontotemporal Dementia/genetics/metabolism/pathology/therapy ; *Dipeptides/genetics/metabolism ; Animals ; DNA Repeat Expansion ; Autophagy ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 was recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management.}, }
@article {pmid42355891, year = {2026}, author = {Calabrese, L and Mion, M and Mandrini, A and Primi, R and Bendotti, S and Ulmanova, L and Currao, A and Morena, A and Dossi, F and Fogagnolo, L and Pizzi, F and Fava, C and Ghiraldin, D and Battioni, A and Genoni, P and Madonini, EMP and Maffeo, D and Dossena, C and Affinito, S and Bertazzoli, G and Pellegrino, M and Papi, G and Frattini, S and Della Torre, M and Fantoni, C and Praderio, A and Tarantino, L and Mongiovì, S and Politi, P and Savastano, S and Baldi, E and All The LombardiaCARe Researchers, }, title = {The Early Implementation of a Hub-and-Spoke Survivorship Pathway for Out-of-Hospital Cardiac Arrest Survivors: A 12-Month Formative Evaluation of the REVIVE Project.}, journal = {Journal of clinical medicine}, volume = {15}, number = {12}, pages = {}, doi = {10.3390/jcm15124722}, pmid = {42355891}, issn = {2077-0383}, support = {8049724//Italian Ministry of Health - Ricerca Corrente/ ; }, abstract = {Background/Objectives: A structured follow-up after out-of-hospital cardiac arrest (OHCA) is recommended, but implementation across regional networks remains challenging. REVIVE introduced a hub-and-spoke survivorship pathway in Lombardy. This 12-month formative implementation evaluation aimed to describe staged pathway progression, operational reach, attrition points, centre-level variation, and documented barriers to assessment completion. Methods: Adult OHCA survivors with Cerebral Performance Category (CPC) 1-2 or Modified Rankin Scale (mRS) ≤ 3 were considered eligible. The evaluation was structured using Proctor et al.'s implementation outcomes framework. Implementation outcomes were operationalised using prospectively collected pathway indicators: eligibility ascertainment, successful contact, T0 assessment completion, completion of planned assessment components, timeliness where available, and documented reasons for non-progression. Analyses were descriptive and used chi-square or Fisher's exact tests for unadjusted centre-level comparisons. Results: Of the 1663 patients hospitalised, 1458 (87.7%) were recorded as deceased or having an unfavourable neurological outcome and were therefore outside the intended REVIVE target population. Among the remaining 205 patients, eligibility could not be determined for 78 (4.7% of the total cohort), and 127 (7.6%) met eligibility criteria. Of eligible survivors, 96 (75.6%) were contacted and 64 completed the T0 assessment (66.7% of contacted; 50.4% of eligible). Pavia showed higher observed rates of eligibility ascertainment, contact, and assessment completion than spoke centres, but these differences were unadjusted and should be interpreted as centre-level implementation variation rather than evidence of causal superiority. Conclusions: REVIVE initiated a structured regional pathway for post-OHCA follow-up, but first-year implementation was partial rather than definitive. The 50.4% T0 completion rate among eligible survivors should be interpreted as an initial internal implementation indicator, not as evidence of established feasibility, effectiveness, or regional benchmarking. Priorities for further optimisation include eligibility ascertainment, transfer of contact information, patient engagement, and spoke-site support for assessment delivery.}, }
@article {pmid42356052, year = {2026}, author = {Manay, B and Aygün, D and Şentürk, A and İbas, M and Güven, R and Belli, &#x15e;}, title = {Association Between Clinical Dysphagia Assessment Tools and Videofluoroscopic Findings in Amyotrophic Lateral Sclerosis: A Retrospective Study.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {62}, number = {6}, pages = {}, doi = {10.3390/medicina62061039}, pmid = {42356052}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Retrospective Studies ; *Deglutition Disorders/diagnosis/etiology/physiopathology ; Female ; Male ; Middle Aged ; Aged ; Fluoroscopy/methods ; ROC Curve ; Video Recording/methods ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease frequently associated with dysphagia and aspiration risk. This study aimed to investigate the relationship between clinical dysphagia assessment tools (EAT-10, GUSS, RSST, and sialorrhea severity) and videofluoroscopic swallowing study (VFSS) findings in patients with ALS. Materials and Methods: This retrospective observational study included 60 patients with ALS classified as spinal-onset (n = 38) or bulbar-onset (n = 22). Relationships between clinical assessments and VFSS findings were analysed using Spearman correlation analysis. Exploratory multivariable regression and receiver operating characteristic (ROC) analyses were performed to evaluate associations and aspiration risk discrimination. Results: Strong negative correlations were observed between PAS-Liquid and RSST and GUSS scores, whereas EAT-10 showed a strong positive correlation (all p < 0.001). ROC analyses demonstrated good discriminative ability for aspiration risk for GUSS (AUC = 0.89), RSST (AUC = 0.88), and EAT-10 (AUC = 0.82). Patients with bulbar-onset ALS demonstrated higher penetration-aspiration severity and lower functional oral intake. Conclusions: Clinical dysphagia assessment tools showed significant associations with instrumental swallowing findings in ALS. GUSS and RSST demonstrated good discriminative ability for aspiration risk and may be clinically useful bedside screening tools. However, instrumental swallowing assessment remains essential whenever feasible.}, }
@article {pmid42357346, year = {2026}, author = {Costanzi, E and Fontana, L and Giroldo, F and Coco, S}, title = {Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.}, journal = {Pharmaceutics}, volume = {18}, number = {6}, pages = {}, doi = {10.3390/pharmaceutics18060730}, pmid = {42357346}, issn = {1999-4923}, support = {P2022LR49L//Ministry of Universities and Research/ ; 202229X8HW//Ministry of Universities and Research/ ; }, abstract = {Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.}, }
@article {pmid42358489, year = {2026}, author = {Lepski, G and Arévalo, A}, title = {Mesenchymal stromal/stem cells for neurological disorders in humans: an evidence-mapped clinical review.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1844360}, pmid = {42358489}, issn = {1662-5102}, abstract = {Mesenchymal stromal/stem cells (MSCs) have been tested clinically across a wide spectrum of neurological disorders, motivated by their immunomodulatory and trophic ("bystander") mechanisms rather than durable neural replacement. Here, we synthesize human prospective clinical trials that administered MSC products for neurological indications, prioritizing study design/goals, disease stage/severity, cell source/manufacturing, dose/route, detailed clinical assessments, quantified score changes, and adverse events (AEs). Across indications, trials frequently demonstrate feasibility and short-term safety, while efficacy signals are heterogeneous and strongly dependent on disease stage and endpoint selection criteria. The most methodologically rigorous signals with quantified motor outcomes include stereotactic intracerebral implantation of SB623 for chronic motor deficits after traumatic brain injury (TBI). In amyotrophic lateral sclerosis (ALS), randomized evidence supports safety and early slope-based signals in selected subgroups after intrathecal MSC regimens, but durable clinical benefit remains unproven. In hypoxic-ischemic encephalopathy (HIE), controlled data suggest functional improvements in small cohorts, and neonatal studies support feasibility adjunctive to hypothermia. We highlight design features most likely to de-risk efficacy interpretation: adequately powered randomized controlled trials, disease-stage stratification, prespecified clinically meaningful change thresholds, standardized rehabilitation co-interventions, and transparent AE adjudication.}, }
@article {pmid40506596, year = {2025}, author = {Sajjad, MW and Muzamil, F and Naqvi, RZ and Amin, I}, title = {QBEmax redefines the precise base editing in crop plants.}, journal = {Functional &amp; integrative genomics}, volume = {25}, number = {1}, pages = {127}, pmid = {40506596}, issn = {1438-7948}, abstract = {Hu et al.‘s new study, published in Nature Biotechnology, introduces QBEmax; a tiny, conformationally sound editing tool with a cytidine deaminase buried within a looping permuted Cas9 (cpCas9). Supported by molecular dynamics models and AlphaFold3 structural predictions, this unique internal fusion creates a structurally protected complex that improves editing accuracy and lowers typical artifacts such as indels and impure base conversions (Hu et al. Nature Biotechnology:1-7, 2025). High precision editing (up to 99.8% purity), lower indels, and lower off target impacts well suit imminent plant transformation events. Its tiny, stable architecture and wider editing window at PAM sites increase its ability for precise and adaptable trait change in complex plant genomes.}, }
@article {pmid40764894, year = {2025}, author = {Sah, AK and Srinivasarao, D and Dey, P}, title = {Comment on "clinicopathological features of fatal mushroom poisoning: a 10-year retrospective autopsy-based study".}, journal = {Forensic science, medicine, and pathology}, volume = {}, number = {}, pages = {}, pmid = {40764894}, issn = {1556-2891}, abstract = {This commentary evaluates Dogan et al.‘s autopsy-based study on fatal mushroom poisoning in Türkiye, highlighting its forensic insights and public health implications. We address potential selection bias and lack of confounder adjustment, advocating for broader surveillance and early intervention. The study advances understanding of amatoxin toxicity and informs targeted prevention efforts.}, }
@article {pmid41088288, year = {2025}, author = {Ikezoe, H and Horiuchi, S}, title = {A qualitative exploration of the mistreatment of women during childbirth in a rural Guatemalan hospital.}, journal = {Reproductive health}, volume = {22}, number = {1}, pages = {197}, pmid = {41088288}, issn = {1742-4755}, support = {Core-to-Core Program, Asia-Africa Science Platforms [(2021-2024) PI: Shigeko Horiuchi]//Japan Society for the Promotion of Science/ ; }, abstract = {BACKGROUND: In Guatemala, many women still give birth together with traditional birth attendants at home particularly in rural settings even though births attended by skilled birth attendants in healthcare facilities have been recommended. Mistreatment of women during childbirth is recognized as one of the obstacles to childbirth in healthcare facilities. However, little research has been conducted on childbirth care and the mistreatment of women during facility-based childbirth in Guatemala. Thus, this study aimed to explore women’s experiences of care during childbirth in a rural Guatemalan hospital. The women narrated their experiences from which themes were derived (whether mistreatment or not, and if mistreatment prevailed, the type). METHODS: This qualitative study involved interviews with 20 women of reproductive age who had given birth in a hospital in Quiché Department, Guatemala, within the past six months. Data were collected by semistructured interviews between December 2022 and February 2023. The contents of the semistructured interviews were past birth experiences, a recent birth experience in a hospital, and care received from healthcare providers. Thematic analysis was performed with deductive and inductive approaches using Bohren et al.’s typology of the mistreatment of women during childbirth. The study was approved by St. Luke’s International University Research Ethics Committee and the study hospital. RESULTS: Women reported experiencing various forms of mistreatment during childbirth in the rural Guatemalan hospital. These included six of the seven categories from Bohren et al.’s typology including physical abuse, verbal abuse, stigma and discrimination, failure to meet professional standards of care, poor rapport between women and providers, and health system conditions and constraints. Specifically, the participants reported experiences of reprimands and neglect by healthcare providers, as well as discrimination of those who do not speak Spanish. It became evident that mistreatment of women by healthcare providers had become normalized, and that culturally appropriate care was not adequately provided. CONCLUSIONS: Eliminating or reducing mistreatment requires a multilevel approach. Healthcare providers must acquire up-to-date knowledge and skills and develop appropriate professional attitudes. Both healthcare providers and women should have increased awareness of women’s rights and mistreatment.}, }
@article {pmid41697496, year = {2026}, author = {Quinn, CJ and Velasco, ES and Wehrens, XHT}, title = {Mitochondria at the Heart of Ischemia-Reperfusion (I/R) Injury: the HOXB5-Sirt5 Axis.}, journal = {Cardiovascular drugs and therapy}, volume = {40}, number = {3}, pages = {805-808}, pmid = {41697496}, issn = {1573-7241}, support = {R01HL153350/NH/NIH HHS/United States ; R01HL153350/NH/NIH HHS/United States ; }, abstract = {Ischemic cardiomyopathy (ICM) arises from restricted myocardial blood flow, leading to ischemia/reperfusion (I/R) injury, mitochondrial dysfunction, and heart failure. This commentary highlights the role of mitochondrial homeostasis in cardiac health, emphasizing dysregulated dynamics, ROS production, and mitophagy in ICM and related conditions like diabetic cardiomyopathy. Li et al.‘s study identifies the HOXB5–Sirt5 signaling axis as a key regulator that protects against I/R injury by reducing apoptosis, oxidative stress, ferroptosis, and mitochondrial fragmentation in vitro and in vivo. Future research should explore cell-specific roles and human models to enhance translational potential.}, }
@article {pmid41961214, year = {2026}, author = {King, H and Derrett, S and Wyeth, EH and Cunningham, R and Peterson, D}, title = {Integrated Care Within New Zealand's Specialist Mental Health and Addiction Services: Qualitative Research to Inform a New Model.}, journal = {Community mental health journal}, volume = {}, number = {}, pages = {}, pmid = {41961214}, issn = {1573-2789}, abstract = {Internationally, and within New Zealand (NZ), specialist mental health and addiction service-users (SMHAS-users) experience increased risks of comorbidities and premature mortality, and poorer health outcomes, compared to the general population. In particular, Indigenous Māori SMHAS-users face significant inequities compared to non-Māori. Integrated care has been found to improve outcomes by improving quality and coordination between services. This research aimed to develop a model of integrated care relevant to SMHAS-users in a NZ context, to inform the development of a questionnaire intended to assess SMHAS-users experiences of integrated care, support SMHAS to improve their services, and in turn, improve outcomes for SMHAS-users. Key informants working for, and/or with lived experience of, SMHAS were interviewed about existing integrated and people-centred care concepts. Barriers to integration were identified. The team met frequently to review and discuss coding, themes, and model development. Ten informants from across NZ were recruited, including five with lived experience of mental distress, and three who were Māori. Singer et al.,’s (Medical Care Research and Review, 68(1), 112–127, 2011) integrated patient care framework and the World Health Organization’s (2016) concept of people-centred care were found to be acceptable, although people-centred constructs were needed more clearly at a model’s core. SMHAS-user controlled funding and participation in multi-disciplinary team meetings were identified as key opportunities alongside other concepts such as cultural responsiveness, de-centralising services (to re-centralise people), and peer navigators. The resulting People-Centred Joined Up Care (PCJUC) model is proposed to convey a paradigm shift from a service-centric system, organised around the efficiencies and needs of services, to a people-centred system. Irrespective of the health workforce’s best intentions, the current service-centric orientation does not empower SMHAS-users. A people-centred model requires power structures to be inverted and the paramount authority of health professionals as the ‘decision-making experts’ to be challenged. Research is now underway exploring the use of a questionnaire developed to measure the concepts within the PCJUC model, to inform service improvements.}, }
@article {pmid41961447, year = {2026}, author = {Tarzian, AJ}, title = {From Wise Counselors to Clinical Ethicists: Historical Milestones and Their Impact on Professional Identity Formation.}, journal = {HEC forum : an interdisciplinary journal on hospitals' ethical and legal issues}, volume = {}, number = {}, pages = {}, pmid = {41961447}, issn = {1572-8498}, abstract = {This paper explores how historical bioethics milestones have shaped the professional identity of clinical ethicists, discussing both the benefits and challenges of professionalizing the role of the clinical ethicist by comparing how a “wise counselor,” an ethics consultant, and a clinical ethicist provide healthcare ethics guidance. I examine the evolution of clinical ethics as a sub-category of bioethics, tracing its origins and key milestones in its development toward professionalization. These include the American Society for Bioethics and Humanities’ (ASBH) Core Competencies for Health Care Ethics Consultation reports, ASBH’s Code of Ethics and Professional Responsibilities for Healthcare Ethics Consultants, Fox et al.’s national surveys of healthcare ethics consultation in the United States, and the emergence of the Healthcare Ethics Consultant Certification (HEC-C) program. Practicing as a clinical ethicist requires mastery of a wide scope of knowledge, skills, and attitudes reflected in each stage of the field’s development. Reflecting on this history may yield clues for how clinical ethicists position themselves for the next phase of the field’s evolution.}, }
@article {pmid42337904, year = {2026}, author = {Morimoto, S and Okano, H}, title = {Are patient-derived models of amyotrophic lateral sclerosis a game changer for novel drug discovery?.}, journal = {Expert opinion on drug discovery}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17460441.2026.2689746}, pmid = {42337904}, issn = {1746-045X}, abstract = {INTRODUCTION: ALS drug discovery has long depended on model systems that incompletely capture human disease heterogeneity, aging, and TDP-43 proteinopathy. Patient-derived platforms have therefore emerged as increasingly important human-relevant complements to animal and molecular models.<br><br>AREAS COVERED: This Critical Perspective examines when patient-derived ALS models genuinely change therapeutic decision-making rather than merely add mechanistic insight. The authors then propose a heuristic framework based on disease-relevant phenotype recapitulation, capture of patient-to-patient heterogeneity, and generation of findings that influence therapeutic prioritization or clinical translation. Furthermore, the authors evaluate iPSC-derived motor neurons, directly reprogrammed neurons, glial co-cultures, organoids, neural networks, and organ-chip systems against these conditions, while also addressing aging fidelity, reproducibility, upper motor neuron modeling, and regulatory implementation.<br><br>EXPERT OPINION: Patient-derived models are not yet standalone decision-grade tools for ALS drug development. Their present value lies in functioning as a human-biology filter for target discovery, reverse translation, biomarker development, and patient stratification when used within rigorous, standardized, and clinically linked workflows. The strongest current evidence supports proof-of-principle rather than generalized predictive validity.}, }
@article {pmid42338703, year = {2026}, author = {Mndolo, NCM and Baluwa, MA and Yeboa, NK and Kazembe, A and Chirwa, E}, title = {Acceptability of Modified Early Obstetric Warning Systems Among Midwives in Malawi; An Exploratory Qualitative Study.}, journal = {International journal of women's health}, volume = {18}, number = {}, pages = {605608}, pmid = {42338703}, issn = {1179-1411}, abstract = {BACKGROUND: The Modified Early Obstetric Warning systems (MEOWS) has received global endorsement as a key strategy for reducing maternal mortality over the past decade. However, evidence on MEOWS acceptability among midwives in sub-Saharan Africa, including Malawi, remains limited. Understanding how potential users perceive a newly introduced intervention is required to assess acceptability prior to implementation.<br><br>PURPOSE: To explore the acceptability of MEOWS among midwives using Sekhon's Theoretical Framework of Acceptability.<br><br>METHODS: We conducted an exploratory qualitative study between June and August 2025. Using purposive sampling, midwives across practicing, supervisory and policy making levels from Bwaila Hospital and Kamuzu Central Hospital were recruited for in-depth interviews. Data were analyzed using a deductive thematic approach with a priori coding guided by Sekhon et al's Theoretical Framework of Acceptability (TFA).<br><br>RESULTS: Thirty participants were interviewed. MEOWS was found acceptable across the seven domains of Sekhon et al's TFA. Participants reported that MEOWS could guide clinical judgement and ease the workload. However, inadequate stationery and equipment were identified as key sources of burden that may threaten sustained use.<br><br>CONCLUSION: This study demonstrated that MEOWS was broadly acceptable among the various levels of midwives. The study identified inadequate stationery and equipment as potential barriers. Addressing these challenges may sustain MEOWS adaptation and implementation,enable early identification of maternal critical illness and reduction of maternal deaths.}, }
@article {pmid42338888, year = {2026}, author = {Sanchis-Sanchis, CE and Sancho-Cantus, D and Sanchis-Sanchis, E and Privado, J and Roig, FJ and Cuerda-Ballester, M and Bargues-Navarro, G and Cubero-Plazas, L and Martínez Bolós, P and Cárdenas Salazar, RG and Ortí, JER}, title = {Interplay between B vitamins, fiber, and Bacteroides abundance: a predictive model for anxiety and depression in amyotrophic lateral sclerosis.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1815390}, pmid = {42338888}, issn = {1664-302X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that not only affects motor function but is also associated with gastrointestinal and emotional disturbances. Recent research highlights the potential role of gut microbiota and diet in modulating these symptoms, suggesting a complex interaction between nutrition, intestinal health, and presence of anxiety and depression in ALS patients. This study aims to investigate the relationship between dietary intake, gut microbiota composition, and presence of anxiety and depression in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODOLOGY: A cross-sectional study conducted with a sample of 48 patients with bulbar-onset or spinal-onset ALS from different regions of Spain. Dietary intake was assessed through 24-h records and food frequency questionnaires, while anxiety and depression were evaluated using validated scales that formed a latent factor called emotional distress. Stool consistency was assessed following the Bristol Stool Scale and the abundance of bacterial microbiota was quantified.<br><br>RESULTS: Confirmatory factor analysis identified a nutritional factor composed of vitamins B1, B2, B9, C, and fiber, revealing a significant inverse association with anxiety and depression levels. The predictive model revealed both direct and indirect effects of this factor on presence of anxiety and depression, mediated by Bacteroides abundance and stool consistency.<br><br>CONCLUSION: This model explained 19% of the variance in psychological distress. Our findings suggest that a diet rich in B vitamins, C vitamin and fiber may help improve emotional well-being in patients with ALS, highlighting the importance of nutritional strategies, as well as the role of Bacteroides related to stool consistency in patients with ALS.}, }
@article {pmid42339807, year = {2026}, author = {Jewer, M and Snyder, J and Caulfield, T and Zenone, M}, title = {The connection between unproven stem cell-based interventions and complementary and alternative medicine in crowdfunding for Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2685157}, pmid = {42339807}, issn = {2167-9223}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease associated with substantial medical and non‑medical costs. In the absence of effective treatments, patients and families may turn to crowdfunding to finance care, including unproven stem cell‑based interventions (SCBIs) that are frequently marketed directly to consumers.<br><br>OBJECTIVE: conduct content analysis of English&#x2011;language GoFundMe campaigns seeking funds for SCBIs for ALS to better understand the market for unproven direct&#x2011;to&#x2011;consumer SCBIs.<br><br>METHODS: 247 campaigns were identified, and their data were collected and analyzed to determine the characteristics of the campaigns, campaigners, and their desired treatments.<br><br>RESULTS: ALS crowdfunding campaigns that collectively requested over $16 million USD. In addition to SCBIs, campaigns frequently requested funding for international travel to access these treatments. Campaigners express relatively high confidence that stem cell treatments would slow disease progression, improve symptoms, or, in some cases, cure or reverse ALS; conclusions that exceed the scientific evidence. Confidence in SCBIs is linked to requests for other alternative therapies and unsupported causes of ALS, supporting an emerging link between proponents of alternative medicines and unproven stem cell therapies.<br><br>CONCLUSION: Crowdfunding for unproven stem cell interventions exposes ALS patients and donors to financial risk, misinformation, and medical exploitation. The frequent linkage between SCBIs, CAM, and exaggerated claims highlights gaps in regulation, patient protection, and access to credible treatment options. These findings underscore the need for stronger oversight of direct&#x2011;to&#x2011;consumer stem cell markets and greater support for patients facing catastrophic illness.}, }
@article {pmid42339846, year = {2026}, author = {Burchert, HH and Stringer, WW and Dash, RK}, title = {Single-O2ligation of hemoglobin links aerobic and anaerobic metabolism.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {}, number = {}, pages = {}, doi = {10.1152/japplphysiol.00454.2026}, pmid = {42339846}, issn = {1522-1601}, abstract = {Oxygen (O2) binding and release by hemoglobin (Hb) are governed by cooperative interactions among its four subunits. During incremental workload exercise, femoral venous oxyhemoglobin (O2Hb) saturation exhibits a reproducible, momentary increase at the gas exchange threshold-coinciding with the inflection point of the in vivo O2 non-equilibrium curve (ONC). This suggests a transient shift in Hb's binding dynamics. We hypothesized that at this threshold, Hb tetramers carrying ≤1 bound O2 become predominant. In this state, the last bound O2 promotes further cooperative binding, but its release confers no cooperative advantage for unloading, biasing toward O2 rebinding. Using the O2 equilibrium curve models of Dash et al. (2016) and Adair, we computed the distribution of Hb's O2 ligation states across 12 pooled mean femoral venous blood samples from incremental workload cardiopulmonary exercise testing of five healthy male participants. At the gas exchange threshold-where the ONC inflects and flattens-tetramers with ≤1 O2 indeed dominated. This ligation-state distribution is consistent with Perrella et al.'s (1999) cryogenic resolution of native human Hb, which shows that carbon monoxide-ligated Hb tetramers peak at ~15-20% saturation, matching femoral venous ranges at the gas exchange threshold. Our results suggest that, at sufficiently low O2Hb saturation, Hb may favor O2 rebinding over cooperative unloading. We propose that glycolytic proton production and other Bohr effectors may counter this predicted binding bias supporting continued O2 unloading. If confirmed, this mechanism unifies long-standing controversies in O2 transport physiology, framing the Hb-Bohr system as a proportional-integral controller of tissue oxygenation.}, }
@article {pmid42341041, year = {2026}, author = {Liu, D and Li, Y and Huang, S and Xu, Y and Sun, L and Li, W and O'Kane, CJ and Rubinsztein, DC and Lu, B and Li, S}, title = {IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {26}, pages = {e2610001123}, doi = {10.1073/pnas.2610001123}, pmid = {42341041}, issn = {1091-6490}, support = {32270825//MOST | National Natural Science Foundation of China (NSFC)/ ; 2023HWYQ-013//| Natural Science Foundation of Shandong Province ()/ ; tsqn202306046//Taishan Scholar Project of Shandong Province/ ; R01AG089752 R01NS084412 and R37NS083417//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Mice ; *Ribosomes/metabolism ; *Proteostasis ; *Endoribonucleases/metabolism/genetics ; Proteotoxic Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.}, }
@article {pmid42341118, year = {2026}, author = {Copley, KE and Dykstra, MM and Miller, MR and Linsenmeier, M and Lai, L and Wang, Y and Chang, YW and Barmada, SJ and Shorter, J}, title = {Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.}, journal = {Science advances}, volume = {12}, number = {26}, pages = {eady0256}, pmid = {42341118}, issn = {2375-2548}, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Protein Isoforms/metabolism/chemistry/genetics ; Humans ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Protein Domains ; Protein Transport ; }, abstract = {Prion-like domain (PrLD)-mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons. Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility in cells and tissue of patients with ALS. Here, we establish that the short, isoform-specific carboxyl-terminal tail of sTDP-43 confers high aggregation propensity, which is encoded by two clusters of steric zippers, and can be mitigated by short RNA chaperones. Disrupting these zippers enhances sTDP-43 solubility at the pure protein level and in neurons. Notably, these steric zippers, rather than a predicted nuclear export signal in the carboxyl-terminal tail, drive cytoplasmic mislocalization and aggregation of sTDP-43 in neurons. Thus, we define the sequence-encoded determinants of aberrant sTDP-43 assembly and provide mechanistic insights into sTDP-43 disease pathology.}, }
@article {pmid42341897, year = {2026}, author = {Hopkins, EL and Williams, PA}, title = {Programmed axon degeneration gene variants in human disease.}, journal = {Experimental neurology}, volume = {}, number = {}, pages = {115891}, doi = {10.1016/j.expneurol.2026.115891}, pmid = {42341897}, issn = {1090-2430}, abstract = {BACKGROUND: Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide adenine dinucleotide (NAD) through loss of the pro-survival enzyme NMNAT2 and activation of the pro-degenerative NADase SARM1. Recent genetic studies have identified pathogenic variants in PAD pathway enzymes associated with severe neurodegenerative phenotypes.<br><br>MAIN BODY: Pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1 have been identified and will be discussed in this review. NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms. NMNAT1 variants are well-characterized causes of Leber Congenital Amaurosis type 9, while NMNAT2 variants result in peripheral neuropathies with childhood onset. SARM1 gain-of-function variants with constitutively active NADase activity are enriched in amyotrophic lateral sclerosis patients.<br><br>CONCLUSION: These findings demonstrate that maintaining proper NAD homeostasis is crucial for axon survival, and disruption through genetic variants leads to distinct neurodegenerative outcomes. Understanding these rare variants provides insight into PAD mechanisms and supports development of broad-spectrum neuroprotective therapies targeting this pathway. Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation, offering hope for treating multiple neurodegenerative diseases.}, }
@article {pmid42342533, year = {2026}, author = {Brodribb, L and Camden, P and Dharmadasa, T and Blizzard, C}, title = {Amyotrophic lateral sclerosis: A rare but aggressive adult-onset disease.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molmed.2026.06.001}, pmid = {42342533}, issn = {1471-499X}, }
@article {pmid42342547, year = {2026}, author = {Messina, E and Borrelli, A and Panebianco, V}, title = {Reply to Andrew R. A. Godtman et al.'s Letter to the Editor re: The PROSA Trial: Some Prosaic Comments. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2026.03.036.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.06.010}, pmid = {42342547}, issn = {1873-7560}, }
@article {pmid42342625, year = {2026}, author = {Forstmann, M and Weiss, A}, title = {Outsourcing moral cognition: Delegation, diffusion of responsibility, and coalitional exclusion.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e141}, doi = {10.1017/S0140525X25101556}, pmid = {42342625}, issn = {1469-1825}, mesh = {Humans ; *Morals ; *Decision Making ; *Cognition ; *Outsourced Services ; Cooperative Behavior ; }, abstract = {Levine et al.'s resource-rational contractualism (RRC) models moral judgment as a cost-sensitive approximation to ideal bargaining among stakeholders. We identify three strategies agents use to reduce moral costs by outsourcing or bypassing virtual bargaining: strategic delegation, diffusion of responsibility, and coalitional boundary-setting. We propose extending RRC with parameters for agency transfer, responsibility tracking, and stakeholder inclusion to better capture real-world moral decision-making.}, }
@article {pmid42342627, year = {2026}, author = {Kuhlmeier, VA and Dunfield, KA}, title = {The third axis: partner choice.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e146}, doi = {10.1017/S0140525X25101684}, pmid = {42342627}, issn = {1469-1825}, mesh = {Humans ; *Choice Behavior ; *Morals ; *Interpersonal Relations ; *Cooperative Behavior ; }, abstract = {Though we find the 'triple theory' of moral cognition, with its emphasis on resource-rational contractualism, to be well argued, we suggest that Levine et al.'s model starts too late in the process. That is, we agree that their proposed abstractions and heuristics can help to develop mutually beneficial arrangements, but effective contracts also require the identification of reliable actors.}, }
@article {pmid42342630, year = {2026}, author = {Bystranowski, P}, title = {The veil and the deal: Bargaining between case-specific solutions and unknown rules.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e136}, doi = {10.1017/S0140525X25101490}, pmid = {42342630}, issn = {1469-1825}, mesh = {Humans ; *Morals ; *Decision Making ; }, abstract = {Levine et al.'s resource-rational contractualism omits how people decide that a situation demands rule-, not case-based, guidance. I propose that moral cognition first tags contexts as rule-governed, then either uncovers an existing norm or forges a plausible one. Coordination stakes and the private-public divide likely trigger this tag. Distinguishing discovery from invention invites targeted experiments and refines the framework.}, }
@article {pmid42343420, year = {2026}, author = {Morisaki, Y and Nomura, N and Ohshima, M and Matsuda, M and Komine, O and Okuda, T and Yamanaka, K and Misawa, H}, title = {Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03919-8}, pmid = {42343420}, issn = {1742-2094}, support = {JP26K10309//Japan Society for the Promotion of Science/ ; JP22K06634//Japan Society for the Promotion of Science/ ; }, abstract = {Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1[G93A] mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.}, }
@article {pmid42343520, year = {2026}, author = {Sun, L and Chen, J and Wu, Y and Bian, S and Wang, Q and Ha, L}, title = {[Effect of electroacupuncture at "Zusanli" (ST36) on TREM2-mediated microglial activation in amyotrophic lateral sclerosis mice].}, journal = {Zhongguo zhen jiu = Chinese acupuncture &amp; moxibustion}, volume = {46}, number = {6}, pages = {948-955}, doi = {10.13703/j.0255-2930.20250113-k0001}, pmid = {42343520}, issn = {0255-2930}, mesh = {Animals ; *Electroacupuncture ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism/immunology ; Male ; Mice ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/genetics/metabolism/immunology ; Humans ; *Membrane Glycoproteins/genetics/metabolism/immunology ; *Acupuncture Points ; Disease Models, Animal ; Mice, Transgenic ; Interleukin-4/genetics/metabolism ; Spinal Cord/metabolism ; Interleukin-1beta/genetics/metabolism ; }, abstract = {OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) on amyotrophic lateral sclerosis (ALS) in mouse models based on myeloid cell trigger receptor 2 (TREM2)-mediated microglial activation.<br><br>METHODS: Thirty-six SPF-grade male human mutant superoxide dismutase 1 (SOD1-G93A) transgenic mice were divided into a model group, an EA group, and a drug group, 12 mice in each group. Besides, 12 wide-type littermates were collected as a control group. In the EA group, EA was performed at the "Zusanli" (ST36), with an intermittent wave, at the frequency of 15 Hz, and for 10 min each intervention; once every other day, 3 interventions a week and for 4 continuous weeks. In the drug group, the intragastric administration of riluzole solution was given at 8 mg/kg, once daily, for 4 continuous weeks. After intervention completion, behavioral assessment of mice was conducted using rotarod test and wire hang test. With HE and Nissl staining adopted, morphology of motor neurons in the anterior horn of the spinal cord was observed. Immunofluorescence was used to detect the fluorescence intensity of TREM2 in the anterior horn of spinal cord. Western blot analysis was performed to measure the protein expression of interleukin (IL)-1&#x3b2;, &#x3b3; interferon (IFN-&#x3b3;), IL-4 and IL-10 in spinal cord tissue. Flow cytometry was used to analyze the proportion of CD86[+] and CD206[+] in spinal cord monocyte suspension.<br><br>RESULTS: Compared with the control group, in the model group, motor neurons in the anterior horn of the spinal cord exhibited disordered arrangement; accompanied by nuclear pyknosis and cytoplasmic shrinkage; the latency to fall in the rotarod test and the cut-off time in the wire hang test were shortened, fluorescence intensity of TREM2 in the spinal anterior horn, the protein expression of IL-1&#x3b2;, IFN-&#x3b3;, IL-4, and IL-10, and the proportion of CD86[+] and CD206[+] in spinal cord tissue increased(P<0.01). When compared with the model group, in the EA and drug groups, motor neurons in the anterior horn of the spinal cord were arranged regularly; nuclear pyknosis and chromatolysis were attenuated, and the structural integrity of neurons was improved; the latency to fall and the the cut-off time were prolonged, fluorescence intensity of TREM2 in the spinal anterior horn was reduced, the protein expression of IL-1&#x3b2; and IFN-&#x3b3; decreased, and that of IL-4, and IL-10 increased in the spinal cord tissue; the proportion of CD86[+] in spinal cord tissue was reduced and that of CD206[+] elevated(P<0.01, P<0.05). Compared with the drug group, the EA group showed the increase of protein expression of IL-1&#x3b2;,and the decrease of IL-4, IL-10 in the spinal cord tissue and the proportion of CD206[+] (P<0.05).<br><br>CONCLUSION: Electroacupuncture at "Zusanli" (ST36) exhibits a certain improvements in motor function of SOD1-G93A transgenic mice. The underlying mechanism may be related to attenuating neuroinflammation via the modulation of microglial activation mediated by TREM2.}, }
@article {pmid42343570, year = {2026}, author = {Ellis, BCS and Avila, AS and Huang, WP and John, SJ and Bonsall, S and Hodgson, RE and Kumar, V and Nolan, M and West, RJH and Campbell, SG and De Vos, KJ and Lagier-Tourenne, C and Robin Highley, J and Cooper-Knock, J and Shelkovnikova, TA}, title = {STMN2 protein depletion via translation deficits and stress granules in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag222}, pmid = {42343570}, issn = {1460-2156}, abstract = {STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, in situ single-molecule analysis of translation and RNA localisation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion under stress. We find that human STMN2 protein level is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translation repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. We find that low pre-stress STMN2 sensitises neuronal cells to stress-induced apoptosis, whereas moderately increased STMN2 is protective under stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS (ALS-FUS) models, which may compensate for translation/stress granule defects in this disease subtype. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common denominators in neurodegeneration - dysregulation of translation and stress granules - in STMN2 depletion, independent of TDP-43 loss of function. It also describes an RNA-based compensatory mechanism in ALS underling the unique vulnerability of neurons with developing TDP-43 pathology.}, }
@article {pmid42344043, year = {2026}, author = {Mantell, JE and Masvawure, TB and Thomas, NA and George, G and Howard, AA and Strauss, M and Ndagije, F and Lethoko, M and Low, A and Hirsch-Moverman, Y}, title = {Health system support and strengthening for cross-border HIV services: key informants' perspectives on testing and linkage for Lesotho-South Africa migrant workers.}, journal = {BMJ public health}, volume = {4}, number = {2}, pages = {e003284}, pmid = {42344043}, issn = {2753-4294}, abstract = {INTRODUCTION: Cross-border migrants, especially those in destination countries with high HIV burden and high population mobility, often face structural challenges in accessing HIV testing and linkage-to-care. There is limited research on the most effective HIV testing and linkage-to-care strategies tailored to cross-border migrants. We conducted a qualitative study to explore barriers and facilitators to HIV testing and linkage-to-care among Lesotho-South Africa cross-border migrant workers.<br><br>METHODS: We conducted in-depth interviews with 15 purposively selected stakeholders from Lesotho who interfaced with migrants, namely administrative and programme staff from the Ministry of Health, non-governmental organisations, community counsellors and testers and migrant advocates. We captured diverse perspectives on barriers and facilitators to HIV services among migrant workers. Template analysis, a rapid form of thematic analysis, was used to synthesise the data. We applied Chee et al's health systems framework differentiating health system support and health system strengthening to analyse our findings and guide actionable programme and policy strategies.<br><br>RESULTS: Participants recommended strategies that both support the health system by improving service provision and strengthen the health system by implementing structural and policy-level changes. Support strategies included expanding migrant-centred access to HIV testing and prevention services, reducing structural and economic barriers to service utilisation and strengthening community-based services. Strengthening strategies included cross-border collaboration and harmonised referral systems for continuity of care, expanding differentiated HIV care models for mobile populations, integrating HIV services into general healthcare, establishing workplace HIV policies for migrant workers and flexible cross-border funding for migrant health.<br><br>CONCLUSIONS: Chee et al's framework allows policymakers and programme implementers to more intentionally distinguish and plan for solutions that merely support versus actually strengthen health systems. Strengthening approaches, in contrast to supporting ones, have the potential to transform HIV services for migrants by ensuring continuity of services in both home and destination venues butrequire greater commitment and action from politicians, policymakers, funders and advocacy groups to implement.}, }
@article {pmid42345500, year = {2026}, author = {Drążyk, M and Pyc, Z and Pietrzyk, SJ and Gajda-Janiak, A and Godziszewski, F and Pioterek, O and Tulski, M and Mazurek, M and Domagała, ZA}, title = {Formaldehyde neurotoxicity: Effects on the mammalian brain, cognitive function, and neurodegenerative risk. A scoping review.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {}, number = {}, pages = {}, doi = {10.17219/acem/209617}, pmid = {42345500}, issn = {1899-5276}, abstract = {Aqueous formaldehyde (FA) solution, known as formalin, is currently the primary agent used for preserving tissue samples and anatomical specimens. Formaldehyde is widely used in laboratories and the chemical industry; it also occurs as an air pollutant and endogenous cellular metabolite. The potential carcinogenic effects of formalin on the respiratory tract are well documented. A less recognized consequence of occupational exposure to FA is its detrimental effect on the central nervous system (CNS) and brain function. A literature review was conducted to investigate the effects of FA on the brain. Five databases were searched: PubMed, Web of Science (WoS), Embase, ScienceDirect, and Google Scholar. To describe the effects of FA exposure and endogenous FA generation, 35 relevant publications were collected and analyzed. The literature review demonstrated that inhalation is the most common route of FA exposure. Several studies have shown that FA may cause hippocampal damage, disrupt melatonin secretion, and induce a wide range of cognitive disorders with varying characteristics and severity. These disorders include memory impairment, disturbances in balance and spatial orientation, learning difficulties, sleep disturbances, impaired judgment, and prolonged reaction times to stimuli. Increased endogenous FA concentration has also been associated with a higher risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis. The literature analysis demonstrated the high neurotoxicity of FA, which may lead to numerous neuropsychiatric disorders. We aim to draw attention to the risks associated with the routine use of formalin, particularly among anatomists and pathologists, and to encourage consideration of less harmful alternative preservation agents.}, }
@article {pmid42345595, year = {2026}, author = {de Sousa, SF and Marques, MDCMP and da Silva Amaral, GMM}, title = {Factors Influencing the Maintenance of Advanced Life Support Competencies Among Critical Care Professionals: A Scoping Review.}, journal = {Nursing in critical care}, volume = {31}, number = {4}, pages = {e70545}, doi = {10.1111/nicc.70545}, pmid = {42345595}, issn = {1478-5153}, support = {UID/06291/2025//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; }, mesh = {Humans ; *Clinical Competence/standards ; *Critical Care/standards ; *Advanced Cardiac Life Support/standards ; }, abstract = {BACKGROUND: Advanced life support (ALS) competence may deteriorate within months after certification, but what supports ongoing competence in critical care remains unclear.<br><br>AIM: To map factors influencing maintenance of ALS competence among critical care professionals working in critical care settings.<br><br>STUDY DESIGN: Scoping review conducted in accordance with Joanna Briggs Institute guidance and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. MEDLINE, CINAHL and the Cochrane Library were searched (from February to March 2025). We included peer-reviewed and grey sources from hospital-based critical care settings that assessed ALS competencies over time. Data were synthesised using inductive thematic analysis.<br><br>RESULTS: Twenty-five sources were included (19 peer-reviewed, 6 grey). Factors were mapped to three domains. Educational factors were most frequently reported and centred on simulation-based rehearsal, structured feedback and debriefing and spaced refreshers delivered in brief, frequent sessions. Institutional determinants related to protected training time, access to resources, standardised roles and content and monitoring through audit and feedback. Individual determinants included clinical exposure and experience, perceived preparedness and self-confidence, stress and cognitive load, engagement in ongoing learning and non-technical behaviours. Outcomes were largely simulation-based or self-reported, and longer-term durability was inconsistently assessed.<br><br>CONCLUSIONS: Maintenance of ALS competence appears to require coordinated educational and organisational supports; longitudinal evaluations with explicit definitions and validated outcomes are needed.<br><br>Critical care services may strengthen ALS competence maintenance by embedding recurrent, context-aligned rehearsal with feedback, supported by protected training time, accessible training infrastructure and ongoing performance monitoring.<br><br>REVIEW REGISTRATION: The review protocol was prospectively registered on the Open Science Framework https://doi.org/10.17605/OSF.IO/PEQJH.}, }
@article {pmid42329964, year = {2026}, author = {Fernandes, APM and Bertucci Borges, LH and Holanda, LJ and Bezerra, BHES and Lopes, ACSM and Silva, MCFD and Valentim, RAM and Bougrain, L and Vasiljevic, GAM and Rodrigues Lindquist, AR}, title = {Applications of electromyography in Amyotrophic Lateral Sclerosis: A systematic review.}, journal = {PloS one}, volume = {21}, number = {6}, pages = {e0350029}, pmid = {42329964}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; *Electromyography/methods ; Motor Neurons/physiology ; Muscle, Skeletal/physiopathology ; }, abstract = {This systematic review examined the use of surface electromyography (sEMG) for the neuromuscular assessment of individuals with Amyotrophic Lateral Sclerosis (ALS), focusing on clinical parameters, the muscle groups evaluated, acquisition protocols, technical properties of the recording systems, integration with other technologies, and signal processing strategies. We included observational studies that applied sEMG to individuals diagnosed with ALS, with or without comparison to healthy controls, and without restrictions on publication year. The analyses included signals recorded at rest and during voluntary contractions, with or without the use of biofeedback. Most studies employed conventional or high-density surface electrodes, with sampling frequencies ranging from 500 Hz to 3000 Hz. The results showed that the primary parameters assessed were muscle fatigue, fasciculation patterns, the number of motor units (MUNE/MUNIX), motor unit firing rates, and signal complexity. These parameters demonstrated sensitivity to disease progression and may contribute to early diagnosis, phenotypic stratification, and functional monitoring of ALS. Additionally, the studies highlighted the increasing use of advanced computational approaches, such as machine learning, for feature extraction and automated classification. In conclusion, sEMG is a promising tool for functional assessment in ALS, with the potential to improve diagnostic accuracy and support new therapeutic strategies based on electrophysiological biomarkers. However, despite technological advances, the included studies displayed substantial methodological heterogeneity and limited protocol standardization. Integration with other neurophysiological modalities also remains underexplored, despite its significant clinical potential.}, }
@article {pmid42332177, year = {2026}, author = {Tang, M and Fleming, E and Gu, J and Shi, H and Xu, Y and Gong, X}, title = {Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {42332177}, issn = {1559-0720}, support = {Grant No. SH2023078//the Zhenjiang Science and Technology Plan Project/ ; Grant No. JDYY2023009//the Medical Education Collaborative Innovation Fund of Jiangsu University/ ; Grant No. 32002235//the National Natural Science Foundation of China/ ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.}, }
@article {pmid42333562, year = {2026}, author = {Srivastava, V and Chakraborty, S and Srivastava, R}, title = {Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0127724328415188260605204430}, pmid = {42333562}, issn = {2772-4336}, abstract = {Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.}, }
@article {pmid42333772, year = {2026}, author = {Amarni, M and Ladjel-Mendil, A and Allala, F and Cherifi, F and Bouanane-Darenfed, A and Moussaoui, H and Merzouagui, R and Ahras-Sifi, N and Laraba-Djebari, F}, title = {Thymol Attenuates Klebsiella pneumoniae Induced Lung Injury via Modulation of Peroxidase-Driven Oxidative Stress and Host-Pathogen Interactions: In Vivo and In Silico Insights.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {7}, pages = {e70997}, doi = {10.1002/jbt.70997}, pmid = {42333772}, issn = {1099-0461}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Klebsiella pneumoniae ; Mice ; *Thymol/pharmacology ; *Host-Pathogen Interactions/drug effects ; *Acute Lung Injury/drug therapy/microbiology/pathology/metabolism ; *Klebsiella Infections/drug therapy/metabolism/pathology ; *Peroxidase/metabolism ; Molecular Docking Simulation ; Male ; }, abstract = {Klebsiella pneumoniae pneumonia drives excessive inflammatory and oxidative responses that culminate in acute lung injury (ALI) and impaired bacterial clearance. Effective therapies capable of restoring host-pathogen balance remain limited, particularly in the context of multidrug-resistant strains. This study investigated the therapeutic efficacy of thymol in a murine model of K. pneumoniae-induced ALI. Oral thymol (5-20 mg/kg) markedly reduced lung injury, suppressed leukocyte infiltration, improved pulmonary histoarchitecture, and significantly enhanced bacterial clearance. Thymol reshaped systemic and local immune responses by decreasing tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP), increasing interleukin-10 (IL-10), and limiting macrophage and granulocyte recruitment. Mechanistically, thymol attenuated heme peroxidase-driven oxidative stress, as evidenced by reduced myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities, decreased malondialdehyde (MDA), hydrogen peroxide (H2O2), and nitric oxide (NO), along with restoration of catalase activity and glutathione levels. Complementary in silico docking predicted stable interactions of thymol with MPO and EPO, as well as essential bacterial metabolic enzymes, including deoxy-D-xylulose-5-phosphate synthase (DXS), acetolactate synthase (ALS), and dihydrodipicolinate synthase (DHDPS). Collectively, these findings suggest that thymol may act as a multi-target bioactive compound capable of modulating host inflammatory and redox pathways while potentially impairing bacterial metabolic fitness, thereby mitigating pneumonia-associated ALI.}, }
@article {pmid42333954, year = {2026}, author = {Harrison, MD and Bradsby, JE and ,  and Kalra, S and Bouvier, L}, title = {Thinning of the oral motor cortex is linked to impaired speech in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2688247}, pmid = {42333954}, issn = {2167-9223}, abstract = {Most individuals with amyotrophic lateral sclerosis (ALS) develop bulbar impairment as their disease progresses. The ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscore and neurological examination of upper (UMN) and lower motor neurons (LMN) are routinely used to assess this dysfunction but have inherent limitations. Speech‑derived measures have shown promise for capturing bulbar decline with greater sensitivity, but their neurobiological correlates remain unclear. This study examined the associations between quantitative speech measures and cortical thinning in ALS. Data from the Canadian ALS Neuroimaging Consortium were analyzed. Speech measures were extracted from audio recordings of the standardized "Bamboo Passage". Cortical thickness was calculated from T1‑weighted MRI scans. General linear models first compared cortical thickness between patients with ALS and healthy controls. Associations between the speech measures and cortical thickness were then assessed within the ALS group. Patients with ALS showed cortical thinning across bilateral frontotemporal regions, with the largest clusters in the bilateral motor cortices. Reduced speaking and articulation rates were associated with thinning in both oral motor cortices. In contrast, the ALSFRS-R bulbar subscore and UMN and LMN bulbar burden showed no significant associations. Measures of pausing behavior were negatively associated with frontal cortical regions. Thinning of the oral motor cortex in ALS was linked to reduced oral motor function, supporting speaking and articulation rate as sensitive markers of bulbar motor neuron degeneration. These measures demonstrated neuroanatomical associations that the ALSFRS-R bulbar subscore and neurological examination findings did not, highlighting their potential value for monitoring bulbar dysfunction in ALS.}, }
@article {pmid42334216, year = {2026}, author = {Riva, N and Schito, P and Russo, T and Ferraro, OE and Durante, G and Tettamanti, A and Riboldi, E and Domi, T and Pozzi, L and Quattrini, A and Comola, M and Agosta, F and Cremona, G and Filippi, M}, title = {Tolerability, Safety and Effectiveness of Sigh Introduction During Non-Invasive Mechanical Ventilation Cycles in Patients With Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {6}, pages = {e70660}, pmid = {42334216}, issn = {1468-1331}, support = {//AriSLA - Fondazione Italiana di ricerca per la SLA/ ; //Giovanni Marazzina Foudation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/physiopathology ; Female ; Male ; Middle Aged ; Aged ; *Noninvasive Ventilation/methods/adverse effects ; *Respiratory Insufficiency/therapy/etiology ; Treatment Outcome ; }, abstract = {BACKGROUND: Respiratory failure is the main cause of death in Amyotrophic lateral sclerosis (ALS), in which the physiological sigh reflex is impaired due to inspiratory muscle weakness. Aim of this study is to assess the tolerability, safety, and effectiveness of adding a sigh cycle to non-invasive mechanical ventilation (NIMV) settings in ALS patients.<br><br>METHODS: In this randomized, blind-controlled proof-of concept study, 44 consecutive ALS patients with indication for NIMV were randomized to: Group I: NIMV with Sigh cycles; Group II: NIMV without Sigh. The primary outcome was the reduction in the Oxygen Desaturation Index (ODI); secondary outcomes included: Overnight Oximetry (OvOx), Arterial blood gas (ABG), and Visual Analog Scale (VAS; 0-10) scores to assess sleep quality, symptom intensity, mask interface, and NIMV tolerance. Assessments were conducted at baseline, after NIMV adaptation (T1) and at 1-month follow-up (T2).<br><br>RESULTS: The Sigh cycle was safe and well tolerated. No significant group differences were observed at T1 or T2 in the primary outcome ODI (median &#x394;ODI: Group A:-4.2; Group B:-4.6: p&#x2009;=&#x2009;0.54), as well as in the OvOx parameters and pO2 and pCO2 ABG values. At T2, secondary analysis showed a significant difference in HCO&#x2083;[-] in favor of the Sigh arm (&#x394;HCO3 [-]: -1.60 vs. 1.35&#x2009;mmol/L, p&#x2009;=&#x2009;0.042). Exploratory Cox-regression models suggested a potential independent effect of SIGH on survival.<br><br>CONCLUSIONS: Sigh is safe, well tolerated in ALS patients. Although this study did not reach the primary outcome, we also cannot rule out that sigh doesn't benefit the patient.}, }
@article {pmid42334507, year = {2026}, author = {Turkmenel, N and Uskun, E}, title = {Associations influencing quality of life in caregivers of patients with amyotrophic lateral sclerosis: a stress-process model approach.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {35}, number = {8}, pages = {}, pmid = {42334507}, issn = {1573-2649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; *Quality of Life/psychology ; Female ; Male ; *Caregivers/psychology ; Cross-Sectional Studies ; Middle Aged ; Social Support ; *Stress, Psychological/psychology ; Aged ; Adult ; Cost of Illness ; Adaptation, Psychological ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Caring for patients with amyotrophic lateral sclerosis (ALS) involves demands that reduce caregivers' quality of life. Although caregiver burden and perceived social support was conceptualized as an independent correlate of quality of life rather than a factor operating primarily through caregiver burden. This study examined these associations within a stress-process framework in which perceived social support was conceptualized as an independent correlate rather than a buffering factor.<br><br>METHODS: This cross-sectional analytical study included 118 informal caregivers of patients with ALS. Primary stressors were defined as patient functional status (ALSFRS-R), caregiving duration, and communication difficulty. Caregiver burden (Zarit Burden Interview) was considered a secondary stressor. Physical and mental quality of life were assessed using the SF-12, and perceived social support was measured with the Multidimensional Scale of Perceived Social Support. Hierarchical regression analyses were performed to examine associations specified in the conceptual model while controlling for caregiver sociodemographic and socioeconomic variables. Additional mediation analyses were conducted to examine whether caregiver burden mediated the relationship between perceived social support and quality of life.<br><br>RESULTS: Poorer patient functional status was significantly associated with higher caregiver burden, whereas communication difficulty showed a positive but non-significant association after adjustment for caregiver characteristics. Caregiver burden showed negative associations with both physical and mental quality of life. Perceived social support remained positively associated with quality of life after adjustment for caregiver burden and contributed additional explained variance in the models. Mediation analyses showed no evidence that caregiver burden mediated the association between perceived social support and either physical or mental quality of life.<br><br>CONCLUSIONS: The findings are consistent with a stress-process framework in ALS caregiving, in which caregiver burden represents a central factor statistically associated with both caregiving stressors and quality of life, while perceived social support shows an independent association with quality of life. These findings suggest that both caregiver burden and perceived psychosocial resources may be relevant to caregiver well-being, although causal and intervention-related implications require further investigation.}, }
@article {pmid42334646, year = {2026}, author = {Totuk, O and Sahin, S}, title = {Behavioral variant frontotemporal dementia associated with a NEK1 missense variant: exploring a possible phenotypic association.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42334646}, issn = {1364-6753}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *NIMA-Related Kinase 1/genetics ; Male ; Aged ; *Mutation, Missense ; Phenotype ; Amyotrophic Lateral Sclerosis/genetics ; Exome Sequencing ; }, abstract = {NEK1 variants are recognized genetic contributors to amyotrophic lateral sclerosis (ALS) and have occasionally been reported within the ALS-frontotemporal dementia (FTD) spectrum. However, their association with isolated behavioral variant frontotemporal dementia (bvFTD) remains unclear. Here, we describe a 69-year-old man who developed progressive behavioral symptoms beginning in his early 60s. Cognitive evaluation demonstrated reduced verbal fluency with relative preservation of memory functions. Structural and functional neuroimaging demonstrated right-predominant frontotemporal atrophy and hypometabolism. Genetic testing for common FTD-associated genes (MAPT, GRN, and C9orf72) was negative. Whole-exome sequencing identified a heterozygous NEK1 c.899T > C (p.Ile300Thr) missense variant, currently classified as a variant of uncertain significance. This observation raises the possibility that NEK1-associated disease may extend beyond ALS or ALS-FTD phenotypes and may include isolated bvFTD presentations. However, further genetic and functional studies are required to clarify the clinical significance of this variant.}, }
@article {pmid42335378, year = {2026}, author = {Rahimi, K and Gupta, A and Malekzadeh, K and Zerze, GH}, title = {Stabilizing Effect of Neighboring Disordered RGG Domain on the Folded State of FUS-RRM.}, journal = {The journal of physical chemistry. B}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jpcb.6c02052}, pmid = {42335378}, issn = {1520-5207}, abstract = {Fused in Sarcoma (FUS) is an RNA-binding protein essential for RNA processing, yet its RNA-recognition motif (RRM) is prone to irreversible unfolding and amyloid aggregation, which is associated with the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the isolated RRM is experimentally known to adopt a stable folded structure, its response to long-range interdomain interactions remains poorly understood. In this work, we address this gap by performing rare-event sampling atomistic molecular dynamics simulations of two systems: isolated RRM and RRM with the flanking RGG sequence using multithermal-multiumbrella on-the-fly probability enhanced sampling (MM-OPES). These simulations allow us to characterize the folding landscape of FUS RRM and examine the specific interactions between the RRM and the adjacent RGG region and how they affect the stability of RRM. Our findings reveal that the disordered RGG segment enhances the stability of the folded RRM by forming stabilizing intramolecular contacts that wrap around the domain. This stabilization is driven by increased fractions of the α1 helix, β2, β3, and the KK loop through a network of targeted multivalent contacts between the RGG and RRM residues. This work reveals how a disordered region stabilizes a folded RNA-binding domain, underscoring the importance of disordered-ordered interdomain coupling in shaping the folding landscape of FUS RRM. These results suggest that disruption of such interactions could destabilize the RRM fold and may contribute to misfolding-prone states relevant to FUS dysfunction.}, }
@article {pmid42335819, year = {2026}, author = {Cheng, Y and Tian, T and Song, D and Ma, Y and Bi, Z and Zhang, X and Zhang, L and Li, Y and Huang, H}, title = {Bionic nanozyme arrays for selective identifying and discriminating sulfonylurea herbicides via recognition site mimicry.}, journal = {Journal of hazardous materials}, volume = {514}, number = {}, pages = {142800}, doi = {10.1016/j.jhazmat.2026.142800}, pmid = {42335819}, issn = {1873-3336}, abstract = {Sulfonylurea herbicides (SUs) are widely used in agriculture owing to their high herbicidal efficacy and low mammalian toxicity. However, their persistence results in residues that pose potential risks to the environment and human health, making it essential to develop rapid and accurate detection techniques for these herbicides. Herein, we designed bionic nanozymes inspired by the structure of acetolactate synthase (ALS), the primary target enzyme of SUs in plants. Using the ALS cofactor thiamine diphosphate and key binding amino acids (arginine, proline, and tryptophan) as ligands, we synthesized bionic nanozymes that exhibited excellent peroxidase-like activity. SUs significantly enhanced the activity of the bionic nanozymes, and the degree of enhancement varied among different SUs. In contrast, organophosphate pesticides (OPs), carbamate pesticides (CPs), and other tested pesticides did not induce such enhancement. Therefore, we constructed a six-channel colorimetric sensor array and achieved 100% accurate discrimination of five SUs across a concentration range of 1-100 µg/mL. Furthermore, the SUs in the four real grain samples and the blind sample were also accurately distinguished by the array. This study not only provides an efficient method for rapid detection of SUs, but also opens new avenues for the bionic design of nanozymes aimed at the precise identification of specific pesticide molecules in complex matrices.}, }
@article {pmid42335888, year = {2026}, author = {Gautier, O and Blum, JA and Nguyen, TP and Cao, S and Klemm, S and Yamakawa, M and Huh, D and Hurt, JA and Sinnott-Armstrong, N and Zeng, Y and Davis, CO and Bombosch, J and Liu, C and Encarnacion, LN and Guttenplan, KA and Chen, D and Kathiria, A and Zhao, L and Moore, S and Meng, A and Ong, K and Cleveland, DW and Ravits, J and Rexach, JE and Greenleaf, WJ and Gitler, AD}, title = {An emergent disease-associated motor neuron state precedes cell death in ALS.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2026.05.047}, pmid = {42335888}, issn = {1097-4172}, abstract = {To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.}, }
@article {pmid42336241, year = {2026}, author = {Stavroulakis, T and White, S and Musson, L and Kime, J and ,  and McDermott, C}, title = {A multi-centre prospective evaluation of post-gastrostomy outcomes in patients with amyotrophic lateral sclerosis.}, journal = {Clinical nutrition ESPEN}, volume = {}, number = {}, pages = {103360}, doi = {10.1016/j.clnesp.2026.103360}, pmid = {42336241}, issn = {2405-4577}, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) often causes significant nutritional decline and weight loss, which negatively impacting prognosis. Gastrostomy is a standard intervention to provide long-term nutritional support, yet its efficacy in stabilising nutritional status and preventing post-procedure weight loss is uncertain. This study explored factors influencing weight change post-gastrostomy.<br><br>METHODS: This multicentre, prospective observational cohort study was conducted across 17 UK sites and involved longitudinal assessments at placement (M0) and at three (M3), six (M6), and nine (M9) months. Data collection included nutritional, clinical and functional parameters. The primary outcome was the percentage weight change between M0 and M3. Secondary outcomes included nutritional intake, functional decline, and survival. Statistical analysis employed hierarchical logistic regression to identify independent predictors of weight change post-gastrostomy.<br><br>RESULTS: Successful gastrostomy was performed in 155 included participants, of which 64 had complete M0 and M3 weight data. Mean percentage weight change from M0 to M3 was -3.3% (SD 7.4%), with 51.6% losing >1 kg in the first three months (p<0.01). Amongst those with available dietary data weight loss (n=21/43) was associated with lower mean daily energy (1620 kcal vs 2022 kcal, p=0.017) and protein intake (64g vs 77g, p=0.048) compared to those who maintained stable or gained weight (n=22/43). At M3, 50% (n=29/58) used a combination of oral and gastrostomy intake, 27.6% (n=16/58) used gastrostomy only, and 22.4% (13/58) were not using the gastrostomy. Based on available data for total daily expenditure energy expenditure (TDEE) calculation (n=39), 61.5% did not meet predicted total daily energy expenditure. Participants who lost weight (>1kg) post-gastrostomy had shorter median survival (270 days) compared to the weight stable/gain group (p=0.018). Hierarchical logistic regression suggested that mean daily water intake may potentially be an independent predictor of weight maintenance or gain, though this finding should be considered exploratory due to the limitations of our study (OR=1.003, p=0.040).<br><br>DISCUSSION: Despite gastrostomy placement, over half of participants in our final analytical cohort continued to lose weight. For a smaller subset of participants, for whom nutritional intake were available, this was potentially due to insufficient energy, macronutrient, and fluid intake, alongside disease-specific catabolism. As post-gastrostomy weight loss negatively impacts survival, these findings highlight a need for proactive, tailored, and ongoing nutritional support and monitoring, to optimise post-gastrostomy outcomes and survival in ALS.}, }
@article {pmid42336630, year = {2026}, author = {Bosó Pérez, R and Littlejohn, J and Willis, M and Lewis, R and Mitchell, KR}, title = {Young people's sexual wellbeing: a systematic review of qualitative studies.}, journal = {BMJ sexual &amp; reproductive health}, volume = {}, number = {}, pages = {}, doi = {10.1136/bmjsrh-2025-203161}, pmid = {42336630}, issn = {2515-2009}, abstract = {BACKGROUND: Young people's adverse sexual experiences contribute to a significant global mental health burden and detract from their quality of life. Sexual wellbeing connects sexual and mental health and can offer a novel perspective on drivers and impacts of young people's sexual behaviour. It is a promising means through which to shift public health focus from risk to aspects of sex relevant to broader wellbeing.<br><br>METHODS: This systematic review aimed to characterise sexual wellbeing for adolescents and emerging adults (aged 16-24 years). We searched four databases for peer-reviewed qualitative literature on young people's accounts relevant to sexual wellbeing published between 1988 and 2025. We intensity sampled and thematically synthesised studies against Mitchell et al's Sexual Wellbeing Conceptual Framework. PROSPERO registration: CRD42022315593.<br><br>RESULTS: We thematically synthesised 93 papers, representing 3152 participants across 25 countries. Our synthesis characterises youth sexual wellbeing as feeling: congruence between one's sexual thoughts, feelings, values, behaviours and emerging identities; driven by curiosity or desire; capable of advocating for one's wants and boundaries; able to authentically express oneself; deserving of care, respect and support; and expectant of a positive sexual future. Women, sexual and gender minorities, sexual violence survivors, youth with disabilities or health conditions, and those in deprived or sexually conservative communities report additional barriers to wellbeing.<br><br>CONCLUSIONS: This first-ever review of youth sexual wellbeing underscores its significance during this life stage, and outlines similarities and differences compared with adults. The findings demand a stronger focus on young people's priorities for sexual wellbeing to support their healthy development.}, }
@article {pmid42323602, year = {2026}, author = {Moll, L and Riessen, R and Dahlmann, P and Häske, D}, title = {Effect of low-dose, high-frequency advanced life support training versus annual full-day training on simulation-based resuscitation performance: a randomized controlled trial.}, journal = {BMC medical education}, volume = {26}, number = {1}, pages = {}, pmid = {42323602}, issn = {1472-6920}, mesh = {Adult ; Female ; Humans ; Male ; *Advanced Cardiac Life Support/education ; *Cardiopulmonary Resuscitation/education ; *Clinical Competence/standards ; Emergency Medical Services ; *Simulation Training/methods ; Young Adult ; }, abstract = {BACKGROUND: Skill decay in advanced life support (ALS) is well documented, yet optimal training frequency remains unclear. This trial compared low-dose, high-frequency ALS training with annual full-day training regarding simulation-based resuscitation performance after one year.<br><br>METHODS: In this randomized, controlled, simulation-based trial, 35 emergency medical services (EMS) professionals were allocated to either low-dose, high-frequency ALS training (intervention group, n&#x2009;=&#x2009;18) or a single annual full-day ALS training (control group, n&#x2009;=&#x2009;17). Performance was assessed at baseline and after 12 months using a validated 29-item rating instrument covering technical and non-technical skills (NTS), with items rated on a 5-point Likert scale (1&#x2009;=&#x2009;poor performance, 5&#x2009;=&#x2009;excellent performance). The primary endpoint was the overall performance score for resuscitation management, defined as the mean across all items. Secondary endpoints included domain-specific performance scores (NTS, defibrillation-related, and cardio-pulmonary resuscitation [CPR] items), calculated as the mean scores for each domain, as well as time to key interventions.<br><br>RESULTS: After 12 months, the intervention group showed significantly higher overall performance scores than the control group (4.7&#x2009;&#xb1;&#x2009;0.2 vs. 4.2&#x2009;&#xb1;&#x2009;0.3; p&#x2009;<&#x2009;0.001). The largest between-group difference was observed for NTS (4.8&#x2009;&#xb1;&#x2009;0.2 vs. 3.9&#x2009;&#xb1;&#x2009;0.5; p&#x2009;<&#x2009;0.001). Scores for defibrillation-related and CPR-related items were also significantly higher in the intervention group. Time to CPR initiation (13&#x2009;&#xb1;&#x2009;2&#xa0;s vs. 18&#x2009;&#xb1;&#x2009;7&#xa0;s; p&#x2009;=&#x2009;0.015), rhythm analysis (29&#x2009;&#xb1;&#x2009;9&#xa0;s vs. 45&#x2009;&#xb1;&#x2009;24&#xa0;s; p&#x2009;=&#x2009;0.015), supraglottic airway insertion (51&#x2009;&#xb1;&#x2009;13&#xa0;s vs. 68&#x2009;&#xb1;&#x2009;30&#xa0;s; p&#x2009;=&#x2009;0.013), as well as hands-off time (4&#x2009;&#xb1;&#x2009;1&#xa0;s vs. 6&#x2009;&#xb1;&#x2009;3&#xa0;s; p&#x2009;=&#x2009;0.002) were significantly shorter in the intervention group. The rating instrument demonstrated good reliability (Cronbach's alpha 0.793; intraclass correlation coefficient 0.794, 95% confidence interval 0.718-0.854).<br><br>CONCLUSION: Low-dose, high-frequency ALS training resulted in higher simulation-based resuscitation performance scores than annual full-day training, particularly for non-technical skills and time-critical processes.<br><br>TRIAL REGISTRATION: The study is registered in the German Register of Clinical Studies under the ID DRKS00024822.}, }
@article {pmid42323648, year = {2026}, author = {Girling, C and Ryan, G and Bradburn, M and Caprioli, T and Dawson, S and Fisher, E and Haynes, N and Herbert, E and Hill, H and Hind, D and May, C and Bianchi, S and Cox, M and Kaltsakas, G and Massey, C and Mayberry, E and Messer, B and Needham, D and Playle, R and McDermott, C and Griffiths, AW and Hobson, E}, title = {Delivering effective non-invasive ventilation in amyotrophic lateral sclerosis using intensive remote support (DENIM): protocol for an embedded process evaluation in a hybrid type 3 implementation-effectiveness trial.}, journal = {Implementation science communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s43058-026-01023-9}, pmid = {42323648}, issn = {2662-2211}, support = {NIHR158715//Health Services and Delivery Research Programme/ ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) is the only intervention that significantly improves survival and quality of life in motor neuron disease, extending life by 8-13 months. However, at least half of patients are unable to reach the recommended ≥ 4 h daily NIV use, and current NHS services provide insufficient follow-up for intensive optimisation. Delivering Effective Non-Invasive ventilation in Motor neuron disease using intensive remote support (DENIM) is a stepped-wedge cluster randomised trial. This protocol describes a process evaluation embedded within DENIM aiming to understand how and why the implementation strategy works (or does not work) across different contexts.<br><br>METHOD: The process evaluation employs a convergent mixed-methods multiple-case study design across twelve NHS ventilation services. We developed a programme theory informed by Normalization Process Theory (NPT), the Consolidated Framework for Implementation Research and Expert Recommendations for Implementing Change, which states how the DENIM implementation strategy is expected to achieve normalisation of evidence-based NIV practice. Data collection across twelve sites include: ethnographic observations of patient-staff interactions; semi-structured interviews with staff (n&#x2009;=&#x2009;24-48) and patients/carers (n&#x2009;=&#x2009;24) exploring implementation experiences; the NoMAD questionnaire measuring normalisation perceptions from healthcare professionals within the services and NIV adherence data from participants' ventilators. Barriers and facilitators to research participation for underserved populations including ethnic minorities, those with low digital literacy, and women over 80 with bulbar onset disease will also be identified. Qualitative data will be analysed using NPT-informed thematic analysis. Integration occurs at three levels (design, methods, interpretation) with joint display tables presenting quantitative and qualitative findings alongside meta-inferences.<br><br>DISCUSSION: This process evaluation will generate explanatory insights into how implementation strategies can address the evidence-to-practice gap in complex, technology-supported care for progressive diseases, with implications for health equity and wider NHS digital transformation.<br><br>TRIAL REGISTRATION: ISRCTN10105285. 16/04/2025.}, }
@article {pmid42324254, year = {2026}, author = {Di Lazzaro, V and Pellegrino, G and Corp, DT and Musumeci, G and Capone, F and Pilato, F and Mazzone, P and Insola, A and Ranieri, F}, title = {Direct evidence of upper motor neuron excitability changes in a patient with ALS.}, journal = {Journal of neurophysiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/jn.00208.2026}, pmid = {42324254}, issn = {1522-1598}, support = {T4-AN-09//Ministero della Salute (Italy Ministry of Health)/ ; }, abstract = {A key feature of amyotrophic lateral sclerosis (ALS) pathophysiology is motor neuron hyperexcitability. However, the mechanisms of hyperexcitability are not well understood. Prior studies have used transcranial magnetic stimulation (TMS) to demonstrate increased motor cortex excitability and reduced intracortical inhibition in human ALS. Yet interpretation of these findings is limited because measurement of muscles responses cannot disentangle specific contribution of upper and lower motor neurons and of cortical interneurons to excitability changes. We had the rare opportunity to record directly the corticospinal output evoked by TMS upstream of the spinal circuitry in an ALS patient who had undergone epidural electrode implantation for intractable pain. Single pulse stimulation was performed both with a coil orientation inducing a current that activates corticospinal neurons directly, and with a coil orientation inducing a current that activates corticospinal neurons trans-synaptically. Short interval intracortical inhibition (SICI) was also studied using paired pulse stimulation. Data obtained in the patient were compared with those recorded in 10 conscious control subjects. Compared to control subjects, patient showed a reduced amplitude in response to direct corticospinal neuron activation, yet an enhanced amplitude of corticospinal output after trans-synaptic corticospinal neuron activation together with a SICI reduction. Present findings provide direct evidence of hyperexcitability of monosynaptic glutamatergic inputs to corticospinal neurons that, in association with reduced intracortical inhibition, can trigger neurodegeneration. Taken together with the extensive body of evidence generated by non-invasive TMS studies, the findings from this single-case study may provide valuable insights into the pathophysiological mechanisms of the disease.}, }
@article {pmid42324612, year = {2026}, author = {Alwarnaidu Vijayarajan, VB and Vijayakumar, I and Ruiz-Partida, R and Runge, F and Torra, J and Lozano-Juste, J and Forristal, PD}, title = {Pro-197 mutations confer resistance to thiencarbazone but not to foramsulfuron in ALS-resistant Poa annua populations.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71051}, pmid = {42324612}, issn = {1526-4998}, support = {//Department of Agriculture, Food and the Marine, Ireland/ ; //European Regional Development Fund/ ; //European Union (FEDER), 'ERDF A way of making Europe'/ ; }, abstract = {BACKGROUND: Poa annua is currently a lower-priority arable weed in Ireland; however, increasing target-site resistance to acetolactate synthase (ALS) inhibitors and declining availability of non-ALS herbicides highlight emerging control challenges. ALS-inhibiting co-formulations of foramsulfuron + thiencarbazone have been specifically developed for use in herbicide-tolerant beet varieties. While foramsulfuron can control grass weeds carrying specific target-site mutations, its efficacy within the co-formulation on ALS-resistant populations remains unknown. We addressed this knowledge gap using genetic characterisation, dose-response and interaction analyses, and ligand docking modelling in 12 independently evolved, ALS-resistant, Poa annua populations carrying Pro-197 or Trp-574 mutations.<br><br>RESULTS: All Pro-197 variants (Thr, Gln or Ala) were thiencarbazone-resistant (resistance index (RI)&#x2009;=&#x2009;20.9-33.3) but remained foramsulfuron-sensitive (2.5-4), while the co-formulation showed reduced efficacy (5.5-6.2). Interaction analyses showed no overall deviation from additivity for Pro-197 populations (P&#x2009;>&#x2009;0.05), although antagonism occurred at reduced rates (P&#x2009;<&#x2009;0.05). Structural modelling and ligand docking analyses indicated that most Pro-197 substitutions did not alter the ALS catalytic tunnel. Foramsulfuron retained extensive hydrogen-bonding and electrostatic interactions, with a more favourable binding free energy than thiencarbazone, which showed fewer interactions and a less favourable free energy. Trp-574-Leu variants exhibited cross-resistance to all treatments, consistent with disruption of key binding interactions.<br><br>CONCLUSION: This study demonstrates that foramsulfuron + thiencarbazone efficacy on Pro-197-resistant Poa annua populations is poor, despite these populations being sensitive to foramsulfuron used alone. Consequently, this co-formulation, developed for ALS-tolerant beet, should be restricted to fields without ALS-resistant weeds to ensure effective in-crop control and avoid selection for resistance. &#xa9; 2026 The Author(s). Pest Management Science published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.}, }
@article {pmid42324839, year = {2026}, author = {Felice, KJ and Leighton, DB and Daniel, AS and Cartwright, NI and Benchaya, LM}, title = {The Impact of Sponsored Genetic Testing in 170 Consecutive Consenting Patients With Amyotrophic Lateral Sclerosis: A Single-Site Retrospective Review.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70313}, pmid = {42324839}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is often categorized as sporadic (sALS) or familial (fALS) based on the family history. Several recent genetic studies have found disease-causing variants in 50%-85% of patients with fALS and 10%-15% of those with sALS. The aim of our study is to review our clinical experience with sponsored genetic testing (i.e., pharmaceutical company-sponsored and cost-free to patient) since its inception.<br><br>METHODS: We reviewed the medical records on all ALS patients seen at our Center who consented to sponsored genetic testing from August 2021 through October 2025.<br><br>RESULTS: Of the 170 medical records reviewed, 22 patients (12.9%) tested positive for a disease-causing variant in a known autosomal dominant disorder. Thirteen of 35 patients with fALS (37.1%) were found to have a disease-causing variant, in contrast to 9 of 135 patients (6.7%) with sALS. Of the 22 disease-causing variants found, the following genes were involved in decreasing frequency: C9orf72 11 (50%), SOD1 6 (27.3%), FUS 2 (9.1%), and one each (4.5%) of SQSTM1, TARDBP, and TBK1. Twenty-eight patients (16.5%) harbored 29 variants of uncertain significance (VUS).<br><br>DISCUSSION: Results of testing led to medically actionable activities including genetic counseling for patients and at-risk family members with positive results, and treatment (i.e., intrathecal tofersen) for the two patients harboring pathogenic SOD1 variants. The lower diagnostic yields than previously published for fALS and sALS patients likely are related to lower numbers of genes tested in the sponsored genetic panels, and these are expected to improve as more genes are added.}, }
@article {pmid42324866, year = {2026}, author = {Hannaford, AM and Supnet, IE and Pavey, N and Menon, P and van den Bos, MAJ and Kiernan, MC and van Alfen, N and Simon, NG and Vucic, S}, title = {Muscle Ultrasound Is a Sensitive Outcome Measure in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70317}, pmid = {42324866}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Muscle ultrasound is a potential outcome measure in amyotrophic lateral sclerosis (ALS), although prospective, multicenter longitudinal studies are lacking. This study aimed to evaluate muscle ultrasound as an outcome in ALS and compare its sensitivity with clinical and neurophysiological metrics.<br><br>METHODS: In this prospective two-center cohort study, adults with ALS underwent baseline and follow-up assessments at least 3 months apart. Clinical measures included the ALS Functional Rating Scale-Revised (ALSFRS-R) and Medical Research Council sum scores. Median nerve abductor pollicis brevis and ulnar nerve first dorsal interosseous compound motor action potential (CMAP) amplitudes were recorded. Muscle ultrasound of 11 bulbar and limb muscles was performed using harmonized protocols, with offline analysis of muscle thickness and echogenicity. Longitudinal change and effect sizes were calculated.<br><br>RESULTS: Twenty-two patients were included (median age 59.3&#x2009;years, follow-up 9.6&#x2009;months, disease duration 23.1&#x2009;months). ALSFRS-R declined by -3.0 points (-0.7% per month; effect size 0.84). Median nerve CMAP amplitude decreased by -1.6&#x2009;mV (-1.2% per month; effect size 0.77). Muscle echogenicity increased by 0.8&#x2009;units (+6.0% per month), yielding the largest effect size (1.09), with increases across multiple muscles. Responsiveness improved with onset-specific muscle selection, with biceps brachii (effect size 1.12) and gastrocnemius (1.18) showing the strongest changes. Muscle thickness and fasciculation frequency did not change.<br><br>DISCUSSION: Muscle ultrasound echogenicity is a sensitive structural biomarker of ALS progression, demonstrating greater responsiveness than ALSFRS-R and CMAP over 3-12&#x2009;months. Its accessibility and sensitivity support its utility as an outcome measure in clinical trials.}, }
@article {pmid42325426, year = {2026}, author = {Luitel, NP and Sainju, P and Lamichhane, B and Khadgi, R and Gautam, K}, title = {Breaking down barriers: A qualitative study of demand- and supply-side barriers to depression care in Nepal.}, journal = {Global mental health (Cambridge, England)}, volume = {13}, number = {}, pages = {e121}, pmid = {42325426}, issn = {2054-4251}, abstract = {Despite global initiatives like WHO's mhGAP, mental health treatment gaps remain substantial, especially in LMICs. Barriers are often presented collectively, with an emphasis on supply-side solutions, while demand-side factors are frequently overlooked. Distinguishing these barriers and implementing tailored strategies is critical for improving access and utilization. This study explores stakeholders' perceptions and experiences of demand- and supply-side barriers to mental healthcare in Nepal. Qualitative interviews were conducted with 65 community stakeholders, including people with lived experience, using vignettes and the McGill Illness Narrative Interview (MINI) guide. Data were analyzed thematically in NVivo and interpreted through Levesque et al.'s access framework, which examines health system characteristics and individual capabilities. Demand-side barriers included spiritual attributions of mental illness, stigma, low perceived need, financial hardship, lack of family support and limited awareness of conditions and available services. These factors hindered recognition, help-seeking, affordability and engagement. Supply-side barriers involved frequent staff transfers, inadequate training, lack of privacy, poor infrastructure and irregular psychotropic medicine supply, affecting service acceptability, availability and appropriateness. Access to mental healthcare in Nepal is shaped by interconnected demand- and supply-side barriers. Addressing these requires culturally sensitive stigma-reduction, mental health literacy programs, workforce stabilization, reliable medication supply, privacy-friendly facilities and financial protection.}, }
@article {pmid42327318, year = {2026}, author = {Mot, AI and Li, Y and Dibaj, P and Tzvetanova, ID and Gerwig, UC and Bogale, TA and Goebbels, S and Möbius, W and Bergles, DE and Morrison, BM and Rothstein, JD and Cleveland, DW and Edgar, JM and Nave, KA}, title = {Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.09.731100}, pmid = {42327318}, issn = {2692-8205}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of 'myelinic nanochannels', narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.<br><br>SIGNIFICANCE STATEMENT: Oligodendrocytes have been implicated in the progression of amyotrophic lateral sclerosis (ALS) but the underlying mechanisms have remained obscure. Here we show in genetic mouse models that the familial ALS causing isoform of a ubiquitously expressed mutant enzyme (SOD1) aggregates in cytosolic channels within myelin that are responsible for delivery of transporters and nutrients necessary to support the axonal compartment. ALS disease progression was accelerated in mice when myelinic channels were collapsed by deleting CNP, a structural protein necessary for myelinic channel maintenance. Disruption of transport through myelinic channels by aggregation of mutant SOD1 may perturb oligodendrocyte support of motor axons and contribute to disease in this form of ALS.}, }
@article {pmid42327368, year = {2026}, author = {Gatt, A and Buhidma, Y and Fodder, K and Humphrey, J and Foti, SC and Frias, B and Benson, BC and Gami-Patel, P and Gittings, LM and Toomey, CE and Lashley, T}, title = {Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in frontotemporal lobar degeneration pathological subtypes.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag197}, pmid = {42327368}, issn = {2632-1297}, abstract = {Frontotemporal dementia is a neurodegenerative disorder with a strong heritable component. Frontotemporal lobar degeneration refers to the pathological changes seen in frontotemporal dementia, characterized by atrophy of the frontal and temporal lobes and the presence of abnormal protein inclusions. In the case of frontotemporal lobar degeneration with hyperphosphorylated TDP-43 positive inclusions (FTLD-TDP), five pathological subtypes (A, B, C, D and E) are observed based on the types and distribution of inclusions found in the brain. In all subtypes, there tends to be a large variability in the number of pathological inclusions observed between cases, with limited correlation to clinical manifestations. TDP-43 is an RNA-binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, which along with other hnRNPs, modulates multiple aspects of RNA processing. HnRNPs other than TDP-43 have been implicated in several neurological diseases, including Amyotrophic Lateral Sclerosis, FTLD-TDP, frontotemporal lobar degeneration with fused in sarcoma (FTLD-FUS) and Alzheimer's disease. Multiple hnRNPs have been found in pathological inclusions in specific subtypes of FTLD-TDP, suggesting potential roles in the disease process. The role of the hnRNP network in frontotemporal lobar degeneration disease pathogenesis, however, has not yet been investigated. This study aimed to comprehensively evaluate the presence and expression of hnRNP proteins in two pathological subtypes of sporadic FTLD-TDP (A and C) as well as the genetic form FTLD-TDP A C9orf72 using immunohistochemistry and gene expression analysis by single-nuclei RNA-sequencing. We found that there was great variability in the frequency of TDP-43 pathology across and within FTLD-TDP pathological subtypes. Our findings suggest that distinct global transcriptomic profiles may underlie the different pathological subtypes of FTLD-TDP. The most prominent transcriptomic changes were observed in oligodendrocytes and astrocytes, involving multiple hnRNPs across frontotemporal lobar degeneration subtypes compared to controls. Transcriptomic co-expression analysis further revealed that glial clusters were more strongly associated with RNA-processing dysfunction and contributed to disease classification. Together, these findings highlight the involvement of the hnRNP network and glial-specific RNA-processing alterations in FTLD-TDP pathophysiology, offering new insight into the molecular distinctions between pathological subtypes and potential targets for future investigation.}, }
@article {pmid42328197, year = {2026}, author = {Safir, AH and Blackwell, AF and Debnath, R}, title = {Resisting epistemic loss in AI image generation.}, journal = {Patterns (New York, N.Y.)}, volume = {7}, number = {6}, pages = {101568}, pmid = {42328197}, issn = {2666-3899}, abstract = {Hintze et al.'s recent study highlights the tendency of current-generation vision-language models to converge on overly generic outputs. We argue that considering AI imageries as epistemic artefact and AI-driven artistic practices as socio-cultural processes can provide better understandings around the implications of such conditions beyond merely technical aspects of image generation. Drawing from our ongoing research, we highlight the necessity of bringing the epistemic vulnerability of marginalized artists and users and their hierarchical relations with these tools into sociotechnical design conversations, and by doing so, to explore the possibility for pluriversal and just AI futures, particularly in the Global South.}, }
@article {pmid42328245, year = {2026}, author = {Dong, J and Lu, M and Chen, Y and Zisman-Ilani, Y and Feng, Y and Zhang, S and Huang, H and Zhou, Y}, title = {Bridging the Gap Between Efficacy and Practice: A Systematic Review of Shared Decision-Making in Severe Mental Illness.}, journal = {Journal of multidisciplinary healthcare}, volume = {19}, number = {}, pages = {610845}, pmid = {42328245}, issn = {1178-2390}, abstract = {Shared decision-making (SDM) is recommended for preference-sensitive treatment decisions in severe mental illness, but its routine use in psychiatric services remains inconsistent. This systematic review synthesized evidence published between 2014 and 2024 and examined clinical, cultural, and organizational factors associated with SDM implementation. We searched PubMed, Embase, CINAHL, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP for studies published from January 2014 to November 2024. Forty-two studies involving 8798 participants were included. Reporting followed PRISMA 2020 and SWiM guidance. Study quality was assessed with design-specific Joanna Briggs Institute tools, and certainty of key findings was appraised using a combined GRADE-CERQual approach. Because of heterogeneity in study design, interventions, outcomes, and settings, findings were synthesized narratively using Popay et al's framework. Patient decision aids were generally associated with lower decisional conflict, greater readiness, satisfaction, involvement, or autonomy, with little evidence of meaningful consultation-time extension. Clinician training and SDM interventions improved short-term engagement and information sharing, but evidence for sustained improvements in adherence, decisional conflict, and clinician behavior was mixed or low certainty. Family-mediated or triadic decision-making was prominent in East and Southeast Asian studies and may support adherence and participation, although it can also create tension between patient autonomy and family preferences. Across studies, clinicians and patients often emphasized different treatment priorities, particularly symptom control versus side-effect tolerability. Evidence was concentrated in Europe and East Asia, with limited data from low-resource regions. SDM in psychiatric care appears most reliable for improving immediate decision processes rather than long-term outcomes. Future implementation should test culturally adapted triadic decision aids, workflow-integrated prompts, and interprofessional decision coaching while using cautious, context-sensitive outcome evaluation.}, }
@article {pmid42329291, year = {2026}, author = {Sathick Batcha, BR and Amarnath, DP and Srinivasan, D and Ramakrishnan, P}, title = {Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42329291}, issn = {1568-5608}, abstract = {Major neurodegenerative disorders, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are pathologically driven by mitochondrial failure and persistent neuroinflammation. Defects in oxidative phosphorylation, excess Reactive Oxygen Species (ROS), and impaired mitophagy cause an imbalance in neuronal energy and promote the release of mitochondrial Damage-Associated Molecular Patterns (DAMPs) that activate microglial inflammasomes and enhance inflammatory signalling. Current therapeutic strategies have largely targeted individual pathways and have been unable to effectively modulate this interrelated mitochondrial immune axis or achieve efficient delivery to the Central Nervous System (CNS). This review addresses the dual promise of berberine therapy, a biologically active plant alkaloid that enhances mitochondrial production via AMPK/PGC-1α and SIRT1, restores membrane potential, promotes mitophagy, and inhibits NF-κB and NLRP3-mediated inflammation. Nevertheless, this compound's weak solubility, limited bioavailability, and extremely poor Blood-Brain Barrier (BBB) penetration limit its therapeutic application. Encapsulation of berberine in polymeric nanoparticles, including Polyethylene glycol (PEG)-based polymeric nanoparticle systems, offers improved stability, bioavailability, and targeted mitochondrial delivery. An effective method for reducing neuroinflammation and mitochondrial dysfunction is this comprehensive phytochemical nanotechnology technique.}, }
@article {pmid42317831, year = {2026}, author = {Afshar, AS and Statland, J and Song, X}, title = {Towards Early Prediction of Amyotrophic Lateral Sclerosis Empowered by Machine Learning and Clinical Big Data.}, journal = {AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science}, volume = {2026}, number = {}, pages = {623-632}, pmid = {42317831}, issn = {2153-4063}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by substantial symptom heterogeneity and overlap with other neurological conditions, often delaying diagnosis. This study developed a consensus-based feature selection framework to identify a stable and parsimonious minimal feature set for early ALS prediction using large-scale observational data. Using multi-year medical claims and multi-site EHRs, we identified 1,716 ALS cases with matched controls. The approach integrated variability across sample, task, and model dimensions to isolate features predictive up to 18 months before diagnosis. Predictive models using LASSO regression and GBT were evaluated with AUROC and classification metrics. The resulting nine-feature set achieved AUROC values above 0.85 across time windows. The GBT model was further evaluated in musculoskeletal, nervous system, and limb or bulbar subgroups, demonstrating reliable discrimination and preserved sensitivity and specificity. These findings highlight the potential of stable minimal feature sets to support earlier ALS identification.}, }
@article {pmid42317872, year = {2026}, author = {Singh, G and Singh, G and Shreya,  and Kumari, A and Aran, KR}, title = {Nutrients and bioactive compounds as modifiers of neurodegenerative trajectories: molecular mechanisms, translational barriers, and precision nutrition.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1819432}, pmid = {42317872}, issn = {2296-861X}, abstract = {The Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS) are a growing health burden across the world with minimal disease-modifying treatment and therapy. It is emerging that neurodegeneration is not only a progressive loss of neurons, but also a nutrient-sensitive systems-level dysfunction that takes the form of redox imbalance, chronic neuroinflammation, mitochondrial dysfunction, impaired proteostasis, and synaptic loss. The aging brain are more prone to metabolic vulnerability, and subclinical deficiencies in essential nutrients and bioactive dietary compounds may exacerbate cellular stress responses that contribute to disease progression. It summarizes the existing data on the effects of nutrients like vitamins, minerals, polyunsaturated fatty acids, and various phytochemicals in modulating neuronal homeostasis by regulating oxidative signaling, inflammatory cascades, mitochondrial resilience, autophagy, and synaptic plasticity. These nutrient-mediated effects collectively influence neuronal survival, synaptic integrity, and cognitive function by affecting disease susceptibility and progression. Additionally newer metabolites of the marine and microbiome act as new neuroactive agents. The evidence from in-vitro and preclinical models, translation to clinical benefit remains inconsistent due to heterogeneity in study design, bioavailability, blood- brain barrier penetration, dosing strategies and disease stage. This review highlights emerging potential of precision nutrition frameworks that integrate nutrigenomics, metabolomics, and microbiome interactions, and individualized metabolic profiling to enable context-dependent and stage-specific interventions. Moreover, conceptualizing neurodegeneration as a nutrient-sensitive, systems level disorder, propose a mechanistically informed and integrative approach that combine targeted nutritional strategies with pharmacological and lifestyle therapies to more effectively modify neurodegenerative trajectories.}, }
@article {pmid42318818, year = {2026}, author = {Bailey, F and Eun, MW and Hobson, E and McDermott, C and Knox, L}, title = {Understanding apathy in people with amyotrophic lateral sclerosis using motivational theories.}, journal = {Journal of health psychology}, volume = {}, number = {}, pages = {13591053261454342}, doi = {10.1177/13591053261454342}, pmid = {42318818}, issn = {1461-7277}, abstract = {Apathy-a reduction in goal-directed behaviour, cognition, and emotional responsiveness-is a highly prevalent, debilitating symptom in people with amyotrophic lateral sclerosis (pwALS). This study investigated the association between apathy in 69 pwALS and their 54 informal caregivers and constructs from social cognitive theory and self-determination theory. Participants also provided subjective accounts of apathy in semi-structured interviews. Multiple regression analysis demonstrated that constructs from both motivational theories were significant predictors of overall apathy scores and its sub-domains (executive, emotional, initiation), accounting for 32%-64% of the variance. Specifically, frustration of the basic psychological need for competence was a consistent and prominent predictor of greater apathy. Qualitative findings revealed that pwALS lack a clear awareness of apathy, often experiencing it as a manifestation of activities requiring increased physical and temporal effort. Future research should use psychosocial theories to understand apathy and develop interventions.}, }
@article {pmid42318821, year = {2026}, author = {Preetam, S and Mishra, R and Thapliyal, S and Mondal, S and Rustagi, S and Govindarajan, RK and Pandit, S and Bora, J and Talukdar, N and Rabbee, MF and Malik, S}, title = {3D-printed lab-on-chip platforms for the detection of neurodegenerative diseases: opportunities and challenges.}, journal = {Journal of materials chemistry. B}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6tb00381h}, pmid = {42318821}, issn = {2050-7518}, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and ALS remain some of the most challenging disorders to diagnose at an early stage. Conventional approaches rely on costly neuroimaging or invasive cerebrospinal fluid sampling, which limit accessibility and early intervention. Recent advances in 3D printing have enabled rapid prototyping of lab-on-chip (LOC) platforms that integrate microfluidics, biosensors, and biological models to detect disease-specific biomarkers with high sensitivity and throughput. Herein, we explore the synergistic role of 3D printing technologies and biomaterials in fabricating LOC systems for NDs. We highlight key biomarkers, and neuron- and organoid-on-chip platforms, and discuss the challenges and opportunities in clinical translation. By combining technical innovation in additive manufacturing with biological relevance, 3D-printed LOC devices represent a transformative approach toward precision diagnostics in neuro-medicine.}, }
@article {pmid42319999, year = {2026}, author = {Pacheco-Ortega, GA and Esquivel-Zapata, O and Piña-Rosales, E and Davila-Ortíz de Montellano, DJ and Yescas Gomez, P and Medina-Rioja, R}, title = {Teaching Video NeuroImage: Beyond Cognition: Amyotrophic Lateral Sclerosis-Like Disease in PSEN1 c.1292C&gt;A (Jalisco Founder Effect) Variant.}, journal = {Neurology}, volume = {107}, number = {2}, pages = {e218247}, doi = {10.1212/WNL.0000000000218247}, pmid = {42319999}, issn = {1526-632X}, }
@article {pmid42320255, year = {2026}, author = {Waqar, K and Shaqfeh, M and Mittal, SO}, title = {POLG-associated Parkinson's disease-ALS overlap: A novel variant and first reported use of continuous subcutaneous foslevodopa/foscarbidopa infusion in Brait-Fahn-Schwartz disease.}, journal = {Parkinsonism &amp; related disorders}, volume = {149}, number = {}, pages = {108398}, doi = {10.1016/j.parkreldis.2026.108398}, pmid = {42320255}, issn = {1873-5126}, abstract = {A 38-year-old Emirati man developed levodopa-responsive young-onset parkinsonism followed by electrophysiologically confirmed amyotrophic lateral sclerosis consistent with Brait-Fahn-Schwartz disease. Whole-genome sequencing identified a novel heterozygous POLG variant (c.2620T > A; p. Leu874Met). Motor fluctuations on oral therapy prompted escalation to continuous subcutaneous foslevodopa/foscarbidopa infusion, achieving near-complete motor normalization at twelve months. This is the first reported use of device-aided therapy in POLG-associated parkinsonian-ALS overlap.}, }
@article {pmid42320366, year = {2026}, author = {Lee, BC and Tsai, JC and Chang, WZ and Wang, CC and Hour, AL and Wang, CC and Tsai, HJ}, title = {Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {201}, number = {}, pages = {119674}, doi = {10.1016/j.biopha.2026.119674}, pmid = {42320366}, issn = {1950-6007}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons (MNs) with few available therapeutic options. Previous ALS studies demonstrated a decrease in phosphoglycerate kinase 1 (Pgk1) secreted from NogoA-overexpressing muscle cells, thus reducing interaction between extracellular Pgk1 (ePgk1) and neural membranous Enolase 2 (Eno2) with consequent inhibition of neurite outgrowth of MNs (NOMN). The negatively charged 419th aspartic acid of receptor Eno2 (Eno2-D419) is a critical residue interacting with the positively charged 353rd lysine of ligand ePgk1-K353. To strengthen the charge attraction, we mutated ePgk1-K353 to arginine (ePgk1-K353R). Compared to wild-type Pgk1, supplementary mutant Pgk1-K353R proved more effective in increasing NOMN derived from NSC34 neural cells cultured in Sol8-vector condition medium. In vivo, Pgk1-K353R-immersed zebrafish embryos exhibited increased caudal primary MNs branching. Intravenous injection of Pgk1-K353R into ALS-mice exhibited more preservative in innervated neuromuscular junctions in gastrocnemius muscle and diaphragm, increased grip strength, higher rearing frequency, 1.6-fold greater locomotive distance and longer survival. For example, median survival days for the control, Pgk1 and Pgk1-K353R groups were 131, 137.5 and 148, respectively. Collectively, we found a single-amino-acid mutant Pgk1-K353R that exhibits higher efficacy to ameliorate neurodegeneration in ALS-mice by delaying disease progression compared to that driven by wild-type Pgk1. We suggest this outcome might be due to more electrostatic attraction between ePgk1-K353R and Eno2-D419 region predicted by in silico analysis. Therefore, mutant Pgk1-K353R protein should be considered a promising neuroprotective drug for ALS treatment.}, }
@article {pmid42320854, year = {2026}, author = {Pagliarello, C and Girardelli, CR}, title = {Response to Zhang X et al.'s "Effectiveness and Tolerability of Baricitinib with or without Prior Corticosteroids in Alopecia Areata: A Retrospective Cohort Study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.05.128}, pmid = {42320854}, issn = {1097-6787}, }
@article {pmid42321151, year = {2026}, author = {Jewett, G and Ferber, R and Josephson, CB and Korngut, L and Lee, J}, title = {Comparison of Consumer Smartwatch and Research-Grade Accelerometer-Derived Step Counts in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70323}, pmid = {42321151}, issn = {1097-4598}, support = {//ALS Canada/ ; }, abstract = {INTRODUCTION/AIMS: Objective, scalable measures of function are needed in amyotrophic lateral sclerosis (ALS). Research-grade accelerometers are promising but may be difficult to deploy for prolonged remote monitoring, whereas consumer smartwatches offer a practical alternative. We evaluated the feasibility of long-term smartwatch monitoring in ALS and compared smartwatch- and accelerometer-derived daily step counts.<br><br>METHODS: In this single-centre prospective observational study, participants wore a Fitbit Sense (smartwatch) on the wrist longitudinally and an ActiGraph GT9X Link (accelerometer) on the opposite wrist during clinic-aligned assessment periods. Device comparison was restricted to concurrent valid days (&#x2265;&#x2009;10&#x2009;h wear) and included paired comparison of mean daily step counts, Pearson correlation, Bland-Altman analysis, and proportional bias assessment.<br><br>RESULTS: Forty participants were enrolled and 39 contributed data across 8093 smartwatch and 915 accelerometer days. Step count comparison included 503 concurrent valid days from 34 participants. Mean daily step counts were 3480 (SD 4365) for smartwatch and 4066 (SD 4797) for accelerometer (p&#x2009;<&#x2009;0.0001), with strong correlation (r&#x2009;=&#x2009;0.91, p&#x2009;<&#x2009;0.0001). Mean bias was -586 steps for smartwatch, with 95% limits of agreement from -4193 to 3021. Among participants with &#x2265;&#x2009;6&#x2009;months of concurrent data, devices showed similar decline over time (interaction p&#x2009;=&#x2009;0.76).<br><br>DISCUSSION: Long-term remote monitoring using a smartwatch was feasible in ALS. Smartwatch-derived step counts were strongly correlated with accelerometer-derived estimates but were systematically lower and showed wide day-level limits of agreement. Smartwatch-derived step counts may be useful for group-level analyses and longitudinal monitoring, though device-specific bias should be considered in interpretation.}, }
@article {pmid42322032, year = {2026}, author = {de Gea Neves, M and Unger, M and Siesler, HW}, title = {EXPRESS: Monitoring a Polyurethane Synthesis by Fiber-Coupled Attenuated Total Reflection Fourier Transform Infrared Spectroscopy and Multivariate Curve Resolution-Alternating Least Squares.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028261464644}, doi = {10.1177/00037028261464644}, pmid = {42322032}, issn = {1943-3530}, abstract = {The step-growth polymerization of 1,4-butanediol with 4,4'-diphenylmethanediisocyanate (MDI) was monitored in situ by fiber-coupled attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy between 40 and 70 °C. In contrast to previous kinetic and two-dimensional correlation spectroscopy (2D-COS) studies of this system, the present work applies multivariate curve resolution alternating least squares (MCR-ALS) to temperature-dependent spectral data. The method enables decomposition of overlapping urethane-related bands and extraction of concentration profiles for chemically and physically distinct species, including dissolved and precipitated polymer phases. The MCR-ALS results are consistent with previously reported kinetic trends while providing additional quantitative insight into transient species and phase evolution. These findings demonstrate the added value of multivariate analysis for the concise interpretation of complex polymerization processes.}, }
@article {pmid42322392, year = {2026}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Moreschi, A and Frisco, F and Dalla Bella, E and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Cappa, SF and Calvo, A and Strong, MJ and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {ECAS-Based Neuropsychological Phenotyping in Amyotrophic Lateral Sclerosis: A Retrospective Study Comparing Different Algorithms.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {42322392}, issn = {2193-8253}, support = {TRANS-ALS//Agenzia Nazionale di Valutazione del Sistema Universitario e della Ricerca/ ; grant number: 2015-0023//Agenzia Nazionale di Valutazione del Sistema Universitario e della Ricerca/ ; POR FESR 2014-2020//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; grant number: 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; grant: RF-2016-02362405//Ricerca Sanitaria Finalizzata - Ministero della Salute/ ; grant: 2017SNW5MB//"Progetti di Rilevante Interesse Nazionale" programme of the Ministry of Education, University and Research/ ; grant: RF H2020-SC1-DTH2020-1//Horizon 2020/ ; grant agreement ID: 101017598//Horizon 2020/ ; }, abstract = {INTRODUCTION: This study aimed to compare different algorithms based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to classify patients with amyotrophic lateral sclerosis (ALS) according to their neuropsychological phenotype to identify possible discrepancies among these systems.<br><br>METHODS: ECAS-Cognitive and -Carer Interview (ECAS-C/-CI) scores of N&#x2009;=&#x2009;901 patients with ALS without a formal diagnosis of dementia were retrospectively retrieved. Patients were classified, pursuant to Strong et al.'s criteria, as cognitively and behaviourally normal (ALScbn), cognitively and/or behaviourally impaired (ALSci/bi/cbi), or Possible ALS-FTD, according the following ECAS-based algorithms: (1) Abrahams', solely addressing ECAS-C total and ALS-Specific subtotals; (2) Poletti et al.'s, addressing single task-level ECAS-C scores; (3) "Subscale", addressing ECAS-C subscales (i.e., Language, Executive, Fluency, Memory and Visuospatial). All algorithms relied on single-item-level ECAS-CI scores for behavioural classifications.<br><br>RESULTS: Whilst agreement rates among these classifications were moderate to high (84-86%; Cohen's k&#x2009;=&#x2009;0.78-0.81), and some discrepancies emerged: (1) "ALScbn-to-ALSci" and "ALSci-to-ALScbn" re-classifications occurred across the three comparisons, ranging from&#x2009;~&#x2009;11% to&#x2009;~&#x2009;24%; (2) the most classificatory disagreements (~&#x2009;43%) occurred for the ALScbi category when comparing single task-level (Poletti) to total-level (Abrahams) algorithms, with patients being re-classified as either ALSbi or Possible ALS-FTD; (3)&#x2009;~&#x2009;24% of Abraham's Possible ALS-FTD cases were re-classified as either ALScbi or ALSbi by the Subscale approach.<br><br>CONCLUSIONS: Different ECAS-based algorithms for deriving Strong's phenotypes might yield slight discrepancies that could under- or overestimate a given classification.}, }
@article {pmid42316486, year = {2026}, author = {Chan, Y and Creer, S and Mere, J and Griffiths, AW and Wright, C and Hobson, EV and McDermott, CJ and Mayberry, EJ}, title = {The Emotional Experiences of Healthcare Professionals Working in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70309}, pmid = {42316486}, issn = {1097-4598}, support = {943-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Healthcare professionals (HCPs) working with people living with amyotrophic lateral sclerosis (ALS) are often exposed to emotive circumstances including end of life care, trauma, loss, and death. Existing reviews have explored the emotional experiences of people living with ALS and their carers but have largely ignored healthcare staff and the impact of this work on them. This systematic review of qualitative research aims to explore the emotional experiences of and impact on HCPs working with people living with ALS using thematic synthesis (PROSPERO reference: CRD42025631749). Electronic databases were searched for journal articles and gray literature (Medline, Scopus, PsycINFO, Google Scholar, King's Fund Library Database, ProQuest Dissertations, Theses Global) for qualitative or mixed-methods studies exploring the emotional impact on HCPs working in ALS. Twelve studies were included, critically appraised, and analyzed. Four themes were identified. The emotional intensity due to the nature of ALS created challenges for HCPs, while they were also faced with absorbing the emotions of others. HCPs learned to balance their emotional involvement, and HCPs also described positive experiences and coping mechanisms. HCPs working in ALS experience multi-faceted emotional challenges, and they do describe positive emotional experiences within their roles. However, HCPs describe having few coping mechanisms and limited formal support systems in place to process the intense emotions or to guide their emotional involvement. The lack of support for staff may ultimately negatively affect patient care. There is an unmet demand for debriefing, supervision, and further training on how to deal with intense, distressing emotions.}, }
@article {pmid42316902, year = {2026}, author = {, }, title = {The ALS Home Health and Durable Medical Equipment Medical Standard Expert Consensus Guideline.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70290}, pmid = {42316902}, issn = {1097-4598}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with escalating disability and complex care needs. Although most individuals with ALS reside at home, existing US guidelines primarily address clinic-based care and provide limited direction on medically necessary home health services and durable medical equipment (DME). The objective of this task force was to develop expert consensus guidance defining minimum medical standards for home health services and DME for individuals with ALS, with the goal of improving patient outcomes, safety, and quality of life. This guideline was developed by a multidisciplinary task force convened by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). The process incorporated a scoping literature review, stakeholder engagement (patients, caregivers, and advocacy groups), and iterative expert consensus. Recommendations were informed by clinical expertise, patient-centered priorities, and existing policy frameworks. This guideline outlines stage-responsive home healthcare recommendations spanning nursing, home health aides, physical and occupational therapy, speech-language pathology, respiratory therapy, nutritional support, and social work. It emphasizes proactive, anticipatory care aligned with the predictable trajectory of ALS, rather than being reactive based on functional decline. The document defines medically necessary DME across domains, including mobility, communication, respiratory support, and activities of daily living, advocating for timely access independent of restrictive payer criteria. Key principles include coordinated interdisciplinary care, continuous reassessment, caregiver support, and integration of palliative care. These recommendations establish a foundational standard for ALS home-based care in the United States. Adoption may reduce delays, prevent complications, and support sustained independence and dignity for individuals with ALS.}, }
@article {pmid42317073, year = {2026}, author = {Stark, T and Müller, S}, title = {PML as a neuroprotective guardian: Leveraging nuclear protein quality control to mitigate neurotoxicity of an ALS-associated NEK1 variant.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70630}, pmid = {42317073}, issn = {1742-4658}, support = {ID 514894665//Deutsche Forschungsgemeinschaft/ ; ID-494535244//Deutsche Forschungsgemeinschaft/ ; ID-465470262//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Insoluble protein aggregates are a hallmark of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The ubiquitin-proteasome system (UPS) serves as a neuroprotective quality control mechanism that clears aggregates. PML nuclear bodies (NBs) were proposed to serve as hubs for SUMO-primed ubiquitylation and degradation of misfolded proteins. Georgiadou et al. provide evidence that an ALS-linked NEK1 truncation mutant is recruited to PML NBs, where it likely undergoes SUMOylation and ubiquitylation. In mice, PML loss exacerbates ALS-like symptoms, while induced PML expression delays disease onset. These findings establish PML as a key regulator of proteostasis and highlight PML induction as a potential therapeutic strategy for ALS and related proteinopathies.}, }
@article {pmid42316301, year = {2026}, author = {Russell, KA and Shahrabi, AA and Akerman, SC and Byrne, MD and Rothstein, JD and Trotti, D and Jensen, BK and Haeusler, AR}, title = {Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02341-8}, pmid = {42316301}, issn = {2051-5960}, support = {R01NS109150/NS/NINDS NIH HHS/United States ; RF1NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, fewer motor neurons, glial activation, sparse phosphorylated TDP-43 pathology, and increased cryptic TDP-43 splicing. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.}, }
@article {pmid42310801, year = {2026}, author = {Fernandes, JB and Almeida, AS and Magsi, F and Maia, AC and Fernandes, S}, title = {Motivations and barriers to engaging in peer review: a qualitative study.}, journal = {Research integrity and peer review}, volume = {11}, number = {1}, pages = {}, pmid = {42310801}, issn = {2058-8615}, abstract = {BACKGROUND: Peer review is a central mechanism of scientific communication. However, despite its critical role in safeguarding research quality and integrity, there is limited evidence on how reviewers themselves perceive the factors that motivate or hinder their engagement. This study explored reviewers' perceptions of the motivations and barriers shaping participation in peer review.<br><br>METHODS: A qualitative, exploratory-descriptive design was adopted. Semi-structured interviews were conducted between June and September 2025 with participants holding an academic title in health sciences who had completed at least one peer review for a scientific journal. Participants were recruited through purposive sampling. Interviews were audio-recorded, transcribed verbatim, and analysed inductively using thematic analysis following Braun et al.'s framework. Data collection and analysis proceeded iteratively until thematic saturation was reached.<br><br>RESULTS: Twenty-seven academics from seven health science disciplines participated in the study. Participants were predominantly female (63%), with similar proportions holding doctoral (52%) and master's degrees (48%), and peer-review activity in the previous 12 months ranging from 1 to more than 10 reviews. Findings were organised into two domains, motivations and barriers, comprising ten themes. Motivations included contribution to science, scientific development, career development, personal satisfaction, and financial incentives. Barriers included high workload, lack of recognition and incentives, perceived competence, research integrity, and editorial shortcomings.<br><br>CONCLUSION: Reviewer engagement appears to be a negotiated process in which academics weigh motivations against barriers when deciding whether to participate in peer review. These trade-offs shape decisions to accept or decline review invitations. Strengthening recognition, transparency, and editorial support may help sustain reviewer participation in the health sciences.}, }
@article {pmid42311066, year = {2026}, author = {Dubbioso, R and Pappatà, S}, title = {Amyotrophic lateral sclerosis as a network disease: from metabolic decline to network failure.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag211}, pmid = {42311066}, issn = {1460-2156}, }
@article {pmid42311422, year = {2026}, author = {Fayez, SM}, title = {Nanomedicine in 2026: Illustrative Quantitative Analyses of EPR Heterogeneity, Clinical Trial Attrition, and Emerging Horizons for Active Nanotherapeutics.}, journal = {International journal of nanomedicine}, volume = {21}, number = {}, pages = {618407}, pmid = {42311422}, issn = {1178-2013}, mesh = {Humans ; *Nanomedicine/trends/methods ; Animals ; Clinical Trials as Topic ; Nanoparticles/chemistry/therapeutic use ; Neoplasms ; Mice ; Immunotherapy ; }, abstract = {2026 is a turning point for nanomedicine, marking the field's transition from decades of preclinical promise toward tangible clinical impact. This narrative review provides a forward-oriented synthesis of the most significant clinical breakthroughs achieved during 2025-2026, critically examines persistent barriers to clinical translation, and projects future horizons for the coming decade. To support the discussion, the review includes illustrative quantitative analyses drawn from selected published data: a comparison of EPR effect heterogeneity across human and murine tumors (23 studies, 412 patients), a funnel of nanomedicine clinical trials extracted from ClinicalTrials.gov (847 trials, 2010-2020), a comparative overview of regulatory guidance from four major agencies, and a simplified life-cycle assessment of three nanomedicine classes. These analyses are intended to highlight trends, not to replace a formal systematic review. We identify four important clinical advances: first Phase II data for hafnium oxide nanoparticle radioenhancers in inoperable lung cancer; logic-gated STING-agonistic nanoparticles for metastasis-specific immunotherapy; ultrasmall silica nanoparticles that remodel suppressive tumor microenvironments independent of a drug cargo; and CNM-Au8 gold nanocrystals advancing toward regulatory submission for amyotrophic lateral sclerosis. Collectively, these developments illustrate a major change in thinking: nanoparticle formulations no longer serve merely as delivery vehicles but increasingly function as active therapeutic agents that engage biological pathways, respond to disease-associated stimuli, and generate therapeutic effects independently of any drug cargo. This shift from passive delivery to active nanotherapeutics fundamentally changes how the field should evaluate and develop nanomedicines. Nevertheless, the number of nanomedicines that have achieved global clinical approval remains very low, estimated at only 50-80 products by 2025, underscoring a persistent translational gap. We analyze principal obstacles to clinical success, including the limited predictive validity of the enhanced permeability and retention (EPR) effect in humans, batch-to-batch manufacturing variability, safety concerns arising from bio-corona formation and organ accumulation, and the absence of harmonized regulatory frameworks. Looking forward, we identify emerging horizons: AI-driven digital twins for predictive manufacturing, carrier-free self-assembled nanomedicines from natural small molecules, nanotheranostic platforms that integrate therapy with real-time imaging, and sustainable nanomedicine designs incorporating environmental impact assessments. By bridging clinical reality with future potential, this review aims to inform researchers, clinicians, and regulatory stakeholders navigating the rapidly evolving landscape of nanomedicine.}, }
@article {pmid42311464, year = {2026}, author = {Li, P and Gao, Y and Liu, W}, title = {GLP-1 Receptor Agonists in Neurological Disorders: From Mechanisms to Clinical Translation.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {613616}, pmid = {42311464}, issn = {1177-8881}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Glucagon-Like Peptide-1 Receptor/metabolism ; }, abstract = {Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, have been used for years to treat type 2 diabetes and obesity. More recently, it has become clear that these receptors are widely distributed throughout the central nervous system (CNS), which has raised the possibility of repurposing these drugs for neurological disorders. In this review we go through the evidence across a range of neurological conditions, discuss the main mechanisms thought to explain their neuroprotective effects, and point out the hurdles that still need to be cleared before they can be used in the clinic. Preclinical work has been fairly consistent. These drugs activate the cAMP/PKA/CREB pathway to boost BDNF expression. They also turn on the PI3K/Akt pathway, which reins in GSK-3β and cuts down tau hyperphosphorylation. At the same time, they put the brakes on NLRP3 inflammasome activation in microglia and get AMPK dependent mitochondrial biogenesis and autophagy going. In animal models of Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, intracerebral hemorrhage (ICH), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression, epilepsy, and spinal cord injury (SCI), these cellular changes add up to less protein aggregation, less neuron loss, and better functional outcomes. Clinical data are harder to interpret. Some trials have shown modest improvements in cognition or motor function, but others have found no meaningful effect on disease progression. One thing that does not get enough attention is that different GLP-1 receptor agonists cross the blood-brain barrier at widely varying rates, and these differences could well explain why trial results have been so mixed. Looking ahead, getting these drugs into the clinic will depend on choosing the ones that actually reach the CNS, developing biomarkers that can predict who will respond, and designing trials that take disease heterogeneity into account. Seen this way, this review offers a practical framework for turning mechanistic insights into real patient benefit.}, }
@article {pmid42311809, year = {2026}, author = {Sakakibara, R and Ozono, H}, title = {Affective Forecasting and Memory Biases during the Tokyo and Beijing Olympics.}, journal = {Affective science}, volume = {7}, number = {2}, pages = {273-281}, pmid = {42311809}, issn = {2662-205X}, abstract = {UNLABELLED: This study examined how people predicted and recalled their emotional experiences during the Tokyo and Beijing Olympics, which were held during the COVID-19 pandemic. Building on the theoretical framework proposed by Buechel et al. (2017), which explains how people are likely to overestimate or underestimate their future emotions depending on outcome specifications (e.g., psychological distance, magnitude, and duration), we extended this approach in our study. We investigated whether this model could be applied to real-world public events. Using longitudinal online surveys conducted in Japan before, during, and after the two Olympics, we analyzed the responses of 2,059 participants in the Tokyo Games and 2,595 participants in the Beijing Games. Consistent with Buechel et al.'s framework, the results showed that positive emotions experienced during the Olympics were generally underestimated beforehand, especially among individuals who initially opposed the events. Furthermore, the recollection of emotional experiences was influenced by contextual factors such as the perceived infection situation at the time of recall. These findings contribute to a deeper understanding of affective forecasting and memory biases in the context of real-world events, and demonstrate the applicability of existing theoretical models to large-scale societal situations outside the laboratory.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42761-026-00361-0.}, }
@article {pmid42312499, year = {2026}, author = {Lavigne-Robichaud, M and Landsbergis, P and Brisson, C and Sembajwe, G and Gilbert-Ouimet, M and Li, J and Milot, A and Trudel, X}, title = {Job strain and ischemic heart disease: the balance of methodological bias and implications for prevention. Response to: Bonde JP et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology.}, journal = {Scandinavian journal of work, environment &amp; health}, volume = {}, number = {}, pages = {}, doi = {10.5271/sjweh.4315}, pmid = {42312499}, issn = {1795-990X}, abstract = {We read with interest Bonde et al's (1) recent review. We agree with their premise: strengthening causal inference is an important objective for occupational epidemiology. However, we believe the conclusion that "at most, any true effect [of job strain on ischemic heart disease (IHD)] appears to be small" is not supported by a valid appraisal of the available evidence. The pooled relative risk estimate (RRE) of 1.14 is most likely underestimated, as common limitations in the available literature tend to bias results toward the null. The authors acknowledge underestimation sources: nondifferential exposure misclassification, overadjustment for cardiometabolic risk factors, and healthy-worker survivor selection (1). Additional sources of underestimation are not discussed. Dichotomizing exposure by combining active and passive exposures into a single "non-high-strain" category may attenuate risk estimates by increasing heterogeneity in the reference group. Indeed, workers with passive exposure may also be at increased IHD risk (2). The pooled RRE may further be attenuated by sex: women develop IHD at older ages partly due to pre-menopausal estrogen cardioprotection, thus working-age follow-up captures fewer events, reducing pooled estimates and precision (3). Sources of overestimation raised also warrant closer scrutiny. For instance, lower estimates in job-exposure matrix (JEM) studies are interpreted as evidence of upward bias in self-reported studies. However, even when exposure values are imputed within subgroups defined by sex and age, JEM do not fully capture individual-level variability in exposure within occupational categories (4). The resulting non-differential misclassification likely attenuates estimates, a limitation the authors acknowledge but do not take into account in their conclusion. The supporting reference for overestimation relies on a 4-item measure of perceived stress (5), limiting its relevance to job strain. An additional source of overestimation is negative affectivity, in which adverse health perceptions inflate individual-level exposure reports. However, this mechanism is not supported in prospective studies with control for anger, hostility, and cynicism (6, 7). Finally, the authors raise concerns about a health-reporting bias: workers with prodromal IHD symptoms may over-report perceived job strain, inflating observed associations. In prospective studies excluding early incident IHD events, associations were not attenuated and, if anything, marginally strengthened (6, 8), providing no support for reverse causation as a source of overestimation. More broadly, methodological characteristics are presented as isolated binary indicators rather than as interdependent dimensions. This hinders the overall appraisal of study quality. These methodological considerations have implications for burden estimation. There has been considerable debate about whether the population attributable fraction (PAF) of 3.4% that the IPD-Work Consortium reported for job strain and IHD (8) was an underestimate when accounting for exposure misclassification, alternative referent group definitions, and other sources of attenuation identified in the literature (9, 10). A subsequent prospective cohort study designed to address several of the sources of underestimation discussed here estimated that 18.2% of incident IHD were attributable to job strain exposure (11). In sum, while we share Bonde et al's emphasis on causal inference, the balance of methodological bias in this literature is more plausibly downward than unpredictable. Given the substantial burden of IHD, debates about the precise magnitude should not delay the development and evaluation of workplace interventions to reduce job strain and improve cardiovascular health. References 1. Bonde JP, Skaaby S, Flachs EM, Dollard M, Keyes K, Rosengren A et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology. Scand J Work Environ Health 2026 Apr. [Epub ahead of print]. https://doi.org/10.5271/sjweh.4299. 2. Xu S, Huang Y, Xiao J, Zhu W, Wang L, Tang H et al. The association between job strain and coronary heart disease: a meta-analysis of prospective cohort studies. Ann Med 2015;47(6):512-8. https://doi.org/10.3109/07853890.2015.1075658. 3. Zahiriharsini A, Gilbert-Ouimet M, Hervieux V, Trudel X, Matteau L, Jalbert L et al. Incorporating sex and gender considerations in research on psychosocial work exposures and cardiovascular diseases: A systematic review of 55 prospective studies. Neurosci Biobehav Rev 2024 Dec;167:105916. https://doi.org/10.1016/j.neubiorev.2024.105916. 4. Schwartz JE, Pieper CF, Karasek RA. A procedure for linking psychosocial job characteristics data to health surveys. Am J Public Health 1988 Aug;78(8):904-9. https://doi.org/10.2105/AJPH.78.8.904. 5. Metcalfe C, Davey Smith G, Macleod J, Heslop P, Hart C. Self-reported stress and subsequent hospital admissions as a result of hypertension, varicose veins and haemorrhoids. J Public Health Med 2003 Mar;25(1):62-8. https://doi.org/10.1093/pubmed/fdg013. 6. Lavigne-Robichaud M, Trudel X, Talbot D, Milot A, Gilbert-Ouimet M, Vézina M et al. Psychosocial stressors at work and coronary heart disease risk in men and women: 18-year prospective cohort study of combined exposures. Circ Cardiovasc Qual Outcomes 2023 Oct;16(10):e009700. https://doi.org/10.1161/CIRCOUTCOMES.122.009700. 7. Tiwa Diffo E, Lavigne-Robichaud M, Milot A, Brisson C, Gilbert-Ouimet M, Vézina M et al. Psychosocial stressors at work and atrial fibrillation incidence: An 18-year prospective study. J Am Heart Assoc 2024 Aug;13(16):e032414. https://doi.org/10.1161/JAHA.123.032414. 8. Kivimäki M, Nyberg ST, Batty GD, Fransson EI, Heikkilä K, Alfredsson L et al.; IPD-Work Consortium. Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data. Lancet 2012 Oct;380(9852):1491-7. https://doi.org/10.1016/S0140-6736(12)60994-5. 9. Choi BK, Schnall P, Landsbergis P, Dobson M, Ko S, Gómez-Ortiz V et al. Recommendations for individual participant data meta-analyses on work stressors and health outcomes: comments on IPD-Work Consortium papers. Scand J Work Environ Health 2015 May;41(3):299-311. https://doi.org/10.5271/sjweh.3484. 10. Kivimäki M, Singh-Manoux A, Virtanen M, Ferrie JE, Batty GD, Rugulies R; IPD-Work consortium. IPD-Work consortium: pre-defined meta-analyses of individual-participant data strengthen evidence base for a link between psychosocial factors and health. Scand J Work Environ Health 2015 May;41(3):312-21. https://doi.org/10.5271/sjweh.3485. 11. Lavigne-Robichaud M, Trudel X, Talbot D, Milot A, Pena-Gralle AP, Mésidor M et al. Coronary heart disease attributable to psychosocial stressors at work. JACC Adv 2025 Oct;4(10 Pt 2):102160. https://doi.org/10.1016/j.jacadv.2025.102160.}, }
@article {pmid42312942, year = {2026}, author = {Zinn, KM and McLaren, MW and Imai, MT and Jayaram, MM and Rothstein, JD and Elrick, MJ}, title = {Enterovirus D68 2A protease causes nuclear pore complex dysfunction and independently contributes to motor neuron toxicity.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42312942}, issn = {2050-084X}, support = {5K12NS098482/NS/NINDS NIH HHS/United States ; K08NS124989/NS/NINDS NIH HHS/United States ; R01NS143998/NS/NINDS NIH HHS/United States ; P50HD103538//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {*Motor Neurons/virology/pathology ; Humans ; *Enterovirus D, Human/enzymology ; *Nuclear Pore/metabolism ; *Viral Proteins/metabolism ; Nuclear Pore Complex Proteins/metabolism ; *Cysteine Endopeptidases/metabolism ; Myelitis/virology/pathology ; Neuromuscular Diseases ; Central Nervous System Viral Diseases ; }, abstract = {Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death; however, the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during infection. We therefore sought to determine the impact of EV-D68 proteases on NPC composition and function. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121, by 2A[pro]. Using reporter systems, we demonstrate that 2A[pro] inhibits nuclear transport of protein cargoes and disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. Independently, we show 2A[pro] is toxic to induced pluripotent stem cell-derived motor neurons by demonstrating a rescue of toxicity with the 2A[pro] inhibitor telaprevir at concentrations insufficient to inhibit viral replication. These findings expand our understanding of EV-D68 neuropathogenesis and provide a rationale for studying the NPC or 2A[pro] as therapeutic targets in AFM.}, }
@article {pmid42313222, year = {2026}, author = {Deng, P and Deng, W and Wang, L and Ye, W and Li, S}, title = {Exercise-Driven NRF2 Activation as a Systemic Neuroprotective Strategy: Integrating Redox Biology, Muscle-Brain Crosstalk, and Therapeutic Targeting in Neurodegeneration.}, journal = {Biochemical genetics}, volume = {}, number = {}, pages = {}, pmid = {42313222}, issn = {1573-4927}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, are characterized by progressive neuronal dysfunction and loss. Recent evidence highlights the importance of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of cellular defense mechanisms, in maintaining neuronal health and function. A narrative literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant experimental, clinical, and review studies on NRF2 signaling, physical exercise, oxidative stress, muscle-brain crosstalk, and neurodegenerative diseases. Keywords included "NRF2", "Nrf2/Keap1/ARE", "physical exercise", "exercise-induced oxidative stress", "myokines", "exerkines", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", and "amyotrophic lateral sclerosis". NRF2 modulates the expression of a variety of antioxidant and cytoprotective genes, contributing to the protection of neurons against oxidative stress, inflammation, and protein aggregation, processes central to the pathogenesis of neurodegenerative diseases. Additionally, physical activity has been identified as a powerful modulator of NRF2 activation, with exercise offering neuroprotective effects through the induction of NRF2-mediated pathways. This review explores the interplay between NRF2 activation and physical exercise in the context of neurodegenerative diseases, detailing the molecular mechanisms by which exercise influences NRF2 activity to combat cellular damage and enhance neuroprotection. We discuss the therapeutic potential of combining exercise regimens with NRF2-targeted therapies, highlighting the promise of this dual approach in slowing disease progression, improving cognitive function, and enhancing quality of life in affected individuals. Furthermore, we examine the challenges and future directions for clinical implementation, including optimal exercise protocols and the development of NRF2-based pharmacological interventions. This review underscores the importance of NRF2 as a central mediator of neuroprotection and the therapeutic promise of physical activity in the management of neurodegenerative diseases.}, }
@article {pmid42313307, year = {2026}, author = {Saini, K and Dhiman, P}, title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42313307}, issn = {1573-4978}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; }, abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.}, }
@article {pmid42313873, year = {2026}, author = {Rohan, H and Bochner, AF and Brown, L and Ortiz, EM and McClelland, A}, title = {COVID-19 alert level systems-Lessons learnt for future public health emergencies: A qualitative study.}, journal = {PloS one}, volume = {21}, number = {6}, pages = {e0351209}, doi = {10.1371/journal.pone.0351209}, pmid = {42313873}, issn = {1932-6203}, mesh = {Humans ; *COVID-19/epidemiology/prevention &amp; control ; *Public Health ; Pandemics/prevention &amp; control ; Qualitative Research ; SARS-CoV-2/isolation &amp; purification ; Emergencies ; Public Health Infrastructure ; }, abstract = {BACKGROUND: During the COVID-19 pandemic, Alert Level Systems (ALS) were widely implemented as public health tools to communicate risk levels and recommend public health and social measures (PHSMs). However, the efficacy of ALS in mitigating disease spread and their impact on public health responses have not been systematically evaluated. This study aims to assess perceptions of ALS implementation across diverse jurisdictions and derive lessons for future public health emergencies.<br><br>METHODS: Key informant interviews were conducted remotely between December 2023 and March 2024 with senior stakeholders who were involved in ALS development and implementation during the COVID-19 pandemic, from eight jurisdictions: California (US), New Zealand, the Philippines, Rio Grande do Sul (Brazil), Singapore, South Africa, the United Kingdom, and the United States. A thematic analysis approach was applied to synthesize insights, focusing on the strengths, challenges, and key lessons from ALS implementation.<br><br>RESULTS: ALS were generally perceived by key informants as useful tools for communicating risk and supporting adherence to PHSMs due to their simplicity and transparency. However, significant challenges were identified, including difficulties in accessing reliable data, lack of clear ALS objectives, and insufficient community engagement. The study highlights the need for ALS to integrate social, economic, and epidemiological data in decision-making processes. Jurisdictions also reported that pre-existing ALS governance structures and stronger community feedback mechanisms could have improved implementation outcomes.<br><br>CONCLUSIONS: ALS can serve as valuable public health communication tools in future epidemics, but their success depends on clear objectives, evidence-based PHSMs, and robust community engagement. Pre-emptive development of ALS structures and governance will improve preparedness for future epidemics. Transparent and flexible decision-making processes will be crucial for sustaining public trust.}, }
@article {pmid42314654, year = {2026}, author = {Yang, R and Fang, Y}, title = {S-acylation of TDP-43: PALMing down aggregation?.}, journal = {Cell chemical biology}, volume = {33}, number = {6}, pages = {742-744}, doi = {10.1016/j.chembiol.2026.05.009}, pmid = {42314654}, issn = {2451-9448}, mesh = {Acylation ; Humans ; *DNA-Binding Proteins/metabolism/chemistry ; Poly Adenosine Diphosphate Ribose/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; }, abstract = {S-acylation is well known for regulating protein stability and trafficking. In a recent issue of Molecular Cell, Xu et al.[1] reveal a distinct, aggregation-suppressing function of this posttranslational lipid modification: S-acylation of the RNA-binding protein TDP-43 antagonizes poly(ADP-ribose)-driven condensation. Moreover, reduced S-acylation levels are linked to ALS pathogenesis.}, }
@article {pmid42314891, year = {2026}, author = {Yadav, P and Malik, I and Joshi, H}, title = {Folding pathways and force-induced unfolding of neurodegeneration associated GGGGCC microsatellite repeat RNA revealed by molecular simulations.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {153101}, doi = {10.1016/j.ijbiomac.2026.153101}, pmid = {42314891}, issn = {1879-0003}, abstract = {An intronic G4C2 hexanucleotide repeat expansion in the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). G4C2 RNA itself directly contributes to disease mechanisms and has emerged as a potential target for small molecules, anti-sense oligonucleotides (ASOs), and CRISPR-based therapeutics. Hence, understanding the folding/unfolding and structural polymorphism is essential for G4C2 RNA-targeting therapies. Here, using equilibrium all-atom molecular dynamics (MD) simulations, we explored potential intermediates metastable conformations of the G4C2 RNA repeats and investigated the effect of repeat length on folding. G4C2 RNA undergoes an ensemble of intermediate metastable states resembling hairpin, knot, and a G-quadruplex (GQ) like structures. Enhanced torsional flexibility and conformational heterogeneity was observed with increasing repeat length. Next, using a crystallized G4C2 RNA structure in GQ conformation, we performed equilibrium MD simulations to reveal its thermodynamic stability. Steered molecular dynamics (SMD) simulations with a reduced model of G4C2 GQ uncover two distinct unfolding mechanisms along the chosen reaction coordinates: strand slippage and unzipping. Overall, our findings provide molecular-level insights into the folding and force-induced unfolding dynamics of G4C2 repeat RNA GQ and set a platform for future studies on small-molecule targeting of ALS/FTD-associated G4C2 RNA.}, }
@article {pmid42315356, year = {2026}, author = {Henders, AK and Ziser, L and Garton, FC and Adams, L and Ernst, K and Furlong, S and Heads, JA and Heggie, S and Krasniqi, R and Bhadravathi Lokeshappa, M and Mazumder, S and McNamara, E and MacShane, A and Mekhael, L and Nunn, L and Orden, B and Ryder, J and Thorpe, K and Toubia, M and Wallace, LM and Wickremeratne, D and Windebank, E and Benyamin, B and Ngo, S and Nicholson, G and Pamphlett, R and Steyn, FJ and Visscher, PM and Willams, KL and Henderson, R and Kiernan, MC and Laing, N and Mathers, S and McCombe, PA and Needham, M and Rowe, D and Schultz, D and Talman, P and Vucic, S and Blair, IP and McRae, AF and Wray, NR}, title = {Strategic Amyotrophic Lateral Sclerosis Australia-Systems Genomics Consortium (SALSA-SGC): cohort profile.}, journal = {BMJ open}, volume = {16}, number = {6}, pages = {e110906}, doi = {10.1136/bmjopen-2025-110906}, pmid = {42315356}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Australia ; *Genomics ; Female ; Male ; Middle Aged ; Aged ; Polymorphism, Single Nucleotide ; Adult ; Cohort Studies ; C9orf72 Protein/genetics ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative motor neuron disease (MND) with heterogeneity in disease onset, progression and treatment response. The Strategic ALS Australia-Systems Genomics Consortium (SALSA-SGC) was established in recognition of the need for large data sets of clinical data matched with biological samples to enable and foster ALS research and better understanding of aetiology and biological mechanisms. SALSA-SGC brought together the major Australian MND clinics to set up sustainable infrastructure that could facilitate long-term human ALS research and clinical trials nationally and internationally.<br><br>PARTICIPANTS: Between April 2016 and December 2024, SALSA-SGC recruited 1813 participants, including 1386 ALS/MND cases, 388 controls and 39 others (asymptomatic relatives and ALS mimics). Clinical data and biospecimens are available for 1333 and 1189 ALS cases, respectively, with longitudinal data spanning 4442 total clinic visits and 3201 samples. An open-access online data explorer showcases collected datasets.<br><br>FINDINGS TO DATE: Detailed clinical and questionnaire data allow an in-depth description of the cohort, informing clinical and health policy research. Screening for known ALS large-effect risk variants identified 125 mutation carriers (11.5% from N=1059), including 70 with C9orf72 expansions. Single Nucleotide Polymorphism (SNP)-array data (N=1088 cases; N=244 controls) have supported multiple published studies. SALSA-SGC resources are actively used by national and international researchers.<br><br>FUTURE PLANS: Ongoing efforts aim to expand recruitment into regional Australia and enhance sample processing for cell-based studies. The SALSA-SGC resource is accessible by researchers under agreements governed by participant consent, human ethics committee guidelines and agreed use of data and samples.}, }
@article {pmid42316173, year = {2026}, author = {Machaku, D and Sunguya, B and Bukusi, E and Waddell, R and Ulrich, CM}, title = {What do Tanzanian Research Ethics Committees prioritise? A quantitative analysis of reviewer comments using Emanuel's framework.}, journal = {BMC medical ethics}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12910-026-01528-x}, pmid = {42316173}, issn = {1472-6939}, support = {Engage Project (D43 TW011809)/TW/FIC NIH HHS/United States ; }, abstract = {BACKGROUND: Research Ethics Committees (RECs) are essential for protecting participants, yet their practical priorities in resource-limited settings remain underexplored. This study assesses how Tanzanian RECs apply Emanuel et al.'s eight-principle ethical framework during protocol review.<br><br>METHODS: A quantitative content analysis was conducted on reviewers' comments from 67 clinical trial protocols submitted between 2021 and 2023 in three Tanzanian RECs. Comments were categorized using a modified ethics framework, and frequencies were calculated to identify patterns.<br><br>RESULTS: RECs demonstrated a dominant focus on protocol structure (28.4% to 43.7%) and scientific validity (7.5% to 23.4%). Principles such as independent review (1.6% to 3.0%) and social value (2.4% to 6.0%) were consistently underemphasized. REC 1 and REC 2 placed greater emphasis on procedural and scientific elements, while REC 3 showed stronger attention to collaborative partnerships. However, REC 3 reviewed only two protocols; its percentages are highly unstable and should be interpreted as illustrative only.<br><br>CONCLUSION: Tanzanian RECs showed selective conformity to Emanuel et al.'s framework, prioritizing procedural and scientific elements over equity-oriented principles. This means they might approve studies that are scientifically sound but ethically inadequate. Recommendations include the implementation of balanced-review templates, enhanced reviewer training, and institutional accountability mechanisms to promote comprehensive ethical oversight.}, }
@article {pmid42303396, year = {2026}, author = {Akers, E and Ameratunga, S and Wilkinson-Meyers, L and Adams, M and Te Ao, B}, title = {Perspectives on the injured child's hospital discharge process and opportunities for improvement: a scoping review protocol.}, journal = {BMJ open}, volume = {16}, number = {6}, pages = {e119916}, doi = {10.1136/bmjopen-2026-119916}, pmid = {42303396}, issn = {2044-6055}, mesh = {Humans ; Scoping Reviews as Topic ; *Patient Discharge/standards ; Child ; *Wounds and Injuries/therapy ; Caregivers/psychology ; Research Design ; }, abstract = {INTRODUCTION: Unintentional injury is a leading cause of hospitalisation and disability in children globally. Families may experience a second crisis of injury after the child's discharge from the hospital, with the traumatic nature of injuries affecting physical and psychosocial recovery. This scoping review aims to summarise the literature on the perspectives of injured children's caregivers and service providers on the hospital discharge process, the challenges and opportunities to improve discharge planning evident from qualitative and interventional studies, and the investigation of inequities in these studies using the Conceptual Framework of Access to healthcare proposed by Levesque et al in 2013.<br><br>METHODS AND ANALYSIS: A scoping review will be conducted involving a search across four databases: CINAHL Plus, Cochrane Library, Embase and Ovid MEDLINE. Empirical literature published in English between 2000 and 2025 will be eligible for inclusion. Included studies will report caregiver or service provider perspectives on current hospital discharge practice for injured children under 18 years old, investigated a priori as a study objective or a posteriori as a finding, or will report the design, implementation or evaluation of interventions intended to improve hospital discharge for injured children. Levesque et al's framework will be used to guide data extraction from the selected studies into predefined data charting forms, informing the review questions. Findings will be presented narratively and in tables to highlight the key characteristics of the studies, the perspectives of caregivers and service providers, the challenges and opportunities to improve hospital discharge, the proposed discharge interventions, the investigation of inequities and the gaps in the literature.<br><br>ETHICS AND DISSEMINATION: The scoping review only uses data in the public domain and does not require ethics approval.}, }
@article {pmid42304808, year = {2026}, author = {Smith, SE and Hughes, B and Miller, TM and Bucelli, RC}, title = {Amyotrophic Lateral Sclerosis Recovery: A New Model System of Care Integrating Neuromuscular Rehabilitation With Clinical Stabilization in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70320}, pmid = {42304808}, issn = {1097-4598}, abstract = {There is currently no consensus on how to define recovery for individuals with amyotrophic lateral sclerosis (ALS). Tofersen treatment for superoxide dismutase-1-related (SOD1) ALS marks a pivot in clinical management: for the first time, clinicians can target disease stabilization and functional recovery in some individuals. This advancement shifts the focus of ALS care toward optimizing functional recovery alongside symptomatic management. However, there are no evidence-based guidelines for prescribing neuromuscular rehabilitation (NMR) to improve functional recovery. Building on our preliminary single-center data of integrated NMR with tofersen, we propose a new ALS Recovery Model System of Care, utilizing a hub-and-spoke infrastructure to combine NMR with novel therapies. This model aims to define ALS recovery, characterize recovery profiles, standardize NMR protocols, and establish a rehabilitation framework adaptable to future disease-stabilizing therapies.}, }
@article {pmid42304913, year = {2026}, author = {Wang, T and Wu, M and Liang, L and Pei, L and Wang, D}, title = {Nicotine Versus Non-Nicotine Constituents in Neurodegenerative Risk: Evidence from Multivariable Mendelian Randomization.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X503957260608154111}, pmid = {42304913}, issn = {1875-6190}, abstract = {BACKGROUND: Nicotine has complex neuropharmacological actions through nicotinic acetylcholine receptors, but its independent role in neurodegenerative diseases remains unclear because tobacco smoke contains many non-nicotine toxicants. This uncertainty limits the interpretation of nicotine- and nAChR-targeted therapeutic strategies, especially as electronic nicotine delivery sys-tems become more common. We used Mendelian randomization to genetically separate nicotine-related effects from smoking-related non-nicotine effects on major neurodegenerative diseases and related prodromal conditions.<br><br>METHODS: We performed univariable two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Summary-level exposure data for cigarettes per day (CPD) and the nicotine metabolite ratio (NMR) were analyzed against individual-level, smoking-stratified outcome data derived from 337,334 UK Biobank participants, to evaluate their respective causal effects across six neurodegenerative outcomes: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tremor, early cognitive impairment (EC), and other neurodegenerative diseases (OND).<br><br>FINDINGS: MVMR analyses revealed that nicotine exposure was a causal risk factor for AD (ever smokers: OR=0.90, 95% CI 0.83-0.98; current smokers: OR=0.76, 95% CI 0.64-0.91). Nicotine exerted a causal protective effect against tremor (OR=1.24, 95% CI 1.03-1.49) and EC (OR=1.14, 95% CI 1.04-1.24) in current smokers. Non-nicotine tobacco constituents were identified as risk factors among former smokers for EC (OR=1.61, 95% CI 1.04-2.50).<br><br>CONCLUSIONS: Exposure to nicotine can increase the risks of AD, while conferring protective effects against tremor and EC. Furthermore, exposure to non-nicotine tobacco constituents acts as a risk factor for the incidence of EC.}, }
@article {pmid42304926, year = {2026}, author = {Mukherjee, S and Ray, SK and Mukherjee, S}, title = {Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273450093260523224914}, pmid = {42304926}, issn = {1996-3181}, abstract = {Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-β deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and müller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.}, }
@article {pmid42305210, year = {2026}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.}, journal = {ACS medicinal chemistry letters}, volume = {17}, number = {6}, pages = {1236-1237}, pmid = {42305210}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.}, }
@article {pmid42307135, year = {2026}, author = {Frycz, S and Więcławski, W and Skotniczny, M and Binder, M}, title = {Brain activity in an end-stage ALS patient suggests the presence of an unresponsive wakefulness syndrome.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2688249}, pmid = {42307135}, issn = {2167-9223}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons. It is widely assumed that cortical structures beyond motor neurons are relatively preserved, and patients in the end-stage ALS are regarded as being in complete locked-in syndrome (cLIS). However, emerging evidence suggests substantial heterogeneity in cognitive functioning among ALS patients, indicating possible extra-motor cortical involvement and impaired levels of consciousness. We report a case study assessing electrophysiological markers and auditory system integrity to evaluate the presence of covert consciousness in end-stage ALS.<br><br>METHODS: The patient was a 42-year-old woman with bulbar-onset, end-stage ALS, a six-year disease duration, and no means of communication. She underwent several EEG-based protocols, including resting-state EEG (RS-EEG), a passive auditory oddball paradigm, and 40&#x2009;Hz auditory steady-state responses (ASSR). Audiological evaluation comprised transient-evoked and distortion-product otoacoustic emissions, as well as auditory brainstem responses (ABR).<br><br>RESULTS: RS-EEG was dominated by prefrontal 1-3&#x2009;Hz activity resembling frontal intermittent rhythmic delta activity. Power spectra were poorly differentiated and consistent with a 1/f profile. No event-related potentials were observed in the oddball paradigm, and no ASSR responses were detected. Audiological testing revealed absent otoacoustic emissions and ABR indicating severe to profound hearing loss.<br><br>CONCLUSIONS: Our findings indicate severe cortical dysfunction and provide no electrophysiological evidence of covert consciousness. The electrophysiological profile closely resembles that observed in unresponsive wakefulness syndrome. This case supports the hypothesis that advanced ALS following cLIS onset may be more appropriately conceptualized as a disorder of consciousness rather than persistent cLIS.}, }
@article {pmid42309005, year = {2026}, author = {Rugarli, EI and Langer, T}, title = {Limiting neurodegeneration in ALS: A phosphatase paves the way.}, journal = {Neuron}, volume = {114}, number = {12}, pages = {2073-2075}, doi = {10.1016/j.neuron.2026.04.030}, pmid = {42309005}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/enzymology/metabolism ; Animals ; Motor Neurons/metabolism ; *Nerve Degeneration ; Mitochondria/metabolism ; *Phosphoric Monoester Hydrolases/metabolism ; }, abstract = {Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.}, }
@article {pmid42309130, year = {2026}, author = {Patel, RJ and Bryson, B and Carlson, T and Demosthenous, A and Jiang, D}, title = {Stability and neurophysiological validity of graph connectivity features for non-stationary motor imagery BCIs.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/ae7ead}, pmid = {42309130}, issn = {1741-2552}, abstract = {Motor imagery (MI) Electroencephalography (EEG) Brain-computer interfaces (BCI) degrade under longitudinal non-stationarity, especially in amyotrophic lateral sclerosis (ALS). Functional connectivity (FC) has been proposed as an alternative feature space, but it remains unclear which FC estimators yield stable, class-informative features across sessions. Approach: Using a multi-session ALS EEG dataset, we computed a broad family of FC estimators per trial to form weighted graphs. We extracted edge weights and node strength features, and quantified (i) feature reproducibility and (ii) LH-RH separability using coefficient of variation and symmetric Kullback-Leibler divergence, respectively. We assessed neurophysiological plausibility via spatial topographies, distance-dependence controls, and evaluated selected feature sets in a strictly temporal cross-session decoding protocol against Common Spatial Patterns, Band Power and Riemannian Methods. Main Results: Coherence-based estimators, particularly magnitude-squared coherence, most consistently produced features exhibiting favourable reproducibility-separability trade-offs across subjects. Node-strength discriminability maps showed lateralised sensorimotor structure consistent with known MI physiology. In temporal generalisation, Magnitude Squared Coherence derived features achieved more consistent test performance than baseline methods for most subjects. Significance: Joint reproducibility-separability profiling provides a principled way to select FC feature spaces for longitudinal MI-BCIs and suggests coherence-based connectivity is a stronger sensor-space candidate under drift.}, }
@article {pmid42309840, year = {2026}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Enhanced spinal motoneuron excitability as a marker of motor neuron dysfunction in primary lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {}, number = {}, pages = {2111978}, doi = {10.1016/j.clinph.2026.2111978}, pmid = {42309840}, issn = {1872-8952}, abstract = {OBJECTIVE: To investigate F-wave parameters as markers of spinal motoneuron excitability in patients with primary lateral sclerosis (PLS).<br><br>METHODS: We prospectively evaluated F-waves and M-waves from the abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. The study included three groups: 27 patients with PLS, 36 with amyotrophic lateral sclerosis with normal right-hand function (ALS-NH), and 30 healthy controls (HC). Recorded parameters included M-wave amplitude, F-wave frequency, latencies, amplitude, and the F/M-waves amplitude ratio. Upper motor neuron (UMN) clinical scores were also assessed. Statistical analysis was performed using One-way ANOVA or Kruskal-Wallis tests for group comparisons, and Spearman's rank test for correlations.<br><br>RESULTS: PLS had a significantly higher UMN score than ALS-NH (p&#xa0;<&#xa0;0.001). F-wave amplitudes were significantly higher in PLS compared to both ALS-NM and HC across all muscles (APB, p&#xa0;=&#xa0;0.01 and p&#xa0;=&#xa0;0.03; FDI, p&#xa0;=&#xa0;0.002 and p&#xa0;<&#xa0;0.001; ADM, p&#xa0;=&#xa0;0.03 and p&#xa0;<&#xa0;0.001, respectively). F/M-waves amplitude ratio was also significantly higher in PLS vs. ALS-NH/HC (APB, p&#xa0;=&#xa0;0.01 and p&#xa0;=&#xa0;0.03; FDI, p&#xa0;<&#xa0;0.001 and p&#xa0;<&#xa0;0.001; ADM, p&#xa0;=&#xa0;0.03 and p&#xa0;=&#xa0;0.001, respectively). No significant differences were found between ALS-NM and HC for these parameters (p&#xa0;>&#xa0;0.05). M-wave amplitudes and other F-wave parameters remained comparable across all groups (p&#xa0;>&#xa0;0.05). No correlation was found between F-wave amplitude and UMN scores in PLS patients (p&#xa0;>&#xa0;0.05).<br><br>CONCLUSIONS: Patients with PLS exhibit significantly increased F-wave amplitudes and F/M amplitudes ratios compared to ALS-NH and HC.<br><br>SIGNIFICANCE: Increased F-waves size serves as a neurophysiological marker of enhanced spinal motoneuron excitability in PLS.}, }
@article {pmid42310079, year = {2026}, author = {Nouraei, H and Amirzadeh, N and Shabanzadeh, S and Zareshahrabadi, Z and Shamsdin, N and Nouraei, M and Naeimi, B and Pakshir, K}, title = {Effect of subsequent passages on biofilm formation intensity, ALS genes expression, and cell surface hydrophobicity variability in clinical Candida albicans isolates.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-58680-y}, pmid = {42310079}, issn = {2045-2322}, support = {32536//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; }, abstract = {Candida albicans is an opportunistic yeast pathogen that have several virulence factors included biofilm formation, cell surface hydrophobicity (CSH), and the expression of adhesion genes. Concerns exist that serial laboratory subculturing may diminish these traits, leading to inaccurate research findings. Aim of this study was evaluated the effect of subsequently subcultures on biofilm formation intensity, ALS gene expression, and surface hydrophobicity properties in clinical C. albicans isolates. Ten clinical C. albicans isolates were serially subcultured up to 20 passages (P). We used qPCR to quantify ALS1 and ALS3 gene expression, the Crystal Violet assay to measure biofilm formation intensity (P1, P5, P10, P15, P20), and a water-octane partitioning assay for CSH variability at different passages. Serial subculturing caused gradual downregulation of gene expression for both ALS1 and ALS3 (p < 0.001). This condition was accompanied by a biofilm-forming capacity that became progressively reduced in 90% of isolates, whereas 60% at P20 were already biofilm-negative (vs. 10% at P1). Cell surface hydrophobicity also decreased progressively, with 100% of isolates displaying low CSH at P15, compared with 40% in the initial P1 state. Serial subculturing leads to a rapid reduction of C. albicans pathogenic fitness with decreased expression of certain key adhesion genes, diminished biofilm formation, and lower CSH. These results highlight the plasticity of the organism and thus strongly suggest that low-passage clinical isolates should be used in studies to reflect true pathogenicity in vivo accurately.}, }
@article {pmid42310298, year = {2026}, author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS}, title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.}, journal = {Cell death &amp; disease}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41419-026-08971-z}, pmid = {42310298}, issn = {2041-4889}, support = {4R01AG068292//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; }, abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.}, }
@article {pmid42310450, year = {2026}, author = {Deo, DR and Okorokova, EV and Pritchard, AL and Hahn, NV and Card, NS and Nason-Tomaszewski, SR and Jude, J and Hosman, T and Choi, EY and Qiu, D and Meng, Y and Wairagkar, M and Nicolas, C and Kamdar, FB and Iacobacci, C and Acosta, A and Hochberg, LR and Cash, SS and Williams, ZM and Rubin, DB and Brandman, DM and Stavisky, SD and AuYong, N and Pandarinath, C and Downey, JE and Bensmaia, SJ and Henderson, JM and Willett, FR}, title = {A mosaic of whole-body representations on the human precentral gyrus.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {42310450}, issn = {1476-4687}, abstract = {Understanding how the body is represented in the motor cortex is key to understanding how the brain controls movement. Although the motor cortex has been mapped in animal models at a fine scale[1-10], characterization in humans remains primarily limited to low-resolution recording[11-16] and stimulation techniques[17-20]. Here we created a comprehensive map of the human motor cortex at single-neuron resolution, spanning microelectrode array recordings from 20 arrays across 8 individuals with paralysis from spinal cord injury, amyotrophic lateral sclerosis or brainstem stroke, all enrolled in brain-computer interface clinical trials. These arrays broadly sample the crown of the precentral gyrus (PCG; thought to be composed largely of the premotor cortex (Brodmann area 6)). We found that body parts were highly intermixed, such that the entire body was represented in all sampled locations of the PCG, although the relative strength of body parts was roughly consistent with the motor homunculus[17,18]. We also found two speech-preferential areas with a broadly tuned, orofacial-dominant area in between them. Throughout the PCG, movement representations of the four limbs were interlinked, with homologous movements of different limbs (for example, toe curl and hand close) having correlated representations. These data provide evidence consistent with an intermixed, interrelated and behaviour-centred organization of the motor cortex[3,21]. The resulting map also provides important targeting information for brain-computer interfaces that seek to restore motor function.}, }
@article {pmid42310788, year = {2026}, author = {Wood, C and Brown, G and Chalk, K and Smith, SH and Williams, H and Broadhurst, G and Ealing, J and Hamdalla, H and Breen, C and Macleod, R and Chaouch, A}, title = {Co-development of a genetic care pathway for ALS: real-world perspectives from the North of England.}, journal = {Orphanet journal of rare diseases}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13023-026-04417-z}, pmid = {42310788}, issn = {1750-1172}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder, with a substantial proportion of cases attributed to genetic factors. Recent advances in gene discovery and genomic technologies have transformed ALS care by enabling genomic testing to inform prognosis, assess familial risk, and facilitate access to novel therapies. However, guidance on the delivery of genetic testing and counselling in ALS remains limited, leading to variability in clinical practice. In response, the Manchester Motor Neuron Disease (MND) Care Centre and the Manchester Centre for Genomic Medicine co-developed a structured genetic care pathway for ALS, drawing on real-world data, patient engagement, and multidisciplinary collaboration.<br><br>RESULTS: A retrospective evaluation of 326 ALS patients at the Manchester MND Care Centre identified significant variability in genetic testing uptake, counselling practices, and record-keeping. Patient survey and engagement sessions revealed uncertainty regarding key genetic concepts and inconsistent recall of pre- and post-test discussions. Priorities for improvement included clearer communication, standardised discussions, and enhanced support for families following genetic findings. Consequently, the Greater Manchester ALS Genetic Testing Pathway was developed by a multidisciplinary team, incorporating consensus-based steps for patient identification, pre-test conversations, consent, testing, results disclosure, and post-test support. This pathway integrates genetic testing into routine ALS care, clarifies team responsibilities, and establishes a framework for ongoing evaluation using key performance indicators. Patient and staff feedback is used to support continuous improvement.<br><br>CONCLUSIONS: The co-developed ALS genetic testing pathway provides a scalable model for standardising genomic care in mainstream clinical settings. By establishing clear processes for genetics discussions, consent, and follow-up, the pathway seeks to improve equity, transparency, and person-centred care. Ongoing evaluation and collaboration with patients, clinicians, and genetic services are essential to ensure the pathway remains responsive to scientific advances and evolving patient needs. Wider adoption of structured genetic pathways may facilitate the integration of genomics into care for rare diseases across healthcare systems.}, }
@article {pmid42299008, year = {2026}, author = {Singh, NK and Singh, A}, title = {Mechanistic Perspectives of Icariin against Neuroinflammation: Taming Glial Activation.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575448388260306051328}, pmid = {42299008}, issn = {1875-5607}, abstract = {Glial-mediated neuroinflammation significantly contributes to major neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Inhibition of glial-mediated neuroinflammation is effective in treating neurodegenerative diseases. Although no permanent cure exists, considerable research aims to identify natural compounds that may slow the disease progression. Icariin is a naturally occurring flavonoid derived from the herb Herba epimedii and has been shown to have several medicinal benefits, including anti-aging, antioxidant, anti-inflammatory, and anti-apoptotic properties. Recent studies have indicated that Icariin, a potent prenylated flavonol glycoside, exhibits neuroprotective effects against glial-mediated neuroinflammation. Icariin attenuates glial pro-inflammatory responses and prevents neurotoxicity in cellular and animal models. Additionally, Icariin is speculated to facilitate neuronal functioning and survival in experimental conditions. The present review highlights the remarkable role of glial cells in neuroinflammatory processes subsequently neurodegeneration, and the potential of icariin to suppress glial-mediated neuroinflammation. We hope that this review will accelerate the pharmacological development of icariin as a potential therapeutic compound against glial-mediated neuroinflammation, which triggers the pathogenesis of several neurodegenerative disorders.}, }
@article {pmid42299014, year = {2026}, author = {Kaur, H and Kaur, M and Sethi, GK and Kaur, AS and Mishra, A and Sharma, N}, title = {Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273440191260226063811}, pmid = {42299014}, issn = {1996-3181}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, with protein aggregation as a central pathological hallmark. Key pathogenic proteins, including TDP-43, SOD1, FUS, and dipeptide repeat proteins (DPRs) from C9orf72 expansions, drive disease progression through diverse but converging mechanisms. TDP-43 proteinopathy, present in nearly all ALS cases, involves cytoplasmic mislocalization, misfolding, and aggregation, disrupting RNA processing, protein transport, and DNA repair. Similarly, SOD1 and FUS mutations promote toxic protein aggregation, impairing cellular homeostasis and contributing to neuronal dysfunction. C9orf72-derived DPRs exert toxicity by interfering with nucleocytoplasmic transport. The propagation of these pathogenic proteins between neurons and glia, often via prion-like mechanisms, underlies the characteristic spread of ALS pathology throughout the nervous system. Cellular protective responses, such as molecular chaperones and the ubiquitin-proteasome system, attempt to mitigate aggregation but are often overwhelmed in disease states. Mitochondrial dysfunction, oxidative stress, and disturbances in calcium homeostasis are also implicated, with evidence showing that SOD1 mutations can alter redox balance and mitochondrial function in both neurons and non-neuronal cells. Impaired DNA repair mechanisms, involving proteins such as TDP-43, FUS, NEK1, and VCP, have emerged as important contributors to ALS pathogenesis, linking protein aggregation to genomic instability. Recent therapeutic strategies focus on directly targeting misfolded proteins using small molecules, peptides, or antisense oligonucleotides to inhibit aggregation or enhance clearance, offering hope for disease modification. Understanding the interplay between protein aggregation, impaired RNA metabolism, and cellular stress responses is crucial for developing effective translational therapies for ALS.}, }
@article {pmid42299015, year = {2026}, author = {Singh, G and Singh, S and Sarkar, A and Sandhu, NK}, title = {Amyotrophic Lateral Sclerosis: Therapeutic Innovations and Evolving Regulatory Approaches.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273438968260318203940}, pmid = {42299015}, issn = {1996-3181}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and respiratory failure. Despite extensive research, riluzole and edaravone remain the only globally approved disease-modifying therapies, offering modest survival benefits. This review summarizes current understanding of ALS pathogenesis, approved pharmacological treatments, and emerging gene-, RNA-, and cell-based therapeutic strategies. Particular emphasis is placed on regulatory considerations and evolving clinical trial designs in ALS drug development. The accelerated approval and subsequent withdrawal of sodium phenylbutyrate-taurursodiol (AMX0035) are discussed as a critical case study highlighting the challenges of regulatory flexibility in rare, fatal diseases. Advances in biomarker development, especially neurofilament light chain, are examined for their growing role in trial design and therapeutic evaluation. Collectively, these insights underscore a shift toward biomarker- informed and precision-based approaches that may improve future ALS therapeutic development.}, }
@article {pmid42300806, year = {2026}, author = {Calma, AD and Pavey, N and Tsuji, Y and Ghapar, AA and Bos, MAJVD and Orden, B and Lee, G and Mekhael, L and Ryder, J and Silva, CS and McDonald, D and Kakar, F and Yiannikas, C and Kiernan, MC and Brown, DA and Menon, P and Vucic, S}, title = {Integration of Serum Neurofilament Light Chain and Cortical Dysfunction Improves Diagnostic Accuracy in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70454}, pmid = {42300806}, issn = {2328-9503}, abstract = {OBJECTIVE: To determine whether integration of serum neurofilament light chain (NfL) and cortical dysfunction improves diagnostic accuracy in amyotrophic lateral sclerosis (ALS) when applied alongside the Gold Coast criteria (GCC).<br><br>METHODS: In this prospective study, 148 participants with suspected ALS were recruited (101 ALS and 47 with ALS mimicking disorders). Participants taking medications known to influence TMS measures were excluded. Serum NfL levels were quantified using a single-molecule array assay. Cortical function was assessed using threshold tracking transcranial magnetic stimulation, with cortical dysfunction defined by reduced mean short interval intracortical inhibition or motor cortex inexcitability. Diagnostic performance was evaluated using sensitivity, specificity, and diagnostic odds ratios (DOR), with 95% confidence intervals (CI).<br><br>RESULTS: Serum NfL demonstrated excellent discrimination (area under the curve 0.92, p&#x2009;<&#x2009;0.001), with cut-off &#x2265;&#x2009;33.5&#x2009;pg/mL providing a sensitivity of 0.85 (95% CI 0.77-0.91) and specificity 0.87 (95% CI 0.75-0.94). Cortical dysfunction demonstrated very good diagnostic performance (sensitivity 0.77 [95% CI 0.68-0.84], specificity 0.77 [95% CI 0.63-0.86]). The GCC achieved a sensitivity of 0.89 (95% CI 0.82-0.94) and specificity 0.89 (95% CI 0.77-0.95). Combining GCC with elevated NfL or cortical dysfunction increased the specificity to 0.98 (95% CI 0.89-1.00) while maintaining high sensitivity at 0.87 (95% CI 0.79-0.92), yielding the highest DOR.<br><br>INTERPRETATION: Integration of serum NfL and cortical dysfunction with the Gold Coast criteria improves diagnostic accuracy in ALS, particularly by increasing specificity. This multimodal approach provides a practical framework for earlier and more definitive diagnosis that may facilitate more efficient clinical trial recruitment.}, }
@article {pmid42300933, year = {2026}, author = {Gray, VP and Cui, Z and Klepsig, M and Letteri, RA}, title = {Designing polymer-peptide conjugates to target dipeptide repeat aggregates implicated in amyotrophic lateral sclerosis.}, journal = {Journal of materials chemistry. B}, volume = {}, number = {}, pages = {}, pmid = {42300933}, issn = {2050-7518}, abstract = {Toxic dipeptide repeats such as the aggregating glycine-alanine (GA)n peptide are implicated in the progression of amyotrophic lateral sclerosis (ALS), a lethal neuromuscular disease with an urgent need for new therapeutics. Here, we report polymer-peptide conjugates that prevent aggregation of (GA)10. Optical density measurements and transmission electron microscopy demonstrate that conjugates prevent aggregation when co-incubated with (GA)10 and disperse pre-aggregated (GA)10. These results represent an important step toward a new generation of therapeutics for ALS and contribute to a growing body of literature demonstrating the potential of polymer-peptide conjugates as therapeutics.}, }
@article {pmid42301686, year = {2026}, author = {Jomaa, AM and Khalid, H and Abozait, HJ and Mudassar, H and Kaur, R}, title = {Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Annals of Indian Academy of Neurology}, volume = {29}, number = {3}, pages = {343-352}, doi = {10.4103/aian.aian_1101_25}, pmid = {42301686}, issn = {0972-2327}, abstract = {OBJECTIVE: To evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol (PB-TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB-TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial.<br><br>RESULTS: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] -1.01 to 4.02; P = 0.24; I&#xb2; =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73-1.11; P = 0.31; I&#xb2; = 61%). A separate trial of TUDCA monotherapy (n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5-10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE.<br><br>CONCLUSIONS: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB-TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.}, }
@article {pmid42301697, year = {2026}, author = {Jomaa, AM and Khalid, H and Abozait, HJ and Mudassar, H and Kaur, R}, title = {Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Annals of Indian Academy of Neurology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aian.aian_1101_25}, pmid = {42301697}, issn = {0972-2327}, abstract = {OBJECTIVE: To evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol (PB-TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB-TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial.<br><br>RESULTS: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] -1.01 to 4.02; P = 0.24; I&#xb2; =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73-1.11; P = 0.31; I&#xb2; = 61%). A separate trial of TUDCA monotherapy (n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5-10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE.<br><br>CONCLUSIONS: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB-TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.}, }
@article {pmid42301897, year = {2026}, author = {Peters, GA and Misra, AJ and Samadian, KD and Chang, W and Chandran, KG and Hurwitz, JA and Muszalski, C and Granich, N and Goldberg, SA and Cash, RE}, title = {Cardiac arrest during interfacility transport with emergency medical services: a preliminary nationwide cross-sectional study.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10903127.2026.2690618}, pmid = {42301897}, issn = {1545-0066}, abstract = {OBJECTIVES: We aimed to provide the first national study of out-of-hospital cardiac arrests (OHCA) witnessed by emergency medical services (EMS) during interfacility transport (IFT).<br><br>METHODS: We used a nationwide prehospital patient care report dataset from 2023 to complete a cross-sectional observational study of EMS encounters for IFT during which OHCA occurred. Descriptive statistics were computed, stratified by level of EMS care provided. Multivariable logistic regression analysis was completed to evaluate factors associated with return of spontaneous circulation (ROSC) at the end of the IFT encounter upon transfer of care to the receiving facility. Finally, we completed a similar multivariable logistic regression analysis restricted to the subgroup of patients with an unshockable initial rhythm.<br><br>RESULTS: A total of 1,466 OHCA incidents occurred during an IFT with EMS: 7.5% with basic life support (BLS), 53.6% with advanced life support (ALS), and 38.9% with critical care transport (CCT). Among these incidents 11.8% were associated with trauma, 9.2% involved cardiopulmonary resuscitation (CPR) prior to EMS unit arrival, 14.7% involved a mechanical device to perform CPR, 22.2% had a shockable initial rhythm, and 58.1% were transported via ground as opposed to air. At the conclusion of the IFT EMS encounter, 50.3% had sustained ROSC. Geriatric age (aOR 0.64, 95%CI 0.44-0.94), BLS care (aOR 0.45, 95%CI 0.22-0.90), and ground transport (aOR 0.58, 95%CI 0.38-0.89) were associated with worse outcomes on adjusted analysis, whereas shockable initial rhythm (aOR 3.86, 95%CI 2.42-6.36) and CCT care (aOR 2.21, 95%CI 1.42-3.48) were associated with better outcomes. The sub-analysis for OHCA during IFT with an unshockable initial rhythm also showed greater odds of ROSC when managed by CCT relative to ALS (aOR 2.65, 95%CI 1.64-4.33) while adjusting for other key factors.<br><br>CONCLUSIONS: Using a large nationwide sample of OHCA incidents that occurred during IFT, we found that higher level of EMS care was associated with superior short-term outcomes while controlling for other key factors. These findings underscore the importance of accurate patient triage at sending facilities and the value of CCT for high-risk patients.}, }
@article {pmid42302423, year = {2026}, author = {Almenara Abellán, JL and Lagares Franco, C and Bordes Bustamante, F and Gracia Romero, M&#xc1; and Santisteban Espejo, AL}, title = {Impact of a simulation-based training program on the acquisition of ultrasound window competencies for the initial assessment of polytrauma patients in advanced prehospital nursing care.}, journal = {Enfermeria intensiva}, volume = {37}, number = {3}, pages = {500604}, doi = {10.1016/j.enfie.2026.500604}, pmid = {42302423}, issn = {2529-9840}, abstract = {INTRODUCTION: Point-of-care ultrasound is essential in the initial assessment of polytrauma patients. The E-FAST protocol enables rapid detection of intra-abdominal free fluid, pericardial effusion, and pneumothorax, with particular usefulness in prehospital settings. However, ultrasound training among emergency nursing staff remains limited, especially within Advanced Life Support (ALS) mobile units.<br><br>OBJECTIVE: To evaluate the effect of a brief, structured training program on the acquisition of competencies for obtaining E-FAST windows in ALS mobile units nurses, assessing knowledge, technical skills, scanning sequence, and perceived confidence.<br><br>METHOD: A quasi-experimental pre-post intervention study was conducted with nurses with&#x202f;&#x2265;6 months of experience in emergency or prehospital care. The intervention included baseline assessment, a 2-h theoretical module, high-fidelity simulation with Ultrasound Mentor&#xae;, and hands-on practice with human models. Final assessment combined a theoretical test, simulator-based practical evaluation, and scanning with a real ultrasound device. Knowledge, execution times, and confidence levels were recorded.<br><br>RESULTS: Fourteen nurses participated, most without previous ultrasound training (85.7%). Initial confidence was low and improved significantly after the intervention. Theoretical performance increased in 5 of the 6 evaluated items, reaching up to 92.9% accuracy in key content areas. Practical assessment demonstrated an organized scanning sequence and appropriate times for prehospital care (medians of 118&#x202f;s [IQR 24.5] in advanced simulation and 237&#x202f;s [IQR 33.3] using a real ultrasound device).<br><br>DISCUSSION: The program enabled the acquisition of essential skills even in professionals without prior ultrasound experience. The combination of theory, simulation, and hands-on practice facilitated rapid competency transfer and protocol standardization.<br><br>CONCLUSIONS: A brief training program improves ALS mobile units nurses' competence and confidence in obtaining E-FAST windows, supporting the safe integration of point-of-care ultrasound into prehospital care.}, }
@article {pmid42302677, year = {2026}, author = {Gong, X and Xie, Y and Deng, X and Sun, Z and Fu, S and Wang, H and Hou, Y and Dong, Z and Zhou, W}, title = {Hydrolytic evolution of propyrisulfuron: wlectronic differentiation and spectroscopic fingerprints of transformation products.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {362}, number = {}, pages = {128245}, doi = {10.1016/j.saa.2026.128245}, pmid = {42302677}, issn = {1873-3557}, abstract = {Propyrisulfuron (PRS), a sulfonylurea herbicide used in paddy systems, undergoes hydrolysis to form structurally distinct transformation products. This study combined DFT/TDDFT calculations with experimental UV-Vis, FTIR, and Raman spectroscopy to characterise PRS and six experimentally identified products (HP1-HP6). Relative electronic descriptors showed that cleavage of the sulfonylurea bridge increased the HOMO-LUMO gaps from 4.572 eV for PRS to 5.978 and 6.229 eV for HP1 and HP2, respectively, whereas HP3-HP5 retained moderate gaps of 4.846-4.923 eV. HP5 showed the most negative Vmin (-71.524 kcal mol[-1]) and the largest dipole moment (16.67 D). Calculated and experimental spectra were consistent, with major UV-Vis peak deviations below 10 nm and characteristic FTIR and Raman deviations generally below 20 and 15 cm[-1], respectively. A validated 1YBH-based docking workflow reproduced the co-crystallized CIE pose with an RMSD of 0.320 Å; within this internally standardized comparison, PRS, HP3, HP5, and HP4 gave scores of -8.480, -7.212, -7.076, and - 6.979 kcal mol[-1], respectively. Docking results are interpreted as relative ALS/AHAS-recognition tendencies rather than direct evidence of toxicity or inhibitory potency. Overall, this work establishes a structure-spectrum framework for tracking PRS hydrolysis and differentiating its major products.}, }
@article {pmid42302791, year = {2026}, author = {Sahu, SK and Memczak, S and Thakurela, S and Lu, J and Gupta, P and Mutukula, N and Hirano, A and Zhang, Y and Hishida, T and Kurita, M and Wang, C and Shao, Y and Williams, A and Shokhirev, M and Tiwari, VK and Rodriguez Esteban, C and Reddy, P and Meissner, A and Li, M and Izpisua Belmonte, JC}, title = {ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.}, journal = {Cell stem cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.stem.2026.05.009}, pmid = {42302791}, issn = {1875-9777}, abstract = {Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.}, }
@article {pmid42020473, year = {2026}, author = {García-Camacho, M and Martínez-Subiela, S and Tvarijonaviciute, A and Cerón, JJ and Rubio, CP and Muñoz-Prieto, A}, title = {Analytical validation of aldolase, microalbumin and myeloperoxidase in canine saliva and their evaluation in canine gingivitis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42020473}, issn = {2045-2322}, support = {22724/FPI/24//Fundaci&#xf3;n S&#xe9;neca/ ; PID2023-149944OB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; PID2023-149944OB-I00//FEDER, EU/ ; RYC2021-034764-I//Ram&#xf3;n y Cajal/ ; RYC2021-033660-I//Ram&#xf3;n y Cajal/ ; }, abstract = {UNLABELLED: Saliva is a biological fluid that offers potential practical advantages for biomarker assessment in dogs due to its non-invasive nature. This study evaluated aldolase (ALS), microalbumin (mALB), and myeloperoxidase (MPO) in canine saliva using automated assays. All assays showed acceptable analytical performance, with adequate precision (coefficients of variation < 15%), accuracy (coefficients of determination close to 1 after serial sample dilutions), and sensitivity (lower limits of quantification of 5.6 IU/L, 2.05 mg/dL, and 26.3 IU/L for ALS, mALB and MPO, respectively). The effect of gingivitis on these salivary analytes was also assessed. Dogs with gingivitis showed significantly higher salivary ALS and mALB results — ALS, 21.9 (14.2–37.3) IU/L; mALB, 13.15 (5.89–25.71) mg/dL — compared with controls — ALS, 7.65 (2.2-12.23) IU/L; mALB, 3.51 (2.32–5.21) mg/dL— (p < 0.0001). Moreover, increasing gingivitis severity was associated with progressively higher levels of ALS and mALB. In contrast, no significant differences were observed in MPO activity between groups. These findings suggest that ALS and mALB may serve as salivary biomarkers for gingivitis assessment. Further studies are warranted to explore their potential applicability in other local and systemic inflammatory conditions in dogs.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-48816-5.}, }
@article {pmid42290625, year = {2026}, author = {Tenenbein, M}, title = {Author response to: Mullins et al. comment on, "We need a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning".}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/15563650.2026.2679164}, pmid = {42290625}, issn = {1556-9519}, abstract = {INTRODUCTION: I have reviewed Mullins et al's critique of my commentary "We need a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning".<br><br>DISCUSSION: I concur regarding this need, and I agree that the original three-bag regimen should be retired. However, we disagree upon its replacement. They challenge my recommendation for a two-bag regimen, and they favour the one-bag two-step approach. The impetus for a replacement acetylcysteine regimen is to decrease the adverse effects and errors associated with the three-bag protocol. However, the one-bag two-step regimen was not designed to decrease adverse effects, and their published reports do not find a decrease of errors. And a fatal adverse effect, acetylcysteine overdose, has emerged with use experience of this regimen.<br><br>CONCLUSIONS: The one-bag two-step regimen should be dismissed from the quest for a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning.}, }
@article {pmid42293320, year = {2026}, author = {Novikova, L and Lang, C and Tumani, H and Klose, V and Kassubek, J and Dreyhaupt, J and Dupuis, L and Wabitsch, M and Ludolph, A}, title = {Thyroid hormones and energy metabolism in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag198}, pmid = {42293320}, issn = {2632-1297}, abstract = {Weight loss, partially caused by hypermetabolism, represents a well-documented and therapeutically relevant feature of the amyotrophic lateral sclerosis phenotype worldwide. In this study, we retrospectively analysed the association between thyroid function and clinical, prognostic and metabolic parameters in a cohort of patients with amyotrophic lateral sclerosis in an experienced centre in Germany (n = 1754). Specifically, we examined the relationship between thyroid stimulating hormone levels, age, glucose and body mass index and-in subgroups-phosphorylated neurofilament heavy chain levels in CSF. There was no association between thyroid stimulating hormone levels and body mass index in patients with amyotrophic lateral sclerosis (n = 954). In contrast with other cohorts, thyroid stimulating hormone levels decreased with age in patients with amyotrophic lateral sclerosis indicating hypothalamic deficiency in the ageing patients. There was no association between thyroid stimulating hormone and phosphorylated neurofilament heavy chain (prognostic marker) in CSF of a subcohort (n = 646). Thyroid stimulating hormone levels correlated with glucose levels, an effect more pronounced in male patients. In conclusion, our results suggest that thyroid metabolism does not significantly contribute to amyotrophic lateral sclerosis-related weight loss or disease prognosis as estimated by phosphorylated neurofilament heavy chain; thyroid dysfunction is unlikely to be a primary driver of the metabolic dysregulation observed in amyotrophic lateral sclerosis. Most interestingly, thyroid stimulating hormone levels show an unexpected negative relation to age in patients with amyotrophic lateral sclerosis.}, }
@article {pmid42293321, year = {2026}, author = {Ma, M and Zhao, B and Gao, N and Sun, X and Shao, K and Lin, P and Li, W and Zhao, Y and Yu, D and Yan, C and Liu, S and Yun, Y}, title = {Quantitative susceptibility mapping reveals widespread brain iron abnormalities in sporadic patients with early-stage amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag190}, pmid = {42293321}, issn = {2632-1297}, abstract = {In the present study, using the novel quantitative susceptibility mapping technique, we aimed to systematically investigate brain iron alterations in a large group of sporadic early-stage amyotrophic lateral sclerosis patients and their correlation with clinical disability. In this study, amyotrophic lateral sclerosis patients at King's stage 1 were defined as early-stage amyotrophic lateral sclerosis patients, and 53 newly diagnosed early-stage amyotrophic lateral sclerosis patients and 50 healthy controls were included. Voxel-based whole-brain quantitative susceptibility mapping analysis was used to explore brain iron alterations. Voxel-based morphometry analysis was also performed. Longitudinal follow-up was performed in amyotrophic lateral sclerosis patients, and the follow-up progression rate was calculated. We found that, compared with healthy controls, early-stage amyotrophic lateral sclerosis patients presented significantly increased susceptibility values, mainly in the motor cortex, prefrontal cortex, hippocampus and cerebellar regions, while volumetric alterations were not detected. Moreover, motor and extra-motor cortex susceptibility values were significantly correlated with upper motor neuron scores and follow-up progression rate (r = 0.452-0.504, P < 0.01) in early-stage amyotrophic lateral sclerosis patients. We demonstrated a clear profile of early motor and extra-motor iron depositions and their important roles in early-stage amyotrophic lateral sclerosis patients. We suggest that quantitative susceptibility mapping is likely a promising neuroimaging approach for assessing early upper motor neuron damage and detecting early extra-motor alterations in amyotrophic lateral sclerosis patients.}, }
@article {pmid42293743, year = {2026}, author = {Mavillonio, A and Rizzini, D and Detassis, S and Denti, MA}, title = {Neurodegenerative spliceosomopathies.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1787859}, pmid = {42293743}, issn = {2296-634X}, abstract = {Spliceosomal syndromes are a group of disorders caused by pathogenic variants in core spliceosomal RNAs or proteins, leading to defective pre-mRNA splicing and tissue-specific disease vulnerability. Although the spliceosome is ubiquitously expressed, its dysfunction preferentially affects highly splicing-dependent tissues such as the retina and the nervous system. This mini-review focuses on neurodegenerative spliceosomopathies, including spinal muscular atrophy, amyotrophic lateral sclerosis, and retinitis pigmentosa, highlighting how alterations in snRNP biogenesis, spliceosome assembly, and splicing fidelity drive neuronal and photoreceptor degeneration. We discuss shared and distinct molecular mechanisms, unresolved questions on tissue specificity, and emerging therapeutic strategies targeting RNA splicing.}, }
@article {pmid42295247, year = {2026}, author = {Panagos, I and Bedi, RP}, title = {Attempting to validate a group psychotherapy session taxonomy: A conceptual replication and extension.}, journal = {Journal of counseling psychology}, volume = {}, number = {}, pages = {}, doi = {10.1037/cou0000890}, pmid = {42295247}, issn = {0022-0167}, support = {//Social Sciences and Humanities Research Council of Canada/ ; }, abstract = {This study attempted to conceptually replicate the five-category typology system for group psychotherapy sessions developed by Li et al. (2021) and aimed to identify whether sessions of one type and one climate valence were more likely to follow sessions of the same type (perseveration effect) and similar valence (climate valence continuity), respectively. Ninety-eight individuals with a history of problematic alcohol use attended one of 19 six-session groups, which were either focused on identity transitions or career development. Following each session, individuals' perceptions of the group climate were assessed on the three dimensions of engagement, avoiding, and conflict. A k-means cluster analysis was performed in an attempt to replicate Li et al.'s taxonomy but failed. As a result, an exploratory hierarchical cluster analysis was conducted followed by a confirmatory k-means cluster analysis. Findings identified three types of group sessions: cohesively collaborative, unenthusiastically detached, and politely aloof. Results did not identify a perseveration effect or climate valence continuity. This new typology identified was inconsistent with that of Li et al., indicating that one classification system may not be suitable for all types of groups. The results provide an alternate session typology that may be used to characterize structured group sessions for individuals with problematic alcohol use. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42295687, year = {2026}, author = {Jürs, AV and Naumann, M and Lehto, A and Schön, H and Kurth, J and Prudlo, J and Hermann, A and Kasper, E}, title = {Cognitive and Neuroimaging Divergence Between Juvenile and Adult FUS Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70447}, pmid = {42295687}, issn = {2328-9503}, support = {//Hermann und Lilly Schilling-Stiftung f&#xfc;r medizinische Forschung im Stifterverband/ ; //Clinician Scientist Program of the Center for Transdisciplinary Neuroscience Rostock/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron degeneration. Fused in sarcoma (FUS)-associated juvenile ALS (jALS) represents a distinct and aggressive subgroup with rapid deterioration and poor prognosis. Certain FUS mutations have been associated with comorbid intellectual disability, suggesting neurodevelopmental involvement. We compared FUS-jALS with adult-onset FUS-ALS cases (aALS) to evaluate the association between premorbid cognitive impairment, genetic and clinical features incorporating neuroimaging data.<br><br>METHODS: Patients with genetically confirmed FUS-ALS were classified as jALS (onset <&#x2009;25&#x2009;years) or aALS (onset &#x2265;&#x2009;25&#x2009;years). Neuropsychological assessment used Mehrfachwahl-Wortschatz-Test (MWT) for verbal IQ, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), with cognitive impairment classified according to Strong criteria. Volumetric analysis was conducted on structural MRI and FDG-PET data.<br><br>RESULTS: All three jALS (P525L [n&#x2009;=&#x2009;2], H517_Q519del [n&#x2009;=&#x2009;1]) showed rapid progression with early severe clinical events. Neuropsychological assessment revealed global cognitive deficits (ALS-ci) with widespread dysfunction beyond typical ALS-specific patterns and reduced verbal IQ, pointing towards premorbid cognitive impairment. aALS demonstrated slower progression and were predominantly cognitively unimpaired (ALS-ni) or showed an ALS-specific impairment. Neuroimaging revealed distinct patterns: jALS cases demonstrated posterior cortical atrophy and hypometabolism on FDG-PET, while aALS showed largely preserved brain volumes and limbic-subcortical hypometabolism.<br><br>INTERPRETATION: Specific FUS mutations (P525L, H517_Q519del) predispose to jALS with severe progression and premorbid cognitive impairments, supporting a genotype-phenotype association. Posterior cortical findings suggest neurodevelopmental delay rather than disease-related neurodegeneration. Genetic FUS screening may be warranted in patients with intellectual disability and motor signs, given emerging targeted therapies.}, }
@article {pmid42295787, year = {2026}, author = {Zangrando, L and Buratti, E and Paron, F}, title = {TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76119}, doi = {10.1002/advs.76119}, pmid = {42295787}, issn = {2198-3844}, support = {//AriSLA 2022-NOSRESCUEALS/ ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA-binding protein that plays essential roles in RNA metabolism, including transcription, splicing, transport, and stability. Pathological TDP-43 aggregates have become a defining hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and a large subset of frontotemporal lobar degeneration (FTLD). In the last decade, increasing evidence has challenged the initial thought of TDP-43 condensates as a purely pathological event, highlighting instead the physiological relevance of reversible self-association, polymerization and liquid-liquid phase separation (LLPS) in regulating TDP-43 functions. In this review, we provide an integrated overview of the structural determinants governing TDP-43 two-faced polymerization, with a particular focus on the prion-like domain and its parallelism with prion proteins. Indeed, while physiological assemblies support normal RNA processing, the dysregulation of LLPS by either disease-associated mutations, altered RNA-binding, aberrant post-translational modifications, or proteolytic cleavage can promote the transition toward irreversible, pathogenic aggregates. Finally, we summarize strategies aimed at eliminating TDP-43 aggregates or modulating its phase-separation behavior. Altogether, this review frames TDP-43 polymerization in both healthy and pathological conditions, offering a prion-like centered view of TDP-43 proteinopathies.}, }
@article {pmid42296226, year = {2026}, author = {Naumann, M and Kretschmer, S and Dorst, J and Lapp, H and Peikert, K and Petri, S and Gess, B and Wolf, C and Rödiger, A and Smesny, U and Pan-Montojo, F and Kerschen, P and Grehl, T and Prudlo, J and Regensburger, M and Ludolph, A and Günther, R and Brenner, D and Lee-Kirsch, MA and Hermann, A}, title = {Innate immune signaling as a potential pathomechanistic biomarker for distinct subtypes in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2663910}, pmid = {42296226}, issn = {2167-9223}, abstract = {Stimulation of the innate immune system has been implicated in ALS and particularly in distinct monogenic forms of ALS. To address whether this is of diagnostic value, we performed a proof-of concept study using qPCR to assess the Interferon score in blood samples of genetic ALS. 56.5% of genetic ALS patients showed significant IFN activation, highest in C9orf72HRE patients (77.3%). About half of FUS-ALS (52.2%), but none of SOD1-ALS patients demonstrated pathological IFN scores. The IFN score significantly correlated with the ALSFRS-R slope and inversely with the time to severe event as a survival surrogate in this genetic ALS cohort. IFN + patients were more likely to be male, showed more rapid disease progression and higher neurofilament levels. The IFN score might have the potential as a stratification and readout tool for biomarker-guided individualized therapy in ALS.}, }
@article {pmid42296263, year = {2026}, author = {Fabry, V and Faruch-Bilfeld, M and El Khalfi, R and Acket, B and Al Achram, Y and Cintas, P}, title = {Whole-body muscle MRI improves diagnostic certainty in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2685160}, pmid = {42296263}, issn = {2167-9223}, abstract = {Introduction: Early diagnosis of amyotrophic lateral sclerosis (ALS) remains challenging due to the absence of a definitive biomarker and the difficulty of demonstrating widespread lower motor neuron (LMN) involvement. Whole-body muscle MRI (WB-MRI) enables comprehensive assessment of muscle involvement and may improve detection of LMN dysfunction. This study aimed to evaluate whether WB-MRI improves diagnostic certainty in ALS when combined with clinical and electromyography (EMG) assessment. Methods: In this prospective single-center study, 47 patients with ALS underwent clinical examination, EMG, and WB-MRI. Diagnostic classification according to the Awaji criteria was assessed using clinical and EMG data alone and after integration of MRI markers of LMN involvement, including fatty infiltration and muscle edema, or muscle edema alone as a surrogate marker. Results: WB-MRI identified additional LMN-involved regions in 27.7% of patients when both fatty infiltration and muscle edema were considered, and in 42.6% when considering muscle edema alone. This resulted in diagnostic upgrading in 14.9% and 25.5% of patients, respectively. The proportion of definite ALS increased from 8.5% to 17.0% when muscle edema alone was considered. MRI had limited impact on diagnostic classification according to the Gold Coast criteria. Among patients without LMN involvement on clinical and EMG assessment (all with bulbar-onset), 50% were reclassified after MRI. Conclusion: WB-MRI improves detection of LMN involvement and increases diagnostic certainty according to the Awaji criteria, with muscle edema appearing to be the most relevant MRI marker for integration into ALS diagnostic assessment.}, }
@article {pmid42297978, year = {2026}, author = {Card, NS and Singer-Clark, T and Peracha, H and Iacobacci, C and Hou, X and Wairagkar, M and Fogg, Z and Offenberg, EC and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Long-term independent use of an intracortical brain-computer interface for speech and cursor control.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {42297978}, issn = {1546-170X}, support = {N/A//Burroughs Wellcome Fund (BWF)/ ; N/A//Burroughs Wellcome Fund (BWF)/ ; N/A//Achievement Rewards for College Scientists Foundation (ARCS Foundation)/ ; A2295-R//VHA Office of Research and Development | Rehabilitation Research and Development Service (Rehabilitation Research &amp; Development Service)/ ; 1DP2DC021055//U.S. Department of Health &amp; Human Services | NIH | NIH Office of the Director (OD)/ ; AL220043//United States Department of Defense | Office of the Secretary of Defense (OSD)/ ; 23-SGP-652//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, abstract = {Brain-computer interfaces (BCIs) can provide naturalistic communication and digital access to people with severe paralysis by decoding neural activity associated with attempted speech and movement. Recent work has demonstrated highly accurate intracortical BCIs for speech and cursor control, but two critical capabilities needed for practical viability were unmet: independent at-home operation without researcher assistance and reliable long-term performance supporting accurate speech and cursor decoding. Here we demonstrate the independent and near-daily use of a multimodal BCI with novel brain-to-text speech and computer cursor decoders by a man with paralysis and severe dysarthria due to amyotrophic lateral sclerosis. Over nearly 2 years, the participant used the BCI for more than 3,800 h at home with no researchers present to maintain rich interpersonal communication with his family and friends, independently control his personal computer and sustain full-time employment-despite being paralyzed. He communicated 183,060 sentences-totaling 1,960,163 words-at an average rate of 56 words per minute. He labeled 92% of sentences as being decoded at least mostly correctly. In formal quantifications of performance where he was asked to say words presented on a screen, attempted speech was consistently decoded with more than 99% word accuracy (125,000 word vocabulary). The participant also used the speech BCI as keyboard input and the cursor BCI as mouse input to control his personal computer, enabling him to send text messages and emails and to browse the internet. These results demonstrate that intracortical BCIs have the potential to support independent use in the home, marking a critical step toward practical assistive technology for people with severe motor impairment.}, }
@article {pmid42297981, year = {2026}, author = {Ding, DY and Bot, VA and Chen, KL and Groves, JW and Pálovics, R and Masuda, D and Farinas, A and Oh, HS and Wagner, V and Lu, N and ,  and Cruchaga, C and Isakova, A and Schott, JM and Wyss-Coray, T}, title = {Plasma proteomic signatures of cellular aging predict human disease.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {42297981}, issn = {1546-170X}, support = {AG072255//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; ARUK-PG2017-1946//Alzheimer's Research UK (ARUK)/ ; SG-666374-UK BIRTH COHORT/ALZ/Alzheimer's Association/United States ; }, abstract = {Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer's Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.}, }
@article {pmid42298083, year = {2026}, author = {Al-Shami, AS and Anwar, MM}, title = {The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {42298083}, issn = {1568-5608}, abstract = {Neurodegenerative and chronic pulmonary diseases represent major global health challenges and have widely been investigated separately. Emerging evidence indicates the existence of a lung-brain axis, through which pulmonary pathology and environmental exposures can influence neurological health. The current review highlights the mechanistic and clinical evidence linking chronic lung inflammation, air pollution, and immune dysregulation to the onset and progression of Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). A pathway-based framework is presented in which lung inflammation, systemic cytokine release, oxidative stress, blood-brain barrier disruption, immune priming, and protein misfolding mediate lung-to-brain communication. Associations between chronic obstructive pulmonary disease, asthma, particulate matter exposure, and adverse neurological outcomes including cognitive decline, brain atrophy, disease progression, and elevated neurodegenerative risk are emphasized. Specific mechanisms are addressed, including immune-mediated effects in multiple sclerosis, inhalation-driven protein aggregation in Parkinson's disease, and vascular and oxidative injury contributing to dementia and amyotrophic lateral sclerosis. COVID-19 is considered a clinical model of acute lung-brain axis disruption, demonstrating inflammation-driven neurocognitive consequences, and its role in this context was also highlighted. Additionally, potential preventive and therapeutic strategies are discussed, highlighting pulmonary health and environmental exposure reduction as modifiable factors that may help mitigate neurological disease. This integrative review underscores the clinical relevance of the lung-brain axis and calls for interdisciplinary strategies to improve neurological outcomes through pulmonary and environmental interventions.}, }
@article {pmid41160352, year = {2026}, author = {Bae, K and Park, Y and Ryu, H and Lee, J and Park, SW}, title = {A Longitudinal Study of the Relationship between Identity Development Processes and Self-Esteem among Korean College Freshmen.}, journal = {Journal of youth and adolescence}, volume = {55}, number = {3}, pages = {780-794}, pmid = {41160352}, issn = {1573-6601}, support = {NRF-2023S1A5A2A01078792//the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea/ ; }, abstract = {Self-esteem may serve both as a psychological resource that facilitates personal identity development processes and as an outcome of a consolidated identity. However, longitudinal evidence remains limited. This study tracked 641 South Korean first-year college students (48.0% women; Mage = 19.13) across four waves spaced three months apart during their first academic year to test bidirectional links between Luyckx et al.’s (2008) five dimensions of personal identity processes (exploration in breadth, exploration in depth, commitment making, identification with commitment, ruminative exploration) and self-esteem. Random-intercept cross-lagged panel models were used to examine how changes in each of the processes may follow and be followed by changes in self-esteem. Results highlight initial volatility and gradually increasing engagement in personal identity development processes. Higher self-esteem predicted greater engagement in identity processes, and a stronger sense of identification with commitment predicted higher self-esteem later in the year but not earlier. By demonstrating that self-esteem is not merely an outcome of identity development but also a psychological resource facilitating identity development, these findings contribute to the literature on the development of the self-system in youth.}, }
@article {pmid41267135, year = {2025}, author = {Zreik, M and Redding, A and Santarossa, S}, title = {From engagement to evidence: a scoping review of qualitative and quantitative measures of adult patient engagement in research.}, journal = {Research involvement and engagement}, volume = {11}, number = {1}, pages = {136}, pmid = {41267135}, issn = {2056-7529}, support = {SOE-2022C2-28911/PCORI/Patient-Centered Outcomes Research Institute/United States ; }, abstract = {BACKGROUND: Patient engagement in research has been found to improve the quality and relevance of research findings. Quantifying levels of patient engagement may be beneficial in measuring engagement quality, yet tools for this purpose remain scarce. A scoping review was conducted to summarize and analyze existing tools used to measure patient engagement in research for the purpose of assessing the content validity of Hamilton et al.’s Patient Engagement In Research Scale (PEIRS). METHODS: The electronic database Ovid MEDLINE was used to conduct a search related to keywords and controlled vocabulary from 2017 - November 10, 2023, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews checklist. Articles were included if they quantitatively or qualitatively measured any outcome of patient engagement in research, exclusively with patients as participants. Data extraction, completed in Microsoft Excel, included the name of the research engagement tool, the type of tool (i.e., questionnaire, survey, or scale), sample size, source, and characteristics, and time frame of data collection. RESULTS: Five articles were ultimately included in this scoping review after an initial search returned 1719 citations. The most common reason for exclusion during the full text review stage was that articles were review articles. Of selected articles that included demographic data, the majority of participants were women and White. Articles highlighted areas for improvement in existing tools, including the need for patient collaboration at each stage of the research process and stronger communication between researchers and patient partners. CONCLUSIONS: Efforts to effectively measure patient engagement in research remain scant. Included studies were limited by inconsistency in defining “patient engagement” and a lack of demographic data collection.}, }
@article {pmid41372737, year = {2025}, author = {Shah, A and Doshi, G}, title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41372737}, issn = {2240-2993}, abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.}, }
@article {pmid41511493, year = {2026}, author = {Yu, J and Zhang, J and Jiang, Y and Ma, C and Wang, W and Zhang, K and Tian, R and Chen, H and Han, H and Sun, H and Peng, C and Zhang, H and Xu, X}, title = {Identification of a novel nonsense variant in ARR3 in a family with early-onset high myopia.}, journal = {Genes &amp; genomics}, volume = {48}, number = {3}, pages = {409-418}, pmid = {41511493}, issn = {2092-9293}, support = {81873677//Natural Science Foundation of China/ ; }, abstract = {BACKGROUNDS: Early-onset high myopia (EoHM) is a severe refractive error that can result in significant vision loss. A known genetic cause involves mutations in the X-linked Arrestin-3 (ARR3) gene, which typically presents with a female-limited inheritance pattern, in which asymptomatic fathers transmit the variant to their affected daughters. OBJECTIVE: This study aims to present a unique case of EoHM characterized by paternal transmission of a novel ARR3 variant and to explore potential underlying molecular mechanisms through an exploratory bioinformatic analysis. METHODS: We collected the clinical phenotypes for the family and sequenced the blood using NGS and Sanger sequencing. Bioinformatic analysis of the GSE5338 dataset revealed a potential interaction network involving ARR3, NR2E3 (a photoreceptor development regulator), and OPN1MW (a cone opsin gene). RESULTS: The proband exhibited severe EoHM with stretched axial lengths (ALs) (24.09 and 24.43 mm) and pronounced myopic astigmatism. The asymptomatic father passed on a new nonsense variation in the ARR3 gene, c.7A > T (p.K3Ter). Exploratory bioinformatic analysis of a murine retinal dataset hinted at a possible regulatory relationship, wherein overexpression of the photoreceptor transcription factor Nr2e3 might be linked to the downregulation of Arr3 and the cone opsin gene Opn1mw. CONCLUSIONS: This study reports a novel ARR3 mutation within a family affected by EoHM, expanding the known mutational spectrum of this disease and offering vital insights for genetic counseling. Furthermore, our bioinformatic analysis has generated a hypothesis that NR2E3-mediated downregulation of both ARR3 and OPN1MW may contribute to the disease phenotype, a link that warrants future investigation in human models.}, }
@article {pmid41530568, year = {2026}, author = {Qingqing, Z and Ruiyi, L and Zaijun, L}, title = {Graphene-oxide dual-stabilized Mg0.3AlVCuZn lightweight high-entropy alloy nanoparticles with ultrahigh catalytic activity, selectivity and stability for electrochemical detection of doxorubicin in human urine.}, journal = {Mikrochimica acta}, volume = {193}, number = {2}, pages = {90}, pmid = {41530568}, issn = {1436-5073}, support = {2021YFA0910200//National Key Research and Development Program of China,China/ ; 2021YFA0910200//National Key Research and Development Program of China,China/ ; }, abstract = {The practical applications of lightweight high-entropy alloys (HEAs) in catalysis and electrochemical sensors are hindered by inadequate chemical stability and catalytic activity. This study presents one groundbreaking synthesis strategy for fabricating Mg0.3AlVCuZn HEA nanoparticles by integrating histidine/serine-functionalized boron-doped graphene quantum dot (HSB-GQD). Mg2+, Al3+, V5+, Cu2+ and Zn2+ are coordinated with HSB-GQD to Me-HSB-GQD complex,followed by thermal annealing and controlled oxidative post-treatment. The resulting Mg0.3AlVCuZn shows single-phase octahedral morphology with a small size of about 50 nm and dual graphene-oxide shielding. Unique structure fully exposes active sites and enhances structural and chemical stability across acidic/alkaline media, interface electron transfer, and improves the affinity with polar electrolyte. The s-p-d orbital hybridization among Mg/Al (s, p) and V/Cu/Zn (s, d) induces electron redistribution to optimize adsorption energetics and catalytic specificity. Mg0.3AlVCuZn shows ultrahigh catalytic activity that is more than 2-fold that of Au nanoparticles. The electrochemical sensor with Mg0.3AlVCuZn exhibits a broad linear range (0.01–100 µM), ultra-low detection limit (0.0057 µM, S/N = 3), and robust selectivity and long-term stability for electrochemical detection of doxorubicin in human urine. This study also offers a generalizable platform for engineering lightweight HEAs with tailored stability and multifunctional efficacy, bridging advances in catalysis, sensing and energy storage.}, }
@article {pmid41697604, year = {2026}, author = {Tutan, MB and Tutan, D}, title = {A bibliometric analysis of diverticulitis: global trends and future directions.}, journal = {Updates in surgery}, volume = {}, number = {}, pages = {}, pmid = {41697604}, issn = {2038-3312}, abstract = {Diverticulitis, an inflammation of colonic diverticula, poses significant clinical challenges due to its rising global incidence and potential complications. Modern dietary habits, sedentary lifestyles, and aging populations contribute to its increasing prevalence, with a notable rise among younger adults. Despite extensive research, a comprehensive assessment of global research trends remains limited. This study conducts a bibliometric and statistical analysis of diverticulitis research (1980–2024) to identify key trends, influential studies, international collaborations, and the correlation between national GDP and research output while projecting future publication trends. A bibliometric analysis of the Web of Science database identified 4459 publications, with 3653 articles, reviews, and meeting abstracts included. The United States led global research contributions (34.22%), followed by Italy and Germany. A strong positive correlation was found between national GDP and research productivity (r = 0.900, P < 0.001). Future projections estimate 289 publications in 2025. The most cited study was Rafferty et al.‘s 2006 “Practice parameters for sigmoid diverticulitis.” Citation analysis revealed growing academic interest, particularly in the past two decades. Diverticulitis has become a global health concern, driven by lifestyle changes and aging demographics, with an increasing incidence among younger populations. This study highlights a marked rise in research activity, predominantly in economically developed nations, and underscores the need for further investigation into prevention, diagnosis, and management strategies. These findings offer valuable insights for clinicians and researchers, guiding future research directions in diverticulitis.}, }
@article {pmid41840453, year = {2026}, author = {Morgan, TL and Carroll, K and Waqar, A and Hudek, N and Mosa, M and Richards, DP and Meeking, K and Granieri, M and Smith, M and Walz, M and Etherington, C and Marlin, S and Gillies, K and Presseau, J and Brehaut, JC}, title = {A meta-review of patient engagement, shared decision-making, and factors influencing equity-deserving populations' participation in clinical trials.}, journal = {Research involvement and engagement}, volume = {12}, number = {1}, pages = {}, pmid = {41840453}, issn = {2056-7529}, support = {PJT-169055/CAPMC/CIHR/Canada ; PJT-169055/CAPMC/CIHR/Canada ; }, abstract = {BACKGROUND: Many equity-deserving populations, including those facing structural health inequities, lack support to participate in clinical trials while facing barriers to participation. Two approaches—patient engagement (PE) and shared decision-making (SDM)—can help trialists better understand and address such barriers. PE can improve the relevance of trials to silenced communities while SDM can align participation decisions among socially disadvantaged groups with their values, needs, and preferences, which may help overcome health inequities. Further, Indigenous community engagement is vital to address the effects of colonialism and promote Indigenous self-determination and health equity. The extent to which existing reviews have identified common barriers, enablers, and strategies across equity-deserving groups and discussed PE and SDM concepts is unclear. PURPOSE: (1) To describe which equity-deserving populations have been the focus of reviews on clinical trial participation and which barriers, enablers, and strategies are relevant to them (2) to explore the extent to which PE and SDM are discussed in these reviews. METHODS: We searched for English-language reviews (including any study design) summarizing trial participation barriers, enablers, and/or strategies among equity-deserving populations in five peer-reviewed databases. We coded data on the (1) equity-deserving population(s) of focus, (2) barriers, enablers, or interventions/strategies mentioned, (3) PE reported, (4) Indigenous community engagement reported, and (5) SDM outcomes discussed. RESULTS: Findings from 100 reviews showed that some equity-deserving populations have been represented more than others (e.g., 76% on racially, ethnically, culturally, or linguistically diverse populations; 29% on sex and gender populations; 2% on educationally disadvantaged populations). More reviews described barriers (84%) than enablers (31%) or strategies to improve participation (69%). Forty-five reviews (45%) reported PE while 11 (11%) reported Indigenous community engagement. Many reviews (74%) mentioned SDM outcomes (i.e., 9/11 [81.8%] outcomes from Gillies et al.’s internationally agreed core outcome set); however, few reviews (29%) discussed SDM outcomes in detail. CONCLUSIONS: Our findings suggest that PE and SDM could be more broadly applied among multiple equity-deserving groups to better serve disadvantaged communities. We advocate for an expanded focus on less-researched equity-deserving groups, improved PE reporting, prioritization of patient outcomes, and engagement with patients and Indigenous communities.}, }
@article {pmid41863721, year = {2026}, author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK}, title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {41863721}, issn = {1573-7365}, abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.}, }
@article {pmid41870724, year = {2026}, author = {Darwish, S and Ballout, S and Shi, L and Negron, R and Cooley, ME}, title = {Social Ties and Behavioral Diffusion of Tobacco Use in Arab American Networks.}, journal = {Journal of immigrant and minority health}, volume = {}, number = {}, pages = {}, pmid = {41870724}, issn = {1557-1920}, abstract = {Arab Americans (AAs) exhibit elevated rates of tobacco use, often influenced by their social networks (SN). Despite this, research has not comprehensively explored the mechanisms through which these relationships sustain tobacco use, and broader studies on social SNs provide limited insight into the influential SN attributes and interactions affecting AA communities. Guided by Berkman et al.’s (2000) SN and health framework, this study examined associations between SN structure, composition, relational and communication dynamics, and tobacco use among AAs. Variables included network size, density, SN compositional and demographic characteristics, contact modality and frequency, and relationship closeness. Data were collected through a cross-sectional survey of 178 AA adults in Massachusetts and analyzed using multivariate logistic regression. Overall, 51.7% of participants were current tobacco users; 45.5% reported hookah use, 13.5% cigarette use, and 18.5% used multiple products. Features of SNs associated with decreased odds of tobacco use included having larger SNs (OR = 0.38, 95% CI: 0.20–0.70), higher proportions of non-tobacco users (OR = 0.98), frequent in-person interactions with non-tobacco users (OR = 0.71), and stronger ties to non-tobacco users (OR = 0.074). Networks with greater Arab representation initially appeared protective but, in adjusted models, were associated with higher use (OR = 1.45), suggesting cultural identity and affiliation may reinforce smoking norms. Gender patterns also differed : networks with more women initially appeared protective, but after adjustment this association reversed (OR = 1.53), highlighting nuanced sociocultural impacts on behavioral change among Arab men and women following migration. Conversely, increased tobacco use was associated with greater contact with tobacco users, particularly through virtual modalities (OR = 1.027), and closer relationships with tobacco users (OR = 5.54). The findings suggest that tobacco use is propagated through both imitation and social reinforcement within strongly connected, homogenous networks. The study offers valuable insights into overlooked SN attributes and relational mechanisms relevant to understanding the transmission of tobacco use behaviors within AA populations. Identifying specific relational attributes may inform culturally tailored cessation interventions that leverage influential network members and key actors, strong social ties, and targeted modes of interaction, both in-person and digital, to enhance tobacco control strategies in AA communities.}, }
@article {pmid41894075, year = {2026}, author = {Kuwar, OK and Tejpal, S and Sharma, V and Sharma, A and Rao, A and Attri, M and Pallavi,  and Dhingra, MS}, title = {Therapeutic potential of sulforaphane in neurodegenerative diseases: mechanistic Insights into Nrf2, NF-κB, TrkB, SIRT1, MAPK, and JAK/STAT signalling pathways.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {41894075}, issn = {1573-4978}, abstract = {Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are chronic and progressive disorders distinguished by neuronal dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. Due to the multifactorial nature of these disorders, current pharmacotherapies provide limited symptomatic relief without altering disease progression. Sulforaphane, a naturally occurring isothiocyanate abundant in cruciferous vegetables like broccoli, has emerged as a potent neuroprotective compound owing to its pleiotropic effects on key cellular signalling pathways. This review provides a thorough overview of the mechanistic insights underlying SFN’s neuroprotective potential, with a focus on the modulation of key signalling pathways such as Nrf2/ARE, NFĸB, BDNF/TrkB, SIRT1, MAPK, and JAK/STAT. Through the activation of antioxidant defenses and suppression of inflammatory cascades, SFN effectively mitigates neuronal damage and supports cellular homeostasis. Preclinical studies consistently demonstrate SFN’s ability to attenuate oxidative stress, inhibit apoptosis, preserve mitochondrial function, and improve neurobehavioral outcomes. While limited clinical evidence supports its safety and bioactivity, further investigations are needed to establish its therapeutic utility in human populations. Overall, SFN represents a promising natural compound with significant potential for the prevention and management of neurodegenerative diseases through multi-targeted pathway modulation.}, }
@article {pmid42009918, year = {2026}, author = {G Diebo, B and E Nassar, J and Lafage, R and Challier, V and Pesenti, S and Lafage, V}, title = {Distinguishing reactive scoliosis: clinical presentation, pathophysiology and a proposed clinical framework.}, journal = {European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society}, volume = {}, number = {}, pages = {}, pmid = {42009918}, issn = {1432-0932}, abstract = {Purpose: This study introduces "reactive scoliosis" as an umbrella term formalizing various scoliosis subtypes that arise secondary to lumbar disc herniation, spondylolisthesis, and benign tumors. It aims to synthesize current evidence on the clinical presentations, pathophysiology, and surgical management of these subtypes, and to propose a preliminary clinical framework to guide their differentiation and treatment.Methods: A comprehensive literature search was conducted in PubMed/MEDLINE, Embase, and Scopus from inception through October 2025, following PRISMA guidelines. Search terms included combinations of "scoliosis" with "lumbar disc herniation", "spondylolisthesis", "osteoid osteoma", "osteoblastoma", and "ganglioneuroma". Studies were included if they addressed pathophysiology, clinical presentation, radiographic features, or surgical outcomes of reactive scoliosis subtypes. Two independent reviewers extracted data on curve magnitude, vertebral rotation, trunk shift, and surgical response.Results: Each reactive scoliosis subtype demonstrates distinct clinical and radiographic characteristics. Spasm scoliosis from lumbar disc herniation presents with short lumbosacral curves, minimal apical rotation, and significant coronal imbalance, typically resolving after discectomy. Pure spasm scoliosis from spondylolisthesis similarly resolves following fusion alone, while olisthetic scoliosis, characterized by vertebral rotation at the slip site rather than the curve apex, requires additional rotational correction. Tumor-driven scoliosis, including osteoid osteomas, osteoblastomas, and ganglioneuromas, demands individualized imaging and surgical strategies, with staged approaches warranted in structurally destructive cases.Conclusion: Accurate identification of reactive scoliosis subtypes is critical for surgical planning. The proposed expanded clinical framework, building upon Guo et al.'s modified Crostelli classification, offers surgeons a structured approach to differentiate these etiologies and optimize management. Prospective studies are needed to validate the algorithm and refine its clinical applicability.Keywords: Reactive scoliosis; Spasm scoliosis; Olisthetic scoliosis; Spondylolisthesis; Lumbar disc herniation}, }
@article {pmid42036486, year = {2026}, author = {Assefa, M and Tsegaye, A and Addissie, A and Worku, A}, title = {Establishing population-based reference intervals for hematological parameters among apparently healthy adults in Northwest Ethiopia, 2023.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-50237-3}, pmid = {42036486}, issn = {2045-2322}, support = {VPRTT/PY-002/20021//Addis Ababa University Thematic Research Fund/ ; VPRTT/PY-002/20021//Addis Ababa University Thematic Research Fund/ ; VPRTT/PY-002/20021//Addis Ababa University Thematic Research Fund/ ; VPRTT/PY-002/20021//Addis Ababa University Thematic Research Fund/ ; }, abstract = {Ethiopian diagnostic facilities currently use Western hematological reference ranges, lacking national standardization. This study establishes hematological reference values for healthy adults in Northwest Ethiopia through a population-based cross-sectional study conducted from June to August 2023. Whole blood samples from 759 participants were analyzed using the Siemens ADVIA-560 hematology analyzer. Data were processed with Stata 17.0, and reference intervals (RIs) were calculated for the central 95% of the distribution, with gender &amp; altitude differences assessed via the Mann-Whitney U test (p < 0.05). Sex and altitude based partitioning was done using Harris &amp; Boyd’s Z-test and Lahti et al.’s proportion criteria. Results showed significant variations by sex and altitude, with males exhibiting higher median values for several hematological parameters. The combined 95% reference intervals (RIs) were: WBC (3.11–9.89 × 10[9]/L), NEU (0.96–6.54 × 10[9]/L), LYM (0.69–2.89 × 10[9]/L), MON (0.31–1.46 × 10[9]/L), and BAS (0.05–0.42 × 10[9]/L), with corresponding differential percentages also established. Sex-specific RIs were defined for key parameters. In men: RBC (4.54–6.39 × 10[12]/L), HGB (13.68–19.21 g/dL), HCT (41.39–57.01%), MCHC (32.01–34.91 g/dL), and PLT (127.10–367.10 × 10[9]/L); and in women: RBC (4.17–5.55 × 10[12]/L), HGB (12.51–16.39 g/dL), HCT (37.91–48.89%), MCHC (31.51–34.70 g/dL), and PLT (146.22–411.00 × 10[9]/L). Altitude-based stratification further revealed higher values at high altitude. In men, monocytes, eosinophils, RBC, HGB, HCT, and PLT were elevated, while in women, higher values were observed for neutrophils, monocytes, basophils, HGB, HCT, MCV, and MCH. These findings demonstrate that hematological reference intervals vary by sex and altitude among healthy adults in Northwest Ethiopia. The study highlights the potential value of using locally derived and context-specific reference intervals to improve interpretation of laboratory results. Further multicenter validation studies across diverse Ethiopian populations are recommended to support their application in clinical practice and research.}, }
@article {pmid42260986, year = {2026}, author = {Sun, X and Dong, J and Liang, X and Peng, J and Chen, Y and Yin, R and Tan, T and Bai, L and Lan, K}, title = {PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/15548627.2026.2686417}, pmid = {42260986}, issn = {1554-8635}, abstract = {Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several malignancies, including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease, harbors a DNA replication helicase encoded by ORF44 that is crucial for viral replication and pathogenesis. In this study, we identified the host PFN1 (profilin 1), a well-known actin-binding factor, as an inhibitor of KSHV lytic replication functioning via the macroautophagy/autophagy-lysosomal degradation pathway targeting ORF44. Mechanistic analyses revealed that PFN1 interacts with ORF44, leading to enhanced polyubiquitination of PFN1. Notably, the E3 ubiquitin ligase TRIM37 (tripartite motif containing 37) facilitates the polyubiquitination of lysine residues at position 116 of PFN1, which serves as a critical recognition motif for the cargo receptor SQSTM1/p62 (sequestosome 1), which is pivotal for the subsequent autophagic degradation of ORF44. Overall, our findings revealed a previously uncharacterized antiviral function of PFN1, highlighting its potential as a novel therapeutic avenue for the treatment of KSHV-associated malignancies.Abbreviations: ALS: amyotrophic lateral sclerosis; Baf A1: bafilomycin A1; co-IP: co-immunoprecipitation; KSHV: Kaposi sarcoma-associated herpes virus; LIR: LC3-interacting region; PFN1: profilin 1; SQSTM1/p62: sequestosome 1; TRIM37: tripartite motif containing 37; UBA: ubiquitin-associated domain.}, }
@article {pmid42281996, year = {2026}, author = {Cooper-Knock, J and Bonsall, S and Kazu, R and King, M and Leung, D and Mahiddine, F and Highley, J and Strange, A and Chen, Y and Sassani, M and Eldahshoury, M and Boyne, J and Collins, M and Monte, E and Harvey, C and Gornall, S and Jangid, A and Treanor, C and Moll, T and van Dijk, C and Cabras, S and Urban, A and Bowden, K and Wareing, H and Huang, Y and Shaw, P and West, R and Kenna, K and Hornstein, E and Zhang, S and Zhou, J and Snyder, M}, title = {Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-9853460/v1}, pmid = {42281996}, issn = {2693-5015}, abstract = {Amyotrophic lateral sclerosis (ALS) causes selective neurodegeneration in primary motor cortex, yet cell-type-specific molecular changes driving this vulnerability remain poorly understood. We present an integrated single-nucleus RNA- and ATAC-sequencing atlas of 778,330 nuclei from the primary motor cortex of 140 genetically characterised donors. ALS is associated with widespread transcriptional reprogramming driven by a common set of transcription factors (TFs) across multiple cell-types. Astrocytes harbour the most differentially expressed genes. Within astrocytes, a WDR49-expressing subpopulation is spatially associated with TDP-43 pathology, and genetic variants within WDR49 confer risk for both sporadic and monogenic autosomal dominant ALS. In patient-derived induced astrocytes, WDR49 protein abundance predicts the survival of co-cultured neurons. WDR49 localises to PML nuclear bodies, where it regulates astrocyte reactivity and secretion of EVs containing protein chaperones. Together, these in vivo and in vitro findings suggest that WDR49+ astrocytes mount a compensatory secretory response to extracellular protein aggregates, and that loss of this capacity lowers the threshold for ALS pathogenesis.}, }
@article {pmid42282536, year = {2026}, author = {Cortez, JD and Avalos, JL}, title = {Heterologous iron-sulfur cluster biogenesis and delivery for cytosolic isobutanol and isopentanol production in Saccharomyces cerevisiae.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.29.728687}, pmid = {42282536}, issn = {2692-8205}, abstract = {Saccharomyces cerevisiae is an excellent microbial platform for sustainable production of next generation biofuels such as the branched chain higher alcohols (BCHAs) isobutanol and isopentanol. A cytosolic pathway for BCHA production is generated from expression of prokaryotic orthologs of branched-chain amino acid (BCAA) enzymes acetolactate synthase (ALS), mutant NADH-dependent ketol-acid reductoisomerase (KARI [P2D1-A1]), and dihydroxy-acid dehydratase (DHAD). The potential for this pathway has been hindered by the availability of iron-sulfur clusters, particularly the 2Fe-2S cluster, required for DHAD to function in the cytosol. ILV3 , the endogenous yeast DHAD located in the mitochondria, can be deleted to create a valine auxotroph. In this study we use bioinformatics, heterologous gene library synthesis, and a valine complementation assay to find prokaryotic iron-sulfur cluster biosynthetic gene clusters (BGC) and accessory genes that aid DHAD function in the yeast cytosol. This work presents, to our knowledge, the first functional BGC that enhances the cytosolic activity of prokaryotic DHADs in S. cerevisiae . The SUF BGC from Bacillus subtilis combined with a ferritin-like protein (FTNB) from Escherichia coli and the Lactococcus lactis DHAD enhanced the production of BCHAs. Combined expression gave an average isobutanol titer of 412mg/L, 1.8-fold greater than L. lactis DHAD expressed alone. This work establishes a blueprint for better biofuel production by improving iron-sulfur cluster dependent enzyme activity in the yeast cytosol.}, }
@article {pmid42282588, year = {2026}, author = {Kochen, NN and Zafari, S and Renaud, A and Schneider, N and Vunnam, N and Liao, EE and Dutton, JR and Braun, AR and Sachs, JN}, title = {From anti-fungal to potential neurotherapeutic: Posaconazole as an effective inhibitor of cellular TDP-43 pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.06.01.728552}, pmid = {42282588}, issn = {2692-8205}, abstract = {Recently, we showed that ketoconazole, a known anti-fungal inhibitor of CYP51, stabilized TAR DNA-binding protein 43 (TDP-43) native self-interactions, reduced TDP-43 pathology and rescued TDP-43-induced SREBP2 downregulation. Despite its promising effects, ketoconazole is not viable for repurposing for ALS due to liver toxicity side effects that occur when orally delivered. To address this, we tested the activities of seven additional known azole-based CYP51 inhibitors in order identify a viable alternative to ketoconazole. Using our established TDP-43 mislocalization and aggregation assay in HEK293T cells, we identified posaconazole, an FDA-approved, CNS-penetrant and orally delivered anti-fungal, as the strongest inhibitor of TDP-43 pathology. Posaconazole was able to reduce insoluble TDP-43 and restore SREBP2 levels, outperforming ketoconazole. Mechanism of action (MOA) experiments suggest posaconazole is able to outperform ketoconazole by inducing a significantly stronger activation of autophagy and upregulation of heat shock proteins known to clear TDP-43. Further MOA experiments show that the effects of posaconazole on TDP-43 are dependent on its known ability to lower cellular cholesterol levels. By correlating our experimental results on the eight CYP51 inhibitors tested, we show that predicted affinity towards human CYP51 strongly correlates with the inhibitors' ability to lower TDP-43 aggregation and mislocalization. Finally, we tested posaconazole in a low dose sodium arsenite ALS model in iPSC-derived motor neurons, showing that it is efficacious at inhibiting TDP-43 pathology in the nanomolar range. Altogether, these results support the repurposing of posaconazole for ALS/FTD as a means to prevent TDP-43 pathology.}, }
@article {pmid42282797, year = {2026}, author = {Yusuf, IO and Silva, RLA and Amoako, GG and Thompson, PR and Xu, Z}, title = {PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.30.729013}, pmid = {42282797}, issn = {2692-8205}, abstract = {BACKGROUND: Dysregulated peptidyl deiminase 2 (PAD2) and aberrant protein citrullination (PC), a posttranslational modification (PTM), are involved in various inflammatory and neurodegenerative diseases. We previously showed in transgenic mice and postmortem human tissues that PC and PAD2 are altered in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons loss, paralysis, and death. Herein, we investigated the role of PAD2 in ALS by PAD2 knockout in a SOD1-ALS mouse model.<br><br>METHODS: To investigate the role of PAD2-induced citrullination in ALS pathogenesis, we generated PAD2 knockout (PAD2KO) in SOD1 [G93A] ALS mouse model and investigated the consequent modulation on the neuropathology and clinical symptoms, using molecular biology techniques such as qPCR, Western blotting, confocal microscopy, and electron microscopy. Additionally, we identified C3 as being citrullinated in human ALS using ionFinder.<br><br>RESULTS: Our results show that PAD2KO blocked the increased PC and reduced myelin basic protein (MBP) aggregates in the ALS model. PAD2KO also improved motor neuron survival and the integrity of myelin, axons, and neuromuscular junctions, and reduced microgliosis in the white matter and C3 protein levels in astrocytes. Clinically, data from monitoring the body weight changes suggests that PAD2KO modulates the course of the disease in the ALS mouse model, accelerating the onset while slowing the progression after the onset, and modestly extending the survival of male mice.<br><br>CONCLUSION: These results show that PAD2 is responsible for the increased PC in ALS and PC contributes to neuroinflammation and degeneration of motor neurons and myelinated axons. The modest modulation of the disease phenotype suggests that the role of PC in ALS is complex, involving altered PC in numerous proteins and in multiple cell types. Future studies are needed to investigate how PC modulates individual protein functions in various cell types to understand the contribution of PC to ALS pathogenesis.}, }
@article {pmid42283221, year = {2026}, author = {Scozzari, S and Columbro, SF and Favagrossa, M and Tortarolo, M and Cagnotto, A and Salmona, M and De Marco, G and Bendotti, C and Calvo, A and Pasetto, L and Bonetto, V}, title = {Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on TDP-43 Proteinopathy.}, journal = {Journal of neurochemistry}, volume = {170}, number = {6}, pages = {e70493}, pmid = {42283221}, issn = {1471-4159}, support = {RF-2018-12365614//Ministero della Salute/ ; GATTALS//AriSLA/ ; }, mesh = {Animals ; *Histone Deacetylase Inhibitors/administration &amp; dosage/pharmacology ; Humans ; Mice ; Acetylation/drug effects ; *Lysine/metabolism/antagonists &amp; inhibitors ; *TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; Mice, Transgenic ; Vorinostat/administration &amp; dosage ; *DNA-Binding Proteins/metabolism ; Male ; }, abstract = {Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isomerase A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA Lys-acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP-43 proteinopathy in vitro and in vivo and how this relates with PPIA. We found that vorinostat/SAHA, a broad-spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP-43 mislocalization in a cellular model of TDP-43 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP-43 proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co-inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP-43 accumulation in the sciatic nerve and acetylcholine receptor γ-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP-43 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of lysine deacetylation inhibition and arimoclomol shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.}, }
@article {pmid42283246, year = {2026}, author = {Fikry, H and Saleh, LA and Sadek, DR}, title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/ca.70147}, pmid = {42283246}, issn = {1098-2353}, abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.}, }
@article {pmid42283497, year = {2026}, author = {Turner, ED and Twelvetrees, AE}, title = {The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.}, journal = {Journal of neurochemistry}, volume = {170}, number = {6}, pages = {e70496}, pmid = {42283497}, issn = {1471-4159}, support = {220192/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Microtubules/metabolism/physiology ; Animals ; *Neurons/metabolism/physiology ; *Molecular Motor Proteins/metabolism/genetics ; Mutation ; }, abstract = {The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.}, }
@article {pmid42283699, year = {2026}, author = {El-Wahsh, S and Bogart, E and Bonnor, S and El-Wahsh, S and Graco, M and Hogden, A and Paynter, C and Raykar, V and Signorelli, M and Thomson, E and Vucic, S and White, S}, title = {Supporting gastrostomy decision-making in motor neurone disease (MND): an Australian survey of healthcare professionals' beliefs, practices, and needs.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/17582024.2026.2687483}, pmid = {42283699}, issn = {1758-2032}, abstract = {INTRODUCTION: Gastrostomy decision-making for people living with motor neurone disease (MND) is complex. While international studies report healthcare professionals' (HCPs) beliefs and practices in this area, little is known about the Australian context.<br><br>AIM: To examine Australian HCPs' beliefs, clinical practices, and support needs regarding gastrostomy decision-making in MND.<br><br>METHODS: A national cross-sectional online survey of Australian HCPs involved in gastrostomy discussions (n&#x2009;=&#x2009;123) was conducted, exploring five domains: 1) initiating discussions and timing; 2) patient education; 3) multidisciplinary coordination; 4) guideline use; 5) and professional development needs. Descriptive statistics were applied.<br><br>RESULTS: Most HCPs initiated discussions about gastrostomy (74%), commonly prompted by swallowing difficulty, weight loss, or patient request. Although 72% believed discussions should occur before clinical indications, only 40% reported doing so. Earlier placement was favored in the context of respiratory decline compared with swallowing impairment, and 56% considered gastrostomy to be performed too late. Almost 40% used no formal guidelines, and 74% wanted further professional development.<br><br>CONCLUSION: Australian HCPs valued person-centered practice, but belief-practice gaps highlight opportunities to improve consistency, timing, and quality of gastrostomy decision-making support. Enhanced national guidelines, improved multidisciplinary communication, and targeted professional development may help reduce delays and better align practice with evidence-based recommendations.}, }
@article {pmid42285406, year = {2026}, author = {Mendoza-Camacho, DM and Espinoza-Gutiérrez, HA and Viveros-Paredes, JM and Flores-Soto, ME and Tejeda-Martínez, AR}, title = {Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.06.011}, pmid = {42285406}, issn = {1873-7544}, abstract = {Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid 2-Arachidonoylglycerol (2-AG) while simultaneously contributing to the generation of arachidonic acid and pro-inflammatory eicosanoids. Pharmacological or genetic inhibition of MAGL increases 2-AG levels and concurrently reduces the biosynthesis of pro-inflammatory lipid mediators, thereby modulating microglial activation, astrocytic responses, and neuronal excitotoxicity. Preclinical studies in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis consistently demonstrate that MAGL blockade attenuates neuroinflammation, preserves synaptic and neuronal integrity, improves motor and cognitive function, and, in some cases, delays disease progression. Although clinical evidence remains limited, the available data position MAGL as a metabolic convergence point between inflammation and neurodegeneration, suggesting that its modulation may represent a therapeutic strategy with disease-modifying potential.}, }
@article {pmid42286474, year = {2026}, author = {Seuren, LM and Versloot, J and Taneja, S and Zeeshan, MF and Wodchis, WP}, title = {Adoption and sustainability of a virtual interprofessional team for primary care in Ontario: a qualitative study.}, journal = {BMC primary care}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12875-026-03411-5}, pmid = {42286474}, issn = {2731-4553}, abstract = {BACKGROUND: Primary care providers across Canada face challenges caring for patients with increasingly complex care needs. Team-based care has been identified as an approach to improve care for patients with complex needs. The Mississauga Ontario Health Team recently adopted SCOPE, a telephone-based support line to improve care coordination between primary care, hospital and community services. To understand how Mississauga Health SCOPE supports primary care providers and how it can be improved, this study addresses the following research question: why do primary care providers adopt or not adopt Mississauga Health SCOPE, and what motivates sustained use or abandonment?<br><br>METHODS: Semi-structured interviews were conducted over Zoom with three stakeholder groups: primary care providers (n&#x2009;=&#x2009;20), general internal medicine physicians (n&#x2009;=&#x2009;3), and members of the project team (n&#x2009;=&#x2009;6). Interviews focused on the adoption and continued use of Mississauga Health SCOPE. Data were analyzed inductively, using Proctor et al.'s Adoption and Sustainability concepts.<br><br>RESULTS: Within the broad concepts of Adoption and Sustainability, we identified seven themes that shaped whether PCPs would use and continue to use MHSCOPE: Broken healthcare system, Awareness of Mississauga Health SCOPE, Service misalignment, Useful and usable, Trying it out, Breaking the habit, and Making PCPs feel heard.<br><br>CONCLUSIONS: Telemedicine support services like Mississauga Health SCOPE can help primary care providers deliver appropriate and timely care to patient in the community. Succcesful implementation requires that clinicians feel supported in using the intervention, have a clear understanding of procedures and benefits, and are prepared to take time to learn to work with new tools to overcome hurdle of initial adoption.}, }
@article {pmid42286604, year = {2026}, author = {Forster, L and Byrne, S and Spielmann-Burkard, H and Weber, S and von Strachwitz, M and Kuehlmeyer, K and Kugler, C}, title = {Linguistic and psychometric validation of a German version of the measure of moral distress for healthcare professionals (MMD-HP GER): results of a study with intensive care nurses.}, journal = {BMC medical ethics}, volume = {27}, number = {1}, pages = {}, pmid = {42286604}, issn = {1472-6939}, mesh = {Humans ; Ethical Dilemmas ; Germany ; *Psychometrics ; Female ; Adult ; Surveys and Questionnaires ; Male ; Reproducibility of Results ; Translating ; *Critical Care Nursing/ethics ; *Stress, Psychological/diagnosis ; *Morals ; Middle Aged ; }, abstract = {BACKGROUND: Moral distress is an increasingly studied phenomenon in nursing science and ethics. It refers to the psychological discomfort experienced when an individual is prevented from acting on a course of action that they recognize as ethically correct. Nurses who work in intensive care are at high risk of experiencing moral distress. Various instruments to assess moral distress, most recently Epstein et al.'s measure of moral distress for health care professionals (MMD-HP), have been developed. At present, there is no validated German language version of the instrument for assessing moral distress in Germany. Therefore, this study aimed, at (1) translating and linguistically validating the instrument, as well as (2) psychometrically validating it among intensive care nurses in Germany.<br><br>METHODS: According to the ISPOR (International Society for Pharmacoeconomics and Outcomes Research) guidelines, the MMD&#x2011;HP was translated, linguistically validated, and psychometrically tested. The German version of the moral distress thermometer (MDT) and the German Nursing Workload Scale (NWS) were used to measure the construct validity of the translated instrument. Institutional ethics review boards of two universities approved the study protocols.<br><br>RESULTS: A total of 187 questionnaires of intensive care nurses remained for analysis after listwise deletion. The mean sum&#x2011;score was 106.9&#x202f;(&#xb1;&#x202f;62) (minimum&#x202f;=&#x202f;3, maximum&#x202f;=&#x202f;325; range&#x202f;=&#x202f;0-400). Criterion validity was supported by a high positive correlation between the German version of the MMD&#x2011;HP and the validated German-language moral distress thermometer (&#x3c1;&#x202f;=&#x202f;0.598, p&#x202f;=&#x202f;0.001, n&#x202f;=&#x202f;168). Factor analyses revealed a four&#x2011;factor solution with correlating factors for the German version. The instrument showed high reliability (&#x3c9;H&#x202f;=&#x202f;0.91, 95&#x202f;%&#x202f;CI&#x202f;=&#x202f;0.88-0.93).<br><br>CONCLUSIONS: Our findings demonstrate that the German adaptation of the MMD-HP shows potential for measuring moral distress among intensive care nurses in Germany. In addition, its psychometric properties preliminarily support its reliability and validity in this cultural context. Further independent validation studies are needed to provide support for the proposed four-factor model.}, }
@article {pmid42286839, year = {2026}, author = {Wheeler, A and Mehta, K and Sanders, D and Chin, C and Zivalic, H and Carey, J and McCaffrey, A and Pant, P and Lewenhaupt, C and Luppino, S and Jacobs, G and Golden, S and Gifford, R and Scirocco, E and Keegan, M and Hatem, M and Yazdanian, T and Uysal, SP and Susco, N and Schwartzman, S and Branch, K and Hall, KE and Barnas, J and Lam, J and Hagar, J and Hannan, CA and Paganoni, S and Berry, JD and Garret, M and Scalia, J and Babu, S}, title = {Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70310}, pmid = {42286839}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Tofersen is a gene-targeted therapy for individuals with superoxide dismutase 1 (SOD1) (+) amyotrophic lateral sclerosis (ALS). Prior to U.S. Food and Drug Administration (FDA) approval, tofersen was made available through expanded access protocol. This study describes the clinical and operational experience of administering tofersen through expanded access protocols at a single academic medical center in the U.S.<br><br>METHODS: Individuals with symptomatic SOD1(+) ALS (&#x2265;&#x2009;18&#x2009;years), who were ineligible for traditional ALS clinical trials, received tofersen via bedside lumbar punctures at Massachusetts General Hospital. Treatment was provided through single-patient and intermediate-sized expanded access protocols prior to FDA approval. Demographic and clinical characteristics, referral-to-treatment timelines, safety outcomes, and operational costs were collected.<br><br>RESULTS: Eleven individuals with SOD1(+) ALS received monthly intrathecal tofersen over a two-year period (July 2021 to July 2023). Most participants were female, and 81.8% had leg-onset ALS. The mean (SD) referral-to-first dose duration was 36 (22.4) days. A total of 120 doses were administered over a two-year period. Tofersen was safe and well tolerated, with no treatment-related serious adverse events. Operational costs totaled $336,620, supported by philanthropy and insurance. The company provided the drug for free.<br><br>DISCUSSION: This experience demonstrates the feasibility of implementing a resource-intensive expanded access protocol within an academic medical center using a mixed funding model to facilitate early access to emerging ALS therapies.}, }
@article {pmid42287757, year = {2026}, author = {Jaberi, KR and Haghighi, MR and Aligholi, H and Takallu, S and Asadi, P and Mirzaei, E and Jaberi, AR and Sahraian, A}, title = {Focused ultrasound-mediated nanocarrier delivery across the blood-brain barrier for neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {201}, number = {}, pages = {119622}, doi = {10.1016/j.biopha.2026.119622}, pmid = {42287757}, issn = {1950-6007}, abstract = {The development of effective therapies for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB). Conventional systemic drug delivery strategies often fail to achieve sufficient central nervous system (CNS) penetration while avoiding peripheral toxicity. Focused ultrasound (FUS), particularly when combined with microbubbles or nanocarriers, has emerged as a non-invasive approach to transiently and precisely open the BBB, enabling targeted delivery of therapeutics to the brain parenchyma. This review provides a comprehensive overview of the mechanisms by which FUS enhances CNS drug delivery, with a dedicated focus on its integration with nanoparticle-based systems, including liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, and exosomes. We discuss how these nanocarriers can be engineered for improved stability, targeting specificity, and stimulus-responsive release upon FUS exposure. Recent advances in ultrasound technology, image guidance (particularly MRI), and therapeutic formulations are summarized, along with preclinical and clinical evidence across key neurodegenerative conditions. Despite promising results, several challenges remain, including long-term BBB stability, regulatory standardization, and scalability for broad clinical application. By integrating principles from acoustics, pharmacology, and nanotechnology, FUS-mediated drug delivery, especially in combination with smart nano systems, represents a significant advancement in precision neurotherapeutics, offering new hope for previously untreatable CNS diseases.}, }
@article {pmid42287763, year = {2026}, author = {Mah, SJ and Bergeron, AM and Hanley, G and Yang, I and Bogach, J and Nguyen, L and Huerne, K and Morais, M and Stuart, H}, title = {Opportunistic salpingectomy during non-gynecologic surgery: Canadian surgeons' experience, barriers and facilitators.}, journal = {Gynecologic oncology}, volume = {211}, number = {}, pages = {1-7}, doi = {10.1016/j.ygyno.2026.06.005}, pmid = {42287763}, issn = {1095-6859}, abstract = {BACKGROUND: Opportunistic salpingectomy during concurrent abdominopelvic surgery has been shown to significantly reduce ovarian cancer risk. Uptake by non-gynecologic surgeons could increase population impact. We conducted a national survey of general and urologic surgeons using Michie et al.'s implementation framework of Capability, Motivation, Opportunity-Behaviour to understand understand current experience with opportunistic salpingectomy, and facilitators and barriers to adoption.<br><br>METHODS: An online survey was administered to Canadian general and urologic surgeons and postgraduate trainees from January-June 2024. A multivariable logistic regression model assessed relationship between demographic factors and motivation to adopt opportunistic salpingectomy.<br><br>RESULTS: 269 surveys were completed by 226 general surgeons and 43 urologists. Although 88% reported motivation to perform opportunistic salpingectomy for cancer prevention, practice duration &#x2265;21&#xa0;years and province of practice were associated with decreased motivation. Only 44% were aware of recommendations endorsing the procedure, and 19% had performed it. Commonly reported barriers to adoption were Capability (consenting patients regarding permanent contraception and ovarian function, and intraoperative technique/complications), and Opportunity (reimbursement). A surgical video was the preferred method to learn salpingectomy by 94%, and patient consent handouts and intraoperative training by a gynecologist were facilitators. Most (92%) stated that opportunistic salpingectomy training should be offered to postgraduate trainees.<br><br>DISCUSSION: Most general and urologic surgeons in Canada were unaware of and have not performed opportunistic salpingectomy but were motivated to offer it. Providing consent resources and training opportunities with gynecologist support, and addressing cultural and regulatory factors may improve uptake by surgeons and decrease ovarian cancer incidence.}, }
@article {pmid42288074, year = {2026}, author = {Tackaert, T and Hemeryck, J and Duchatelet, C and Vanwulpen, M and Hachimi-Idrissi, S}, title = {Mean airway pressure as the missing link in CPR physiology: A prehospital comparison of manual and mechanical chest compressions.}, journal = {The American journal of emergency medicine}, volume = {108}, number = {}, pages = {80-85}, doi = {10.1016/j.ajem.2026.06.012}, pmid = {42288074}, issn = {1532-8171}, abstract = {BACKGROUND: The impact of manual versus mechanical chest compressions on mean airway pressure (mPAW) during cardiopulmonary resuscitation (CPR) is poorly understood. This exploratory pilot study assessed intratracheal airway pressures during prehospital CPR in out-of-hospital cardiac arrest (OHCA).<br><br>METHODS: Adult OHCA patients treated by the prehospital Medical Emergency Team of the Ghent University Hospital (Belgium) were prospectively enrolled. Intratracheal pressure was recorded immediately after intubation, mPAW was calculated for both the first and last minutes of advanced life support (ALS). The results were compared between mechanical compressions using the Stryker LUCAS3&#xae; device and manual chest compressions (with chest compression feedback).<br><br>RESULTS: Nineteen patients were included (manual n&#xa0;=&#xa0;10; mechanical n&#xa0;=&#xa0;9). Initial median mPAW was low (7.74&#xa0;mbar) and showed a slight increase over time. Mechanical compressions generated higher early mPAW than manual compressions (8.96 vs. 6.54&#xa0;mbar). mPAW increased over time with manual compressions and decreased with mechanical compressions. Patients who achieved return of spontaneous circulation (ROSC) showed higher mPAW, though this difference was not statistically significant.<br><br>CONCLUSIONS: Prehospital mPAW values were substantially lower than those reported in previous ED-based studies. While airway pressure patterns differed between compression modalities, overall pressures were similar. These findings highlight complex airway mechanics during CPR and support further research into whether higher airway pressures could improve airway patency, oxygenation, and hemodynamics in selected OHCA patients.}, }
@article {pmid42288493, year = {2026}, author = {Wang, N and Li, Y and Li, N and Shen, L and Wang, C and Zhu, H and Zhou, Z and Ding, Y and Zhang, J and Fang, L and Bai, B}, title = {Quantitative Proteomics Unveils Comprehensive Tissue-Specific VCP Interaction Networks in Mice.}, journal = {Scientific data}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41597-026-07626-0}, pmid = {42288493}, issn = {2052-4463}, support = {32071256//National Natural Science Foundation of China/ ; 82172354//National Natural Science Foundation of China/ ; }, abstract = {Valosin-containing protein (VCP), a conserved AAA ATPase hexamer, participates in multiple biological processes including ERAD, ubiquitin-dependent degradation by extracting misfolded proteins for proteasomal degradation. Although its interactions with cofactors are well-characterized, and its dysregulation is implicated in multisystem proteinopathy, amyotrophic lateral sclerosis, and cancer, the tissue-specific VCP interactomes underlying its functional versatility remain elusive. Here, we generated HA-N-tagged VCP knock-in mice via CRISPR/Cas9 strategy and performed affinity purification coupled with data-independent acquisition (DIA) mass spectrometry to systematically profile VCP interactors across eight mouse tissues, yielding a high-confidence dataset. We identified 923 robust VCP-binding partners, including established interactors (UBX2B, UFD1, proteasomal subunits) and novel candidates implicated in energy metabolism (TCA cycle, oxidative phosphorylation) and protein quality control (proteasome, ERAD). Notably, we validated the interaction of VCP to two hepatic candidate proteins, DAXX and PRKAG2 (AMPK γ2 regulatory subunit), using HepG2 cells. This study establishes the first in vivo atlas of the VCP interaction network, providing mechanistic insights into its tissue-specific roles and highlighting potential therapeutic avenues for VCP-related disorders.}, }
@article {pmid42289132, year = {2026}, author = {Jamil, V and Aldoski, M and Selivany, B and Jameel, D}, title = {MORPHOLOGY AND PREVALENCE OF C-SHAPED CANALS IN MANDIBULAR FIRST MOLARS OF AN IRAQI KURDISTAN REGION POPULATION: A CONE-BEAM COMPUTED TOMOGRAPHY ASSESSMENT.}, journal = {Georgian medical news}, volume = {}, number = {373}, pages = {215-218}, pmid = {42289132}, issn = {1512-0112}, mesh = {Humans ; Female ; Male ; *Cone-Beam Computed Tomography ; Iraq/epidemiology ; *Molar/diagnostic imaging/anatomy &amp; histology ; Adult ; Adolescent ; Middle Aged ; *Dental Pulp Cavity/diagnostic imaging/anatomy &amp; histology ; *Tooth Root/diagnostic imaging/anatomy &amp; histology ; Retrospective Studies ; *Mandible/diagnostic imaging/anatomy &amp; histology ; Young Adult ; Prevalence ; }, abstract = {BACKGROUND: Root canal morphology variations, particularly C-shaped canal configurations, pose substantial challenges to successful endodontic therapy. Accurate preoperative assessment of these complex anatomical patterns remains essential, with cone-beam computed tomography (CBCT) offering superior three-dimensional visualization compared to conventional radiography.<br><br>OBJECTIVES: This study aimed to determine the prevalence and morphological characteristics of C-shaped canals and comprehensively evaluate root and canal configurations of mandibular first molars within an Iraqi Kurdish population using CBCT imaging.<br><br>METHODS: In this retrospective analysis, CBCT images from 323 patients (186 males, 137 females; aged 18-50 years) originating from Duhok, Erbil, and Suleimani underwent evaluation. Two calibrated endodontists independently examined axial, sagittal, and coronal reconstructions to document root numbers, canal counts, and configurations. Root canal morphology was classified according to Vertucci's system, while Fan et al.'s classification was applied only to confirmed true C-shaped canals. Chi-square analysis assessed gender-based differences, with statistical significance set at p&#x2264;0.05.<br><br>RESULTS: Two-rooted molars predominated (94.1%), typically exhibiting three (64.4%) or four canals (28.8%). Gender differences proved non-significant for root (p=0.653) and canal numbers (p>0.05). Mesial roots consistently demonstrated Vertucci Type IV morphology (90.1%), while distal roots displayed greater diversity: Type I (58.5%), Type IV (20.1%), and Type II (18.6%). Cross-sectional morphology was not analyzed using Fan classification for non-C-shaped canals. True C-shaped canal configurations were rare (0.6%; 2/323 teeth), with no significant gender association (p>0.05).<br><br>CONCLUSION: Iraqi Kurdish mandibular first molars typically exhibit predictable mesial root Type IV anatomy alongside variable distal root morphology requiring careful clinical exploration. The low true C-shaped canal prevalence (0.6%) underscores ethnicity-specific anatomical patterns. These findings advocate judicious CBCT utilization for complex endodontic cases while emphasizing systematic distal canal detection protocols.}, }
@article {pmid42289668, year = {2026}, author = {Pillay, S and Head, J and Horn, A and de Wet, W and Davidge, R and Dickson-Hall, M and Felix, G and Kali, G and Khan, W and Klein, B and Nakwa, F and Venter, M and Vlok, N and Wege, M and Stassen, W}, title = {The development of a consensus-based curriculum for a Bespoke Online Neonatal Education for Transfers (BONNETs) course.}, journal = {BMC medical education}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12909-026-09377-3}, pmid = {42289668}, issn = {1472-6920}, abstract = {BACKGROUND: High neonatal mortality in Sub-Saharan Africa (SSA) is driven by multiple systemic barriers, including insufficient neonatal transport infrastructure and limited provider training. Although specially trained neonatal retrieval teams are recommended for interfacility neonatal transfers, resource constraints lead to non-specialist emergency medical services (EMS) cadres performing these roles, potentially compromising the safe transport of critically ill neonates.<br><br>OBJECTIVE: To develop a bespoke, online neonatal interfacility transfer curriculum, informed by expert consensus and South African research to address critical gaps in provider knowledge and confidence, thereby improving neonatal transfer outcomes.<br><br>METHODS: Building on Kern's Six-Step Framework for curriculum development, an initial curriculum was derived through a comprehensive literature review, a retrospective chart analysis of neonatal cases in South Africa, and detailed interviews with experts and learners. Consequently, consensus on this curriculum was sought using a virtual, modified Nominal Group Technique (NGT) over two consensus rounds. A refined course curriculum is proposed.<br><br>RESULTS: Fourteen expert participants (neonatologists, paediatricians, neonatal nurses, and Advanced Life Support (ALS) providers with &#x2265;&#x2009;3 years of experience) allocated potential outcomes to Core, Extended, or Advanced tiers based on EMS scope of practice. A 75% consensus threshold was applied. Eleven experts completed both rounds (21% attrition). Most were ALS providers (43%), largely employed in the public sector (71%). The final curriculum consists of three sequential courses (Core, Extended, Advanced) which scaffolds learning. The Core course consists of five modules, with each curriculum item achieving&#x2009;>&#x2009;90% agreement on foundational skills including basic assessment, recognition of critical instability, and escalation pathways. This open-access online course is tailored to resource-limited settings.<br><br>CONCLUSION: A consensus-driven neonatal interfacility transfer curriculum for South Africa was successfully developed, providing a tiered, evidence-based approach to reinforce provider knowledge and confidence. By leveraging expanding internet accessibility, the Bespoke Online NeoNatal Education for Transfers (BONNETs) framework mitigates geographic disparities while integrating best practices for safe neonatal transfer. However, rigorous validation across diverse contexts and attention to broader systemic challenges, is essential to achieving sustained improvements. Future research should assess the curriculum's performance in improving knowledge and confidence, as well as long-term clinical impact on neonatal outcomes.}, }
@article {pmid42290091, year = {2026}, author = {Khamies, MS and Mortada-Mahmoud, A and Laklouk, M}, title = {Naviculectomy combined with 'à la carte' soft-tissue releases: is it a practical solution for congenital vertical talus in adolescence?.}, journal = {Journal of pediatric orthopedics. Part B}, volume = {}, number = {}, pages = {}, doi = {10.1097/BPB.0000000000001364}, pmid = {42290091}, issn = {1473-5865}, abstract = {Neglected congenital vertical talus in adolescents often necessitates extensive soft-tissue dissection, leading to increased surgical trauma and worsening outcomes. We propose that excising the navicular bone can shorten the foot's medial column and loosen the ligaments around the talonavicular joint, thus improving reduction. This study aimed to evaluate whether naviculectomy and 'à la carte' soft-tissue releases could enhance the outcomes in these patients or not. A retrospective case series study was conducted on 15 adolescent patients (average age 10.67 years) with neglected congenital vertical talus from June 2020 to 2025, with a median follow-up of 24 months. All cases were idiopathic, neglected, virginal feet that had not undergone any manipulative casting before. Clinical assessments followed Zorer et al.'s criteria, and pain levels were evaluated using the visual analog scale (VAS). There were 11 boys and 4 girls. The median Zorer score increased from 2 preoperatively to 11 postoperatively, with a mean difference of 10 (P < 0.001), reflecting marked functional recovery. The median VAS score showed significant improvement at the final follow-up from 7 to 2 (P < 0.001). Significant improvement was observed in all radiographic measurements. Naviculectomy combined with 'à la carte' soft-tissue releases could be a practical, effective solution for adolescents with neglected congenital vertical talus in terms of pain relief, clinical, and radiological improvement while reducing complications associated with extensive surgical soft-tissue releases on short-term outcomes.}, }
@article {pmid42290559, year = {2026}, author = {Martyniuk, &#x41e; and Mushii, O and Pavlova, A}, title = {Integrated Analysis of hsa-miR-26b-5p and hsa-miR-186-5p in Blood Serum and Tumor Tissue Reveals their Prognostic and Predictive Significance in Breast Cancer.}, journal = {Experimental oncology}, volume = {48}, number = {1}, pages = {31-39}, doi = {10.15407/exp-oncology.2026.01.031}, pmid = {42290559}, issn = {2312-8852}, mesh = {Humans ; *MicroRNAs/genetics/blood ; Female ; *Breast Neoplasms/genetics/blood/pathology/mortality ; Prognosis ; *Biomarkers, Tumor/genetics/blood ; Middle Aged ; Adult ; Gene Expression Regulation, Neoplastic ; }, abstract = {BACKGROUND: Breast cancer (BC) heterogeneity signifi antly complicates diagnosis, prognosis, and prediction of treatment response. MicroRNAs (miRNAs) have emerged as promising biomarkers due to their involvement in tu- mor progression and in regulating therapy sensitivity. however, the combined clinical signifi ance of circulating and tumor-associated miRNAs, such as hsa-miR-26b-5p and hsa-miR-186-5p, remains insuffi tly elucidated. Materi- als and Methods. Expression levels of hsa-miR-26b-5p and hsa-miR-186-5p were analyzed in serum and tumor tis- sue of 124 BC patients. Associations with clinicopathological parameters were assessed. The prognostic signifi ance was evaluated based on disease progression and recurrence within 3 years. The predictive value was determined in patients receiving neoadjuvant chemotherapy (4AC regimen) using response assessment and ROC analysis. Re- sults. young BC patients (≤45 years) demonstrated signifi antly lower circulating levels of both miRNAs. Serum hsa-miR-186-5p expression was associated with early-stage disease, tumor size, lymph node status, and molecular subtype. Increased circulating hsa-miR-26b-5p levels were linked to disease progression, whereas decreased hsa- miR-186-5p levels were observed in patients with unfavorable outcomes. In tumor tissue, hsa-miR-26b-5p expres- sion correlated with tumor grade, size, and metastatic status, showing elevated levels in poorly differentiated tumors and reduced expression in metastatic disease. In contrast, hsa-miR-186-5p was associated with the molecular sub- type and lymph node involvement, with the highest expression observed in hER2-positive tumors and in patients with recurrence. Elevated levels of hsa-miR-186-5p in both serum and tumor tissue were associated with reduced sensitivity to doxorubicin-based neoadjuvant chemotherapy. ROC analysis confi med its predictive value (AUC = 0.750 for serum and 0.818 for tumor tissue). No signifi ant association between hsa-miR-26b-5p and chemothe- rapy response was observed.<br><br>CONCLUSIONS: hsa-miR-26b-5p and hsa-miR-186-5p demonstrate complementary roles in BC biology. hsa-miR-26b-5p is primarily associated with tumor aggressiveness and cancer progression, whereas hsa-miR-186-5p refl cts its molecular characteristics and response to chemotherapy. Their combined assessment in serum and tumor tissue represents a promising approach for improving prognostic stratifi ation and predicting treatment effi acy in BC patients.}, }
@article {pmid42279231, year = {2026}, author = {Mesches, MH and Granholm, AC and Paredes, D and Mesches, K and Oguma, Y and Dezawa, M}, title = {Stem Cell Therapy for Parkinson's Disease: A Mechanistically Distinct Role for Muse Cells.}, journal = {Journal of clinical medicine}, volume = {15}, number = {11}, pages = {}, doi = {10.3390/jcm15114370}, pmid = {42279231}, issn = {2077-0383}, abstract = {Cell replacement therapy is a promising investigational approach for Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although current PD therapies provide symptomatic relief, none halt or reverse disease progression. Early transplantation studies using fetal dopaminergic neurons provided proof of concept for PD cell replacement, with recent efforts focusing on pluripotent stem cell-derived dopaminergic progenitors that are now entering clinical testing. These strategies face challenges, however, including immune compatibility, tumorigenic risk, and the need for controlled differentiation and functional integration. Multi-lineage differentiating stress-enduring (Muse) cells are endogenous, non-tumorigenic pluripotent-like stem cells that home to sites of tissue injury and differentiate in response to the host microenvironment. A targeted literature search of PubMed and Scopus, however, did not identify prior reviews specifically addressing Muse cells in the context of PD, highlighting a gap in the literature. Here, we examine current limitations of established cell-replacement approaches and consider whether Muse cells may represent a mechanistically distinct cell source. Early clinical studies of Muse cell therapy in stroke and amyotrophic lateral sclerosis suggest an encouraging safety profile and preliminary signals of potential therapeutic benefit, although these findings are based on small, early-stage trials and require confirmation. The evidence supporting Muse cell therapy in PD is currently limited to a single preclinical animal study, supported by mechanistic in vitro findings and indirect evidence from other neurologic disease models; therefore, its relevance to PD remains to be established, and current evidence is insufficient to support conclusions regarding clinical efficacy. Together, these observations provide a rationale for further targeted preclinical investigation and support the systematic evaluation of Muse cells as a mechanistically distinct candidate for regenerative therapy in PD.}, }
@article {pmid42280649, year = {2026}, author = {Liu, Q and Zhang, R and Sun, L and Lu, X and Xu, G and Tong, H and Zhang, B and Liu, X and Du, S}, title = {Mechanism of Echinochloa crus-galli Resistance to the ALS-Inhibiting Herbicide Pyrazosulfuron-ethyl in China.}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {11}, pages = {}, doi = {10.3390/plants15111611}, pmid = {42280649}, issn = {2223-7747}, abstract = {Rice (Oryza sativa L.) is a staple food crop, feeding more than 3.5 billion people. With the increasing demand for food in the 21st century, weed infestation poses the most significant biotic threat to global food security, and herbicides remain the most effective and economic way to manage it in field. However, weeds can rapidly adapt under herbicide selection pressure due to their high competitiveness, rapid growth, and reproductive capacity. Hence, we collected Echinochloa crus-galli populations from Heilongjiang and Hebei provinces in China and investigated their resistance mechanisms to pyrazosulfuron-ethyl (PSE), a sulfonylurea herbicide that inhibits acetolactate synthase (ALS). Dose-response experiments confirm that the resistant (R) population exhibits 52.9-fold resistance to PSE compared with the susceptible (S) population. Inhibitor bioassays with malathion and NBD-Cl, together with ALS activity assays, ALS gene sequencing, and molecular docking, collectively suggest that resistance is strongly associated with the ALS Trp-574-Leu target-site substitution, with a possible additional contribution from enhanced herbicide metabolism. However, because the S and R populations originate from geographically distinct locations, some of the observed physiological and molecular differences may also reflect inherent population variation. Specifically, the ALS W574L substitution is predicted to reduce key interactions between ALS and PSE. This study provides valuable evidence for the risk of PSE resistance evolution in E. crus-galli and elucidates the molecular mechanism conferring resistance to ALS inhibitors.}, }
@article {pmid42281786, year = {2026}, author = {Tsai, AC}, title = {Defining a shift estimand on forgivingness without domesticating forgiveness: Comment on Cowden et al.}, journal = {SSM. Mental health}, volume = {9}, number = {}, pages = {}, pmid = {42281786}, issn = {2666-5603}, abstract = {This commentary responds to Cowden et al.'s (2026) careful epidemiologic study of the population-wide changes in well-being that might follow from two explicitly defined "shift" scenarios applied to a three-item forgivingness measure. I value the paper's candor about its counterfactual aim: it is not asking whether forgiveness is good in the abstract, but what could plausibly happen if the distribution of measured forgivingness were moved in specified ways. I argue that Cowden et al.'s (2026) methodological clarity surfaces what remains ethically and theologically decisive. In Christian thought, forgiveness is not simply an emotion-regulation technique or a general prosocial disposition; it is a demanding practice formed by grace and ordered toward truth, justice, mercy, and (where possible) repair. When we compress that "thick" practice into a several-item scale for administration in population surveys, we risk treating qualitatively different moral realities as interchangeable. This thinning is subject to the same critique when applied to intervention: a shift estimand tells us what might follow from a distributional change but not how to bring it about; and different ways of cultivating forgiveness may not be morally or practically interchangeable, even if they produce the same numerical shift. While the rigor Cowden et al. (2026) bring to this literature is commendable, the remaining challenge is to connect distributional shifts in forgivingness scores to the concrete practices and communal disciplines that form forgiveness as a moral reality rather than a psychological technique.}, }
@article {pmid42272365, year = {2025}, author = {Mishra, V and Shekhar, S and Bisht, S and Chatterjee, R and Pandey, L and Pandey, A}, title = {Incidental Radiation Exposure to the Internal Mammary Lymph Nodes in Breast Cancer Patients Undergoing Intensity-Modulated Radiation Therapy: A Retrospective Analysis.}, journal = {The Gulf journal of oncology}, volume = {1}, number = {49}, pages = {16-21}, pmid = {42272365}, issn = {2521-3881}, mesh = {Humans ; Female ; *Radiotherapy, Intensity-Modulated/methods/adverse effects ; Retrospective Studies ; Middle Aged ; Adult ; *Breast Neoplasms/radiotherapy/pathology ; *Lymph Nodes/radiation effects/pathology ; *Radiation Exposure ; Radiotherapy Planning, Computer-Assisted/methods ; Radiotherapy Dosage ; }, abstract = {BACKGROUND: Breast cancer (BC) remains the most common malignancy among Indian women, with Stage III being the most frequent at diagnosis. While radiation therapy (RT) plays a pivotal role in the adjuvant treatment of breast cancer, the inclusion of internal mammary lymph nodes (IMLNs) in the radiation field remains controversial due to potential cardiopulmonary toxicity. However, the extent of incidental radiation to the IMLNs, especially with forward planning intensity-modulated radiation therapy (IMRT), remains under-explored.<br><br>OBJECTIVE: This study aimed to evaluate the incidental radiation dose received by the IMLNs in patients with leftsided breast cancer treated with forward planning IMRT.<br><br>MATERIALS AND METHODS: A total of 36 left-sided breast cancer patients, aged 35-60 years, who underwent modified radical mastectomy followed by adjuvant RT using IMRT, were retrospectively analyzed. CT-based planning and contouring were performed according to RTOG guidelines, with IMLNs contoured retrospectively using Jetwa et al.'s method. Dosimetric parameters for the planning target volume (PTV) and IMLNs were extracted and analyzed using dose-volume histograms. Statistical comparisons were made using the dependent Student's t-test.<br><br>RESULTS: The PTV received effective radiation coverage with a mean D95 of 38.47 Gy and a mean Dmean of 40.10 Gy. The IMLNs, although not directly targeted, received significant incidental radiation, with a mean D95 of 8.49 Gy, D50 of 21.59 Gy, and Dmean of 21.40 Gy. The maximum dose to the IMLNs (Dmax) reached 38.14 Gy. Comparative analysis revealed statistically significant differences in both Dmax and Dmean between PTV and IMLNs (p = 0.004 and p < 0.001, respectively).<br><br>CONCLUSION: Forward planning IMRT provides substantial incidental radiation exposure to the IMLNs, which may have therapeutic implications in reducing recurrence risk. However, this exposure also necessitates careful consideration of potential long-term toxicities to adjacent organs. Further prospective studies are warranted to evaluate the clinical outcomes associated with incidental IMLN irradiation.}, }
@article {pmid42274555, year = {2026}, author = {Khan, MS and Zafar, I and Noman, M and Yang, G and Kang, KS and Bopassa, JC}, title = {Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks.}, journal = {Cells}, volume = {15}, number = {11}, pages = {}, pmid = {42274555}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Signal Transduction/drug effects ; *Polypharmacology ; Animals ; Oxidative Stress ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial-ROS-inflammatory signaling, aggregation-proteostasis failure, synaptic-neuroimmune dysfunction, and gut-brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways-play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood-brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles.}, }
@article {pmid42274577, year = {2026}, author = {Schuldt, ON and Leitch, SR and Jones, LK and Buckley, PR and Morrison, BE}, title = {Neuroinflammatory Remodeling by Type 2 Immune Pathways Links Allergic Signaling to Neurodegenerative Disease.}, journal = {Cells}, volume = {15}, number = {11}, pages = {}, pmid = {42274577}, issn = {2073-4409}, support = {R15HL165397//National Heart Lung and Blood Institute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/immunology/pathology ; Animals ; *Signal Transduction/immunology ; *Hypersensitivity/immunology ; *Neuroinflammatory Diseases/immunology ; }, abstract = {The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington's disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson's disease, where epidemiology suggests an important role in dementia/Alzheimer's disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration.}, }
@article {pmid42274592, year = {2026}, author = {Sgalletta, B and Agostini, F and Bisaglia, M}, title = {The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword.}, journal = {Cells}, volume = {15}, number = {11}, pages = {}, pmid = {42274592}, issn = {2073-4409}, mesh = {Humans ; *Iron/metabolism ; *Homeostasis ; Animals ; *Neurons/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neurogenesis ; Neurodevelopment ; Brain/metabolism ; }, abstract = {Iron is an essential micronutrient that plays a central role in numerous biological processes. Despite its relatively low abundance in the human body, iron is particularly critical for brain function. Systemic and cerebral iron homeostasis is tightly regulated through coordinated mechanisms involving absorption, transport, storage, and recycling. Within the brain, iron metabolism is further controlled by the blood-brain barrier and specialized neural cell populations, including neurons, astrocytes, oligodendrocytes, and microglia. Iron is indispensable for neurodevelopment, supporting neurogenesis, myelination, and neurotransmitter synthesis. However, both iron deficiency and iron overload have detrimental consequences. Early-life iron deficiency disrupts neural development and leads to long-lasting cognitive, motor, and behavioral impairments, whereas excessive iron accumulation promotes oxidative stress, ferroptosis, and neuroinflammation. These mechanisms have been described to contribute to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation, and amyotrophic lateral sclerosis. This review first outlines systemic and brain iron metabolism, highlighting how neural cells regulate homeostasis. Next, it examines iron's physiological roles, particularly in neurogenesis and neurodevelopment. Finally, it explores iron's involvement in neurodegenerative diseases, emphasizing neuroinflammation as a primary mechanism of iron toxicity.}, }
@article {pmid42274906, year = {2026}, author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X}, title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {42274906}, issn = {1995-8218}, abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.}, }
@article {pmid42274979, year = {2026}, author = {Ojha, GJ and Talwar, T}, title = {Exploring the Role of Spirituality in Neuropalliative Care: An Integrative Review.}, journal = {Journal of religion and health}, volume = {}, number = {}, pages = {}, pmid = {42274979}, issn = {1573-6571}, abstract = {Neuropalliative care aims to address the physical, psychosocial and spiritual needs of persons with progressive and life-limiting neurological conditions, while spiritual care fosters hope and meaning in life. Progressive neurological disorders with an uncertain disease trajectory present a set of complex challenges that have far-reaching consequences on the patient's self-belief, questioning the very existence, self-identity, and belongingness. A typical neuropalliative care team consists of neurologists, nurses, psychologists, occupational therapists, and spiritual care providers. Previous research indicates that spiritual care improves coping and quality of life in persons with Parkinson's disease and Amyotrophic lateral sclerosis. This study aimed to explore how spiritual needs are addressed in the area of neuropalliative care, examining the theoretical frameworks and empirical studies that incorporate spirituality as a component of neuropalliative care. The databases PubMed, PsycINFO, Cochrane Library, Scopus and two peer-reviewed journals were searched using a strategy based on three sets of terms "spirituality," "progressive neurological conditions" and "neuropalliative care." Articles included were in the English language, and mentioned spirituality in the context of neuropalliative care or palliative care for neurological conditions. Initial screening yielded 744 articles, of which 29 were selected for synthesis. Results highlighted the various challenges in ascertaining and meeting the spiritual needs in neuropalliative care. The review concludes that palliative services should be initiated early following the diagnosis of a progressive neurological condition so that the patient and family have enough time to reflect, create memories, and prepare in advance for the inevitable through dignity and resilience.}, }
@article {pmid42275159, year = {2026}, author = {Ito, D and Iida, M and Iguchi, Y and Hashizume, A and Yamada, S and Kishimoto, Y and Komori, S and Obara, K and Nishisaki, S and Yokoi, S and Shimamura, T and Takemoto, Y and Nakatochi, M and Akashi, T and Hinohara, K and Lee-Okada, HC and Okada, Y and Niwa, J and Sobue, G and Tanaka, S and Takashina, K and Yokomizo, T and Katsuno, M}, title = {Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.198842}, pmid = {42275159}, issn = {2379-3708}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.}, }
@article {pmid42276279, year = {2026}, author = {Gurung, N and Choi, DY and Park, PH}, title = {Naringenin as a Multi-Target Neuroprotective Agent in Neurodegenerative Diseases.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {106203}, doi = {10.1016/j.neuint.2026.106203}, pmid = {42276279}, issn = {1872-9754}, abstract = {Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) are characterized by progressive neuronal loss driven by complex and multifactorial pathogenic mechanisms. Naringenin (NAR), a citrus-derived flavanone, has attracted considerable interest as a neuroprotective molecule due to its pleiotropic pharmacological activities such as antioxidant, anti-inflammatory and ability to modulate multiple cellular targets. This review provides a comprehensive overview of NAR pharmacokinetic profile, mechanistic actions, and therapeutic potential across major ND. We highlight how NAR's multi-target effects-including redox homeostasis maintenance, suppression of neuroinflammation, protein aggregation inhibition, and modulation of signaling pathways-contribute to neuroprotection in various experimental models of AD, PD, HD, ALS, and MS. Preclinical studies demonstrate that NAR can ameliorate cognitive and motor deficits in toxin and transgenic models of neurodegeneration, attenuate pathological hallmarks such as amyloid-beta toxicity, dopaminergic neuronal loss, and neuroinflammation, and induce cytoprotective pathways including Nrf2-mediated antioxidant response and autophagy. However, NAR's clinical translation is challenged by poor bioavailability; thus, novel delivery systems are being explored to enhance brain uptake. NAR emerges as a promising multi-functional neuroprotective agent that can simultaneously target diverse pathogenic processes in ND. Further research including advanced formulation development and well-designed clinical trials is warranted to fully establish NAR's therapeutic efficacy and safety in humans.}, }
@article {pmid42276329, year = {2026}, author = {Abzhanova, E and Kawae, Y and Mizuno, H and Umemoto, T and Ciftci, H and Tsuboi, M and Hirabayashi, Y and Mizuno, H}, title = {ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.}, journal = {Neuroscience research}, volume = {}, number = {}, pages = {105079}, doi = {10.1016/j.neures.2026.105079}, pmid = {42276329}, issn = {1872-8111}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons that gradually causes muscle weakness and paralysis, eventually resulting in death. While ALS was once believed to specifically target motor neurons, recent clinical studies have revealed sensory involvement. The pathological hallmark of ALS is TAR DNA-binding protein 43 (TDP-43) aggregation in cytoplasm, with increasing evidence of its presence in both motor and sensory neurons. However, sensory abnormalities remain poorly characterized. To address this research gap, we analyzed the effects of TDP-43 expression on layer 2/3 (L2/3) pyramidal neurons of the primary somatosensory cortex in mice projecting through corpus callosum. In utero electroporation (IUE) was performed to express GFP alone (control) or in combination with TDP-43. Compared with the control, mice co-expressing GFP and TDP-43 showed disturbed callosal axonal projections of L2/3 neurons. Mutant TDP-43 variants displayed a more pronounced phenotype, indicating pathogenic role during fetal cortical development. To distinguish developmental from maintenance effects, tamoxifen-inducible TDP-43 expression was used to initiate postnatal TDP-43 expression. Postnatal induction resulted in shorter axonal length and reduced branching rather than gross projections disturbance. Taken together, these results demonstrate that TDP-43 expression can disturb the integrity of axonal projections, such as callosal projections of L2/3 neurons in the somatosensory cortex.}, }
@article {pmid42276614, year = {2026}, author = {Karthikeyan, K and Velmurugan, G and Upadhyay, R and Sevanan, M and Chinnathambi, S}, title = {Glutamate and glutamine metabolism in neurodegenerative diseases.}, journal = {International review of neurobiology}, volume = {186}, number = {}, pages = {1-24}, doi = {10.1016/bs.irn.2026.01.008}, pmid = {42276614}, issn = {2162-5514}, mesh = {Humans ; *Glutamic Acid/metabolism ; *Glutamine/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; }, abstract = {Glutamate is known as the most important excitatory neurotransmitter in brain. Glutamate and glutamine recycling is very essential to maintain the nitrogen metabolism. Despite of its major functions, its dysregulation is a basic pathology which is common to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). Amyloid-β and Tau in AD disrupt glutamate uptake and the glutamate-glutamine cycle, accelerating synaptic failure, whereas loss of astrocytic EAAT2 in ALS generates unrelenting excitotoxicity and motor neuron demise. Toxic α-synuclein aggregation in PD exacerbates dopamine-glutamate imbalance through destabilizing corticostriatal transmission. This review explores on the key mechanisms by which glutamate impairment leads to the pathogenies of neurogenerative disorders and also about current medications like amantadine, memantine, and riluzole which are glutamate antagonists, are shown to partially alleviative but cannot halt the advancement of the disease. One of the potential targets for disease-modifying treatments could be the receptor modulation, astrocytic function, and elimination of excess glutamate.}, }
@article {pmid42276630, year = {2026}, author = {McRae, M and Hart, L and Wolf, L}, title = {Accreditation as opportunity: Preparing future nursing leaders through faculty collaboration and succession planning.}, journal = {Journal of professional nursing : official journal of the American Association of Colleges of Nursing}, volume = {65}, number = {}, pages = {137-141}, doi = {10.1016/j.profnurs.2026.04.007}, pmid = {42276630}, issn = {1532-8481}, abstract = {Preparing for Commission on Collegiate Nursing Education (CCNE) accreditation requires extensive faculty engagement, yet the literature offers limited guidance on operational strategies to cultivate collaboration and mentorship during this process. This article describes the Keigwin School of Nursing's adaptation of Benner's novice to expert framework and Haverkamp et al.'s (2018) "map for accreditation" to design a collaborative approach for developing the self-study report and preparing for a site visit. Junior faculty were paired with experienced mentors in dyads, assigned to analyze key elements of the CCNE Standards, and reported findings back to cross-program Standard Teams. This structure fostered faculty development, enhanced understanding of accreditation processes, and promoted succession planning. Standardized meeting minutes, end-of-year committee reports, and the use of stoplight tracking tools provided systematic evidence of continuous quality improvement. Faculty-wide meetings and individualized support further strengthened readiness and confidence for site visit engagement. The outcome was full faculty participation, successful alignment of undergraduate and graduate program reaccreditation cycles, and no accreditation compliance concerns reported for any program. These results underscore the value of mentorship, collaboration, and succession planning in accreditation preparation and highlight the potential to address national challenges in faculty shortages, destabilization of higher education, and the need for a unified nursing faculty voice in academic advocacy.}, }
@article {pmid42276908, year = {2026}, author = {Covas Moschovas, M and Falagario, U and Pellegrino, F and Wiklund, P and Patel, V}, title = {Reply to Alexander Light, Max Peters, Manit Arya, et al's Salvage Focal Therapy vs Radical Prostatectomy for Localized Radiorecurrent Prostate Cancer. JAMA Oncol 2026;12:364-73. https://doi.org/10.1001/jamaoncol.2025.6448.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.05.031}, pmid = {42276908}, issn = {1873-7560}, }
@article {pmid42265426, year = {2026}, author = {Johannsen, L and Koger, A and Straub, ER and Stephan, DN and Kiesel, A and Koch, I and Müller, H}, title = {Contrasting cognitive control in the Simon and spatial Stroop tasks regarding their interference with the control of standing balance.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42265426}, issn = {2045-2322}, abstract = {The scientific understanding of any interaction between cognition and balance control is advanced by methods that capture event-related effects of cognitive processes on balance with high temporal resolution and precision. We developed such an approach to examine how cognitive conflict interferes with the control of body balance during upright standing. Participants stood on a force plate while performing two cognitive conflict paradigms: a Simon task, which according to Kornblum et al.'s dimensional overlap model[41] mainly induces spatial stimulus-response conflict during response selection, and a Spatial Stroop task, which additionally elicits a stimulus-stimulus conflict during stimulus encoding. By aligning force plate time series data to the onset events of target and response across all trials, we assessed the temporal dynamics of spatial congruency effects on force moment variability as a marker of balance control activity. Across both experimental cognitive tasks, we observed strong congruency effects in cognitive task performance, when considering trials after previous congruent trials. Further, incongruent trials were associated with systematic transient reductions in force moment variability along the mediolateral axis in balance control. These observations are in line with the assumption that the recruitment of cognitive processes for conflict resolution temporarily inhibits, suppresses, or postpones balance adjustments. Importantly, regarding the impact of cognitive interference on body balance, data confirm our previous observations using improved methods and demonstrate that reduction in balance control activity during resolution of cognitive conflict generalizes to a task with multiple conflict loci (Spatial Stroop task). Thereby, this extended range of conflict does not result in correspondingly stronger interference effects in balance control. From a theoretical perspective, the results align with predictive models of postural regulation and intermittent, event-driven accounts of balance control.}, }
@article {pmid42265532, year = {2026}, author = {Ella, A and Bar-Kalifa, E}, title = {Relational Memory Reconsolidation: A New Lens on Change Mechanisms in EFT for Couples.}, journal = {Family process}, volume = {65}, number = {2}, pages = {e70172}, doi = {10.1111/famp.70172}, pmid = {42265532}, issn = {1545-5300}, abstract = {This paper presents a new framework to account for change mechanisms in Emotion-Focused Therapy for Couples (EFT). Building on Lane et al.'s (2015) integrated memory model, the Relational Memory Reconsolidation model described here posits that EFT reshapes partners' relational memory structures through emotionally intense moments of expressed vulnerability and responsiveness. These vulnerability-responsiveness events allow partners to access and transform memories of past relational experiences (i.e., episodic memory) as well as associated beliefs about themselves and the relationship (i.e., semantic memory). This process of emotional activation and reconsolidation allows maladaptive interaction patterns, which are rigid and stressful, to evolve into more adaptive, emotionally responsive exchanges. These emotional moments activate and transform relational self-states that are responsive to interpersonal cues and can shape partners' self-concepts in a relational context. As therapy progresses and emotionally significant interactions are repeated, the coactivation of adaptive and maladaptive self-states updates neocortical memory traces, leading to changes in higher-order relational semantic structures (i.e., the relational self). These moments foster alignment in partners' perceptions of their shared reality, characterized by mutuality in feelings, practices, memories, goals, and identity. Clinically, the framework highlights the need to elicit one partner's core vulnerable emotions and, within the reconsolidation window, disconfirm related expectations (e.g., rejection) through the other partner's empathic and supportive response. This process may transform key components of partners' relational memory, including relational episodic memories, semantic structures, and procedural emotional responses.}, }
@article {pmid42265600, year = {2026}, author = {Jiang, S and Chen, F and Ma, H and Wu, S and Tang, X and Pan, X and Li, Q and Tao, A and Xu, J and Qi, J and Fang, P and Chen, J and Zhang, L}, title = {Cloning and functional verification of endogenous U6 promoters for developing an efficient CRISPR/Cas9-mediated genome editing system in kenaf (Hibiscus cannabinus L.).}, journal = {BMC plant biology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12870-026-09228-9}, pmid = {42265600}, issn = {1471-2229}, support = {32472219//the National Natural Science Foundation of China/ ; 2023J01443//Fujian Provincial Natural Science Foundation of China/ ; CARS-16//China Agricultural Research System of MOF and MARA/ ; KFB23001//Science and Technology Innovation Project of Fujian Agriculture and Forestry University/ ; ASTIP-IBFC-01//Agriculture Science and Technology Innovation Program/ ; }, abstract = {BACKGROUND: The U6 promoter is a critical component of the CRISPR/Cas9 system, as it drives the transcription of single-guide RNAs (sgRNAs) to enable precise genome editing. Endogenous promoters typically exhibit higher transcriptional activity than their exogenous counterparts, which can significantly enhance editing efficiency. However, the endogenous U6 promoter in kenaf (Hibiscus cannabinus L.), an important fiber crop, has not yet been characterized.<br><br>METHODS: Using the Arabidopsis U6-26 (AtU6-26) promoter as a reference, we performed a homologous sequence search and identified two candidate U6 promoters in kenaf, designated HcU6-1 and HcU6-14. Promoter fragments were amplified from the kenaf cultivar 'Fuhong 952' and cloned into a &#x3b2;-glucuronidase (GUS) reporter vector. Histochemical GUS staining assays revealed that both HcU6 promoters were transcriptionally active, with HcU6-14 showing significantly stronger expression levels compared to HcU6-1.<br><br>RESULTS: To further evaluate the utility of these promoters for genome editing, we constructed CRISPR/Cas9 vectors targeting the kenaf acetolactate synthase (ALS) gene, driven by either HcU6-14P or the exogenous cotton GbU6-9P promoter. Agrobacterium rhizogenes K599-mediated transformation was used to induce hairy roots, and mutation analysis of the ALS gene was performed via Sanger sequencing. Notably, targeted mutations in the ALS gene were detected in hairy roots transformed with the HcU6-14P-driven CRISPR/Cas9 vector, whereas no mutations were observed in roots transformed with the exogenous GbU6-9P promoter. These results demonstrate that the endogenous HcU6-14 promoter confers superior genome editing efficiency compared to the heterologous promoter, which facilitates the development of improved varieties with enhanced agronomic traits.}, }
@article {pmid42265995, year = {2026}, author = {Ozlu, C and Schwaede, A and McGowan, B and Zhang, L and Finch, M and Wolfe, LF and Ajroud-Driss, S and Franz, C and Kuntz, N}, title = {Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70314}, pmid = {42265995}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) patients are rarely encountered before age 25 years, often associated with genetic variants. SOD1 gene variants are well-known to account for a subset of adult-onset ALS but have only been described in a handful of early onset patients. Variants affecting residue 125 in SOD1 have been described in adult-onset ALS patients with a rapid progression. Here we report two such patients.<br><br>METHODS: The clinical, genetic, and electrodiagnostic findings of two unrelated adolescents with juvenile onset rapidly progressive SOD1-ALS are described.<br><br>RESULTS: Patient 1 presented at 16 and patient 2 at 15&#x2009;years-of-age with lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions. Both patients underwent extensive laboratory, electrophysiologic, and radiologic testing ruling out any alternate etiologies. For both patients, whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers.<br><br>DISCUSSION: These two patients expand the phenotypic spectrum of SOD1-ALS, demonstrating a rapidly progressive juvenile lower limb onset phenotype associated with the p.Asp125Gly variant inherited with incomplete penetrance. Recognition and further characterization of juvenile SOD1-ALS are important in light of the advances in targeted therapies.}, }
@article {pmid42266360, year = {2026}, author = {Ilczak, T and Ćwiertnia, M and Sumera, K and Babik, P and Białoń, P and Dutka, M and Malinowska-Lipień, I and Augustyn, M and Majewski, M and Lis, A and Leszczyński, P and Stasicki, A and Abramczyk, P and Kukla, P and Pollok-Waksmańska, W and Trojak-Piętka, J and Kawecki, M}, title = {Nontechnical Skills (NTS) and the Quality of Conducting Prehospital Advanced Cardiopulmonary Resuscitation Among Paramedics.}, journal = {Emergency medicine international}, volume = {2026}, number = {}, pages = {2207053}, pmid = {42266360}, issn = {2090-2840}, abstract = {INTRODUCTION: It is common knowledge that the correct application of cardiopulmonary resuscitation (CPR) requires technical skills such as defibrillation, high-quality chest compressions, and efficient airway management. However, scientific research is increasingly underlining the role of appropriate training in nontechnical skills (NTS).<br><br>RESEARCH AIM: This exploratory study aimed to assess the relationship between NTS and the quality of advanced CPR among paramedics.<br><br>MATERIALS AND METHODS: The research involved 51 paramedics randomly assigned to 17 three-person teams. Each team participated in a 15-min cardiac arrest scenario. After the first session, the teams were divided into two groups: the intervention group (Group 1), which underwent specialized NTS training, and the control group (Group 2), which did not receive the initial training. Directly after the training phase, all teams from both groups carried out a second attempt during a simulated sudden cardiac arrest (SCA) scenario identical to the first one.<br><br>RESULTS: The lowest CPR result in the intervention group (Group 1) was Min&#x2009;=&#x2009;-3.00, and the highest Max&#x2009;=&#x2009;13.00, while in the control group (Group 2), the lowest result was Min&#x2009;=&#x2009;-42.00, and the highest Max&#x2009;=&#x2009;8.00 (p&#x2009;<&#x2009;0.05). In Group 1, a statistically significant correlation (p&#x2009;<&#x2009;0.05) was noted between the change in the NTS score and the change in the CPR result. A higher NTS score was accompanied by a higher CPR score.<br><br>CONCLUSIONS: A short NTS training session was associated with improved NTS application by paramedic resuscitation teams. Furthermore, higher chest compression quality positively correlated with NTS proficiency.}, }
@article {pmid42267592, year = {2026}, author = {Malik, MMUD}, title = {Moral Injury, Peer Support and Allied Health Integration: Three Extensions to Gilmore et al.'s Account of Mental Health Crisis Care in Homelessness.}, journal = {Journal of psychiatric and mental health nursing}, volume = {}, number = {}, pages = {}, doi = {10.1111/jpm.70156}, pmid = {42267592}, issn = {1365-2850}, }
@article {pmid42267597, year = {2026}, author = {Held-Bradford, EC and DeMarco, E and Zocher, S and Weaver, K and Forsman, K and Hayat, G and Subramaniam, DS and Doherty, M}, title = {Functional Motor Change Across Time and Phenotypes in Patients With Amyotrophic Lateral Sclerosis: A Descriptive Study.}, journal = {Neurorehabilitation and neural repair}, volume = {}, number = {}, pages = {15459683261445435}, doi = {10.1177/15459683261445435}, pmid = {42267597}, issn = {1552-6844}, abstract = {PURPOSE: Progressive disability occurs in persons with amyotrophic lateral sclerosis (pALS), but change over time across phenotypes remains understudied, limiting clinical decision-making. This descriptive study describes functional motor change with detailed measures across ALS phenotypes to enhance clinical decision making.<br><br>MATERIALS AND METHODS: Electronic health record data from an interdisciplinary ALS clinic (n&#x2009;=&#x2009;109 pALS, 2018-2022) including demographics, disability (ALS Functional Rating Scale-[ALSFRS-R]), and functional motor scores (10&#x2009;m Walk, Handheld dynamometry [grip and ankle]) was utilized. Phenotype groups were defined by site of onset (bulbar, limb onset; upper limb or lower limb). Analysis was conducted using R and included changes scores and measures of central tendency in 3-month intervals.<br><br>RESULTS: PALS included n&#x2009;=&#x2009;43 bulbar, n&#x2009;=&#x2009;32 upper limb, n&#x2009;=&#x2009;34 lower limb onset, age 65, 60 to 71 (median, interquartile range). ALFSRS-R decline was greatest in bulbar, and similar in upper and lower limb. Patterns of change within motor scores suggest greatest loss of grip strength in bulbar and upper limb, ankle strength in upper limb, walking speed in lower limb, and preservation of community ambulation in upper limb.<br><br>CONCLUSION: While ALSFRS-R scores were similar in upper and lower limb, detailed functional motor measures indicated differences in groups. These patterns provide insight to guide clinical decision making and future research to enhance care in pALS.}, }
@article {pmid42267908, year = {2026}, author = {Donati Della Lunga, I and Cerutti, L and Barabino, V and Figus, GG and Callegari, F and Oneto, L and Tedesco, M and Bacchetti, F and Milanese, M and Massobrio, P and Brofiga, M}, title = {Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag185}, pmid = {42267908}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved. In this study, we reconstruct the developmental trajectory of cultured cortical networks derived from SOD1G93A mouse embryos using a multimodal approach, by combining morphometric, electrophysiological, pharmacological, molecular, computational, and machine-learning techniques. We prove that ALS neurons fail to acquire mature polarization and connectivity, displaying a transient phase of hyperexcitability that precedes a progressive collapse of network organization. Astrocytic dysfunction emerges early and impairs synchronization, establishing a causal link between glial dysfunction and neuronal instability. The analysis of synaptic transmission reveals an excitatory bias followed by maladaptive inhibitory recruitment and GABA/glutamate co-release, causing fragmented and inefficient network topologies. Finally, in silico modelling identified deficient intrinsic adaptation as a key driver of hyperexcitability. Together, our findings position ALS as a developmentally rooted disorder of cultured cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures. By demonstrating that cortical dysfunction is embedded before degeneration, this work provides a unifying framework connecting early network instability to disease progression and establishes electrophysiological network signatures, detected by machine learning classifiers, as candidate biomarkers for early diagnosis and therapeutic screening.}, }
@article {pmid42268433, year = {2026}, author = {Sytwu, HP and Jih, KY and Tsai, YS and Fang, SY and Liao, YC and Lee, YC}, title = {FUS-associated ALS in Taiwan: genetic spectrum, clinical features, and a founder haplotype of p.H517D.}, journal = {Journal of neurology}, volume = {273}, number = {7}, pages = {}, pmid = {42268433}, issn = {1432-1459}, support = {112-2314-B-075-034-MY3//National Science and Technology Council/ ; 114-2314-B-075-021-MY3//National Science and Technology Council/ ; 113-2314-B-075-018-MY3//National Science and Technology Council/ ; }, abstract = {OBJECTIVE: To characterize the genetic spectrum and clinical features of FUS-associated amyotrophic lateral sclerosis (ALS) in a Taiwanese cohort and to investigate whether the recurrent p.H517D variant represents a founder mutation.<br><br>METHODS: All coding exons and flanking intronic regions of FUS were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Clinical characteristics of patients carrying FUS variants were evaluated. Haplotype analysis using polymorphic microsatellite markers flanking FUS was performed to assess a potential founder effect of the p.H517D variant.<br><br>RESULTS: Eight distinct heterozygous pathogenic FUS variants were identified in 11 probands and five affected relatives, including six missense and two frameshift variants. The most frequent variant was p.H517D, detected in four probands. A novel frameshift variant, p.G499Vfs*30, was identified as a de novo mutation in a juvenile-onset ALS patient. Compared with the non FUS-associated ALS cohort, patients with FUS-associated ALS had a significantly younger mean age at onset (40.1 vs 56.6&#xa0;years) and more frequent bulbar onset (50% vs 19%). Haplotype analysis suggested a common founder for the p.H517D variant.<br><br>CONCLUSIONS: FUS mutations accounted for 1.7% of ALS cases in this Taiwanese cohort. The recurrent p.H517D variant appears to represent a population-specific founder mutation. Patients with FUS variants presented with earlier disease onset and heterogeneous clinical phenotypes, and de novo variants contributed to juvenile-onset disease.}, }
@article {pmid42268660, year = {2026}, author = {Roy, &#xc9; and Blais, M and Dion, P and Rouleau, GA and Dupré, N and Picher-Martel, V}, title = {Oligogenic variants in NEK1 and ATXN2 in amyotrophic lateral sclerosis: report of two cases and review of the literature.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2685158}, pmid = {42268660}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects the upper and lower motor neurons and leads to progressive paralysis. More than 40 genes have been implicated in familial ALS, which represents about 10% of ALS cases. Some genes, including C9orf72, SOD1, FUS and TARDBP are undoubtedly considered causative, but many others have uncertain pathogenicity and low penetrance. Here, we described the cases of two siblings affected by ALS and carrying both an ATXN2 heterozygous 32 CAG trinucleotide repeat expansion and a novel NEK1 heterozygous c.1674_1677dup. The segregation of both variants in this large family with thirteen siblings may support a role for these variants as susceptibility alleles within an oligogenic model. Our review of the literature suggests that NEK1 variants are frequently found in combination with other variants and repeats expansion in the ATXN2 gene appears to be more associated with monogenic ALS, but also frequently combined with C9orf72 repeat expansion.}, }
@article {pmid42269975, year = {2026}, author = {Ma, M and Cui, B and Sun, X and Liu, S and Shao, K and Liu, F and Lin, P and Li, W and Zhao, Y and Yu, D and Lou, J and Yun, Y}, title = {Progressive choroid plexus enlargement across disease stages in patients with sporadic amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107481}, doi = {10.1016/j.nbd.2026.107481}, pmid = {42269975}, issn = {1095-953X}, abstract = {BACKGROUND: The choroid plexus (CP), a key structure involved in cerebrospinal fluid homeostasis and glymphatic function, is increasingly recognized as an interface for neuroimmune communication. Recent studies have identified CP abnormalities as potential neuroimaging markers in several neurodegenerative disorders, including sporadic amyotrophic lateral sclerosis (sALS). However, whether CP enlargement occurs early and progresses across clinical stages or over time in patients with sALS remains unclear. Given the role of the CP in peripheral-central nervous system immune crosstalk, the association between neuroinflammation and CP abnormalities in sALS also requires clarification. In this prospective study, we used structural MRI to examine cross-sectional and longitudinal CP volume changes in patients with sALS and to evaluate their associations with CSF inflammatory markers.<br><br>METHODS: This prospective study included 161 newly diagnosed patients with sALS who underwent genetic testing and structural MRI, and 64 healthy controls (HCs) who underwent structural MRI. Disease stage in patients with sALS was assessed using the King's staging system. Longitudinal MRI was performed in a subset of 42 patients, of whom 38 also underwent baseline CSF inflammatory protein assessment.<br><br>RESULTS: Compared with HCs, patients with sALS at all King's stages showed significantly larger CP volumes after Bonferroni correction (all p&#x202f;<&#x202f;0.05). CP volumes were significantly greater in patients at King's stage 3 than in those at King's stage 1 or stage 2 after Bonferroni correction (all p&#x202f;<&#x202f;0.05). In the longitudinal subgroup, CP volume increased significantly from baseline to follow-up. Multivariable analysis showed that higher CSF CHIT1 and IL-6 levels were independently associated with larger CP volume in patients with sALS (&#x3b2;&#x202f;=&#x202f;0.348-0.456; p&#x202f;<&#x202f;0.01).<br><br>CONCLUSIONS: Our findings provide evidence that CP enlargement occurs early and progresses across disease stages and over time in patients with sALS. Higher CSF CHIT1 and IL-6 levels were associated with larger CP volume, supporting a potential link between neuroinflammation and CP abnormalities in sALS. These findings support CP enlargement as a promising neuroimaging marker for monitoring disease progression and neuroinflammatory processes in patients with sALS.}, }
@article {pmid42270846, year = {2026}, author = {Wood, H and Hamdi, N}, title = {Advancing amyotrophic lateral sclerosis research in Egypt.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41582-026-01230-x}, pmid = {42270846}, issn = {1759-4766}, }
@article {pmid42271582, year = {2026}, author = {Ito, M}, title = {[Re-evaluating ALS Medical Care in Japan: An International Comparison of Japan, Europe, the United States, and Canada-Insights from Mechanical Ventilation, Support for Social Participation, End-of-Life Care Options, Approved Drugs, and Precision Medicine].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {6}, pages = {654-657}, doi = {10.11477/mf.188160960780060654}, pmid = {42271582}, issn = {1881-6096}, abstract = {Amyotrophic lateral sclerosis (ALS) care in Japan should be re-evaluated not simply as a matter of clinical choice but as a function of the public support system structure. In Japan, care is distinguished by a publicly funded model that supports home-based living and social participation following tracheostomy invasive ventilation. In contrast, Europe reflects a model centered on non-invasive ventilation and palliative care, and the United States reflects a system in which precision therapies are approved earlier but access remains highly unequal. Further, Canada reflects a model integrating multidisciplinary ALS clinics with Medical Assistance in Dying within a shared policy framework. These differences extend beyond treatment preferences and instead reflect broader social, institutional, and ethical configurations that shape the future of individuals with ALS. As access to emerging disease-modifying therapies increasingly depends on genetic testing, the central challenge in ALS care is shifting from end-of-life decision-making to the equitable distribution of precision medicine. Comparative reappraisal of national care models is therefore critical for understanding ALS not only as a neurological disease but also as a condition shaped by welfare systems, care infrastructure, and policy design.}, }
@article {pmid42271589, year = {2026}, author = {Kunieda, K}, title = {[Clinical Management of Dysphagia and Nutritional Disorders in Neurodegenerative Diseases].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {6}, pages = {695-700}, doi = {10.11477/mf.188160960780060695}, pmid = {42271589}, issn = {1881-6096}, abstract = {Dysphagia is common in patients with neuro degenerative diseases. It is associated with aspiration pneumonia, malnutrition, and reduced quality of life. Swallowing assessment should incorporate therapeutic perspectives, including the use of compensatory strategies. In conditions such as amyotrophic lateral sclerosis, weight loss is associated with a poor prognosis, and nutritional therapy may function as a disease-modifying intervention. Clinical ethical issues may arise, including decisions regarding gastrostomy or care for patients with impaired decision-making capacity. A multidisciplinary team approach is essential for managing dysphagia and nutritional problems in these patients.}, }
@article {pmid42272352, year = {2026}, author = {Lizio, A and Farè, M and Gerardi, F and Collesi, M and Sansone, VA and Lunetta, C and Diamanti, L and Cerri, F}, title = {Impact of treatment burden on medication adherence and quality of life in amyotrophic lateral sclerosis: a prospective multicentre study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2683691}, pmid = {42272352}, issn = {2167-9223}, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) face substantial barriers to medication adherence as disease progression necessitates complex drug formulation adjustments, such as crushing tablets, mixing with liquids, or delivering via feeding tubes. These modifications may not only increase the time and effort required but could also impact drug efficacy and safety.<br><br>OBJECTIVE: To evaluate the prevalence and the impact of treatment burden on medication adherence and patient-reported quality of life (QoL) in ALS.<br><br>METHODS: This prospective multicenter study enrolled ALS patients across three Italian reference centers, with assessments at baseline, 6, and 12&#x2009;months. Key measures included the Multimorbidity Treatment Burden Questionnaire (MTBQ), ALSFRS-R, DYALS (dysphagia), Morisky Medication Adherence Scale, SSS-8 (somatic symptoms), INQoL (QoL), SWAMECO (swallowing/medication difficulties), alongside comorbidities and current therapies. Associations between treatment burden, QoL, and adherence were analyzed using multivariable models.<br><br>RESULTS: A total of 114 consecutive ALS patients were enrolled. Clinically significant treatment burden was observed in 69.3% of patients, with over half reporting moderate-to-high levels according to the MTBQ classification. Elevated burden was independently related to greater somatic symptom severity and formulation modification needs. Moreover, higher burden associated with poorer QoL and diminished adherence after confounder adjustment. Longitudinally, patients experiencing worsening burden over 1 year showed accelerated QoL decline compared to those remaining stable, though adherence trajectories were unaffected.<br><br>CONCLUSION: Treatment burden, particularly driven by drug formulation complexities and somatic symptoms, emerges as a pivotal, modifiable determinant of adherence and QoL in ALS. Targeted interventions to alleviate modifiable burden components hold promise for optimizing clinical outcomes and enhancing patient-centred care.}, }
@article {pmid42259394, year = {2026}, author = {Zhang, K and Kong, S and Ma, Y and Kan, C and Zheng, T and Sun, X}, title = {Natural Monomer Compounds in Neurodegenerative Diseases: Targeting Ferroptosis and Neuroinflammation.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {116319}, doi = {10.1016/j.bbr.2026.116319}, pmid = {42259394}, issn = {1872-7549}, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss driven by oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Ferroptosis, an iron-dependent and lipid peroxidation-associated form of regulated cell death, has recently been identified as a key contributor to neuronal vulnerability. Emerging evidence demonstrates that purified natural monomer compounds derived from medicinal plants exert potent neuroprotective effects by targeting ferroptosis and neuroinflammatory pathways. Representative agents such as curcumin, baicalin, resveratrol, and ginsenoside Rg1 activate nuclear factor E2-related factor-2 and glutathione peroxidase 4 signaling to preserve redox balance, while suppressing microglia-mediated inflammation through inhibition of toll-like receptor 4 pathways. This review highlights the interplay between ferroptosis and neuroinflammation in NDDs, summarizes the regulatory effects of bioactive herbal monomer compounds, and discusses recent advances in multi-omics profiling, nano-delivery strategies, and translational research. By modulating the ferroptosis-neuroinflammation axis, these compounds may represent promising therapeutic candidates for NDDs.}, }
@article {pmid42260601, year = {2026}, author = {Yoshida, M}, title = {Development and validation of the creative personality and thinking styles scale: a multifaceted measure for assessing creativity-related individual differences.}, journal = {BMC psychology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40359-026-04959-8}, pmid = {42260601}, issn = {2050-7283}, abstract = {BACKGROUND: Creativity is the process of generating contextually useful novel outcomes by uniquely reconfiguring existing knowledge and information. While various measures examine specific aspects of creativity, multifaceted measures that holistically assess creativity as a domain-general factor are still needed. This study developed the Creative Personality and Thinking Styles Scale (C-PETS), which measures personality, thinking styles, and creativity-related motivation based on Plucker et al.'s theory of creativity.<br><br>METHODS: The initial C-PETS item pool was developed by referencing existing scales, followed by a qualitative screening process to ensure theoretical consistency. Exploratory factor analysis involving 572 participants was conducted to examine the underlying factor structure. Subsequently, confirmatory factor analysis and a higher-order model analysis involving 943 participants were performed to verify the model fit.<br><br>RESULTS: Exploratory factor analysis identified a five-factor, 16-item scale comprising Broad Thinking, Thorough Thinking, Information Manipulation, Challenge-Seeking, and Ambiguity Tolerance. The higher-order CFA model demonstrated an excellent fit (GFI = .97, CFI = .98, RMSEA = .02). Criterion-related validity was supported by significant correlations with the Short Scale of Creative Self-Efficacy (r = .75), Aesthetic Experiences Scale (r = .30), and Divergent Association Task (r = .18). Test-retest reliability after two weeks was strong (r = .87). Additionally, a positive correlation was observed with educational attainment.<br><br>CONCLUSIONS: The C-PETS represents a valuable contribution to creativity assessment by providing a multifaceted measure of creativity-related personality, thinking styles, and motivation.}, }
@article {pmid42261056, year = {2026}, author = {Bromberg, MB}, title = {The Flail Limb Syndrome.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70307}, pmid = {42261056}, issn = {1097-4598}, abstract = {The flail limb syndrome is primarily a lower motor neuron disorder that initially affects proximal arm muscles (flail arm syndrome-FAS) or distal leg muscles (flail leg syndrome-FLS). Both were recognized early on (1886 for FAS and 1918 for FLS) as somewhat distinct from classic amyotrophic lateral sclerosis (ALS). Descriptions in the literature are case series with limited information on electrophysiologic features (central and peripheral), cognitive involvement, and genetic mutations. What follows is a compilation of these features. The flail limb syndromes are rare, representing ~7%-8% of ALS. They have a higher ratio of males to females compared to classic ALS. Both are defined by predominant focal arm or leg weakness for ~2 years before progression to other regions, although there can be early and mild clinical or electrophysiologic evidence for denervation and reinnervation in other regions during the initial period. Ultimately, there is progression to respiratory failure, but at a slower rate compared to classic ALS. Upper motor neuron clinical signs are variable, but transcortical magnetic stimulation paradigms and magnetic resonance imaging tractography support upper motor neuron loss. Tests of the split hand pattern show it is rare compared to ALS. Dementia is also rare. Genetic testing supports a spectrum of ALS-related gene mutations but at a lower frequency than with classic ALS, and no gene mutation is predominant. Diagnosis requires ~2 years of regional stability to predict the better prognosis for the flail limb syndromes.}, }
@article {pmid42261159, year = {2026}, author = {Shirbhate, E and Singh, V and Mishra, OK and Koch, B and Tiwari, AK and Yasin, HKA and Rajak, H}, title = {The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X462214260429080002}, pmid = {42261159}, issn = {1875-6190}, abstract = {The review specifically examines the pivotal role of HDAC6 in the pathophysiological pathway of Amyotrophic Lateral Sclerosis (ALS), an escalating neurodegenerative ailment marked by the discerning damage to motor neurons. Several lines of evidence implicate inadequate proteostasis in significantly influencing neuronal degeneration. The accumulation of misfolded proteins and proteotoxicity are highlighted as significant factors in ALS pathophysiology. Key pathological hallmarks include ubiquitin-positive inclusions, disrupted RNA metabolism, cytoskeletal perturbations, and compromised axonal transport systems. HDAC6 dysregulation disrupts axonal transport, impairing mitochondrial function and increasing oxidative stress, leading to rapid motor neuron damage and cell death. The enzyme's aberrant deacetylation of α-tubulin destabilizes microtubules and impairs intracellular trafficking. Despite HDAC6's participation in these unfavorable processes, it also exerts neuroprotective properties. It deacetylates tubulin, promoting efficient axonal transport and autophagic clearance. HDAC6 helps form aggresomes and stress granules, which are essential for cellular defence against proteotoxic stress. Through its zinc finger ubiquitin-binding domain, HDAC6 interacts with polyubiquitinated proteins, facilitating their autophagic degradation. HDAC6 inhibition can boost autophagic flux and reduce protein aggregation, while its activation may amplify the protective effects. This dichotomous behaviour of HDAC6 may pose an obstacle to the design of targeted therapy. Illuminating the complex mechanisms through which HDAC6 influences neurodegeneration and neuroprotection is important before constructing effective treatments for ALS. The review provides a clear understanding of the complex role of HDAC6 in ALS pathogenesis and highlights potential strategies to improve the prognosis of people affected by this neurological illness.}, }
@article {pmid42262533, year = {2026}, author = {Korade, G and Kharat, S and Rathi, K}, title = {Nitric oxide in neuroinflammation and neurodegeneration: dual roles, inflammasome crosstalk, and biomarker opportunities.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42262533}, issn = {1432-1912}, abstract = {Nitric oxide is a short-lived gas that plays a critical role in numerous physiological processes, including vascular regulation, neurotransmission, and immune responses. In the CNS NO's role is complex, as it can both protect and damage neurons. Microglia, the brain's resident macrophages, produce excessive NO in response to stimuli like endotoxins and cytokines, leading to chronic inflammation and neuronal damage associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. NO's dual role as a pro-inflammatory and anti-inflammatory mediator is intricately linked to its impact on neuronal health and disease progression. This review is aimed at summarizing and critically discussing the roles of NO in neuroinflammation, neurodegeneration, inflammasome regulation, and related therapeutic perspectives. A narrative literature review was conducted using electronic databases (e.g. PubMed and Google Scholar) to identify experimental and clinical studies on NO, neuroinflammation, neurodegenerative diseases, inflammasomes, and related biomarkers and therapies, with emphasis on mechanistic and translational work. Research into NO's effects on inflammasomes, key components of the innate immune system, reveals that NO can inhibit inflammasome activation, influencing inflammatory responses. Despite progress, challenges remain, including the need for cell-type-specific models, advanced technological approaches, and the development of selective NO modulators. Overall, current evidence indicates that NO exerts both neuroprotective and neurotoxic effects in the CNS, mediated by its complex interactions with neural, glial, and immune pathways. Future research should focus on the dual nature of NO, explore lesser-known inflammasomes, and incorporate human-centric models to develop targeted therapies.}, }
@article {pmid42262640, year = {2026}, author = {Tavassoli, T and Marco, EJ and Puts, N}, title = {Sensory Reactivity in Autism: Integrating Behavioural, Affective, Physiological, and Neural Dimensions.}, journal = {Current psychiatry reports}, volume = {28}, number = {1}, pages = {}, pmid = {42262640}, issn = {1535-1645}, abstract = {PURPOSE OF REVIEW: The goal of this paper is to synthesise recent research on sensory reactivity differences in autism across the lifespan, using He et al.'s sensory taxonomy as an organising framework. The review aims to address how behavioural, affective, perceptual, physiological, and neural levels of processing contribute to sensory reactivity differences, and how these differences relate to broader outcomes such as mental health, adaptive functioning, and quality of life.<br><br>RECENT FINDINGS: Across behavioural studies, autistic youth show elevated and variable sensory responsivity, with hypersensitivity predicting internalising symptoms and sensory seeking linked to externalising behaviours. Affective reactivity is consistently elevated across cultures, associated with anxiety and caregiver stress, and sensory seeking may function as a coping mechanism. Psychophysical research reveals domain&#x2011;specific perceptual differences-such as reduced tactile adaptation, altered motion noise exclusion, and enhanced pitch discrimination-rather than overarching hyper&#x2011; or hyposensitivity. These perceptual findings often show limited correspondence with questionnaire&#x2011;based measures. Physiologically, autonomic dysregulation is implicated, or pharmacological approaches show emerging promise. Neuroimaging evidence highlights excitation-inhibition imbalance and altered connectivity, including dissociations between exogenous and endogenous networks in sensory&#x2011;reactive autistic children. Across multiple levels of processing, sensory reactivity differences in autism are robust, heterogeneous, and meaningfully linked to mental health and daily functioning. Key conclusions include: &#x2022;&#xa0;Sensory hyperreactivity predicts internalising challenges, while sensory seeking may reflect regulatory strategies. &#x2022;&#xa0;Perceptual differences are domain&#x2011;specific &#x2022;&#xa0;Physiological and neural evidence converges on autonomic dysregulation and differences in connectivity patterns.}, }
@article {pmid42262849, year = {2026}, author = {Deleu, B and Dupont, P and Bracaval, K and Ombelet, F and Hobin, F and Lamaire, N and Van Laere, K and Van Damme, P and De Vocht, J}, title = {[18]F FDG-PET correlates of motor neuron disease motor variants.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2026.2682820}, pmid = {42262849}, issn = {2167-9223}, abstract = {While [18]F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease (MND) motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of MNDs, including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), and ALS. We retrospectively included 18 PMA, 25 PLS, and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.}, }
@article {pmid42262924, year = {2026}, author = {Mastromarco, GJ and Earnshaw, R and Moore, G and Xu, XYS and Sadek, NH and Cui, F and Lo, N and Lee, HO}, title = {Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.}, journal = {Cell reports}, volume = {45}, number = {6}, pages = {117326}, doi = {10.1016/j.celrep.2026.117326}, pmid = {42262924}, issn = {2211-1247}, abstract = {Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.}, }
@article {pmid42263252, year = {2025}, author = {Bétourné, A and Texakalidis, P and Raheb Khelo, R and Campbell, M and Sadiq, SA and Boulis, NM}, title = {Intrathecal Administration of Riluzole in Amyotrophic Lateral Sclerosis.}, journal = {Neurosurgery}, volume = {}, number = {}, pages = {}, doi = {10.1227/neu.0000000000003859}, pmid = {42263252}, issn = {1524-4040}, abstract = {BACKGROUND AND OBJECTIVES: Riluzole is the only treatment known to improve survival in amyotrophic lateral sclerosis (ALS) patients. However, its efficacy and dosing are limited by hepatic toxicity and interindividual pharmacokinetic variability. Recent experimental studies in hounds have shown that continuous intrathecal (IT) administration of riluzole is well tolerated and achieves significantly higher spinal cord tissue levels. We report the first 2 human ALS cases treated with IT riluzole.<br><br>METHODS: A catheter was inserted into the lumbar cistern and advanced to the midcervical region under fluoroscopic guidance and connected to a subcutaneous pump. Therapy was initiated at 0.1 mg/h of riluzole. The infusion rate was gradually increased until it reached a maximum of 4.8 mg/d.<br><br>RESULTS: The 2 patients tolerated dose escalation and treatment for over 2 years without apparent motor or sensory complications. Patients reported no asthenia, a central side effect often reported as a reason to abandon oral therapy.<br><br>CONCLUSION: This is the first report of chronic IT riluzole infusion in humans at a dose found to be safe in canines. A phase 1 study is planned to establish the maximum tolerated human dose, followed by a randomized placebo-controlled trial to determine the safety and tolerability of IT riluzole in patients with ALS.}, }
@article {pmid42263370, year = {2026}, author = {Deveci, &#x15e; and Matur, Z and Erzurumluoğlu, SS}, title = {Sensory abnormalities and entrapment neuropathies identified by nerve conduction studies in patients with amyotrophic lateral sclerosis.}, journal = {Neuromuscular disorders : NMD}, volume = {64}, number = {}, pages = {106463}, doi = {10.1016/j.nmd.2026.106463}, pmid = {42263370}, issn = {1873-2364}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons; however, non-motor symptoms, including sensory and autonomic disturbances, are increasingly recognized. This retrospective cross-sectional study evaluated the frequency of sensory and entrapment neuropathies in 114 patients with ALS using electrodiagnostic (EDX) studies. Demographic characteristics, comorbidities, and sensory and autonomic symptoms were documented. Electrophysiological evidence of sensory neuropathy was identified in 20 patients overall (20/114, 17.5%), including 10 patients without diabetes mellitus (DM), whereas entrapment neuropathy was detected in 28 patients overall (28/114, 24.6%), including 16 of those without DM or hypothyroidism. Sensory neuropathy was significantly associated with both DM and a history of chronic disease. In contrast, these comorbid conditions were not significantly associated with entrapment neuropathy. Furthermore, patient-reported symptoms showed no correlation with electrophysiological evidence of sensory involvement on EDX. Sensory neuropathy was more frequent in patients with spinal-onset than bulbar-onset disease, although the difference was not statistically significant. This study confirms that sensory involvement is not uncommon in ALS. Although clinical symptoms are poor predictors, electrophysiological abnormalities consistent with sensory and entrapment neuropathies are common. A significant proportion of these abnormalities are idiopathic and may directly reflect the disease process itself, particularly in spinal-onset cases.}, }
@article {pmid42263417, year = {2026}, author = {Chung, J}, title = {A two-continua model of sleep health and sleep disorders: Why framework proliferation is a feature.}, journal = {Sleep medicine reviews}, volume = {88}, number = {}, pages = {102320}, doi = {10.1016/j.smrv.2026.102320}, pmid = {42263417}, issn = {1532-2955}, abstract = {Multi-dimensional sleep health (MDSH) frameworks emerged in the 2010s to articulate positive sleep health beyond the absence of sleep disorders. Meng et al. (2026) [1] provide the first systematic review directly comparing the two leading instruments, the Ru-SATED scale (Buysse, 2014; Ravyts et al., 2021) [2, 3] and the Sleep Health Index (SHI) (Knutson et al., 2017) [4], and surface two unresolved tensions: a conceptual question (what is the relationship between sleep health and sleep disorders?) and an operational question (will sleep science converge on a single MDSH framework?). This perspective elaborates Meng et al.'s brief observation that MDSH is orthogonal to sleep disorders into a Two-Continua Model (TCM), drawing on the dual-continua model of mental health. The TCM defines a sleep disorder continuum (X-axis) and an orthogonal sleep health continuum (Y-axis), generating a four-quadrant typology. Implications: the typology identifies under-attended populations for surveillance; MDSH complements rather than replaces disorder-focused science; joint-axis modeling integrating disorder and health information yields more powerfully predictive frameworks; and a proliferation of tailored MDSH frameworks is a feature of a maturing research program, not a defect.}, }
@article {pmid42263783, year = {2026}, author = {Lai, TF and Liao, Y and Tzeng, PL and Wen, CJ and Chan, DC}, title = {Association of Brief Bouts of Vigorous Physical Activity and Frailty in Older Adults With Regular and Irregular Exercise Habits.}, journal = {Journal of aging and physical activity}, volume = {}, number = {}, pages = {1-7}, doi = {10.1123/japa.2024-0332}, pmid = {42263783}, issn = {1543-267X}, abstract = {Brief bouts of vigorous physical activity such as vigorous intermittent lifestyle physical activity (VILPA) have emerged as a flexible alternative to traditional structured exercise, requiring less time commitment, preparation, and access to facilities. This study explored the association between VILPA and the odds of prefrailty or frailty in 195 older adults aged 65 and above at National Taiwan University Hospital. Frailty status was evaluated using Fried et al.'s criteria, which include slowness, weakness, weight loss, exhaustion, and low physical activity. VILPA was measured using a waist-worn accelerometer. Multivariate binary logistic regression models revealed that meeting the VILPA duration or bouts thresholds was linked to lower odds of prefrailty or frailty. These associations were significant in those with irregular exercise habits, with adherence to VILPA duration or bouts thresholds correlating with reduced prefrailty or frailty likelihood (odds ratio = 0.21, 95% confidence interval [0.05, 0.89]). However, no significant associations were observed in individuals with regular exercise habits. Adhering to VILPA thresholds may be associated with lower frailty odds, particularly in older adults with irregular exercise habits. These findings suggest that promoting brief bouts of vigorous physical activity in daily life may have potential implications for frailty reduction in older adults, especially those who do not engage in regular exercise. This approach offers a potentially accessible and flexible alternative to structured exercise programs for maintaining health in aging populations.}, }
@article {pmid42264115, year = {2026}, author = {Pynn, SR and Jørgensen, H and Vanstone, C and Mosewich, AD and Holt, NL and , }, title = {A narrative scoping review exploring parents' emotion knowledge and abilities in youth sport.}, journal = {Psychology of sport and exercise}, volume = {}, number = {}, pages = {103187}, doi = {10.1016/j.psychsport.2026.103187}, pmid = {42264115}, issn = {1878-5476}, abstract = {The purpose of this narrative scoping review was to explore how parents identify, express, use, understand, and manage their own and others' emotions in the context of youth sport. Mikolajczak's (2009) tripartite model of emotional intelligence (EI) was used as the conceptual lens for this review. Using Levac et al.'s (2010) framework for conducting scoping reviews, we reviewed 87 relevant sport parenting studies and conducted consultation focus groups with 10 sport parents and six former youth athletes. Qualitative data analysis techniques were used to map the findings into themes based on the dimensions of EI (i.e., identification and expression of emotions, using emotions, understanding emotions, and managing emotions). Findings indicated that parents identified and articulated their own emotions and empathised with their children in the sport context. This emotional awareness informed their emotionally supportive behaviours, such as providing encouragement and comfort. Parents' understanding of their children and sport shaped how and when they provided appropriate support in emotional situations. Parents also engaged in efforts to manage their own emotional reactions, drawing on self-awareness and knowledge of the sport environment to regulate their behaviour during competition. These findings provide insight into the specific aspects of youth sport parents' emotional competencies and can be used to inform sport parent education initiatives.}, }
@article {pmid42264185, year = {2026}, author = {Baker, A and Okorie, M}, title = {UK Foundation Programme training needs a national minimum standard for advanced life support.}, journal = {Clinical medicine (London, England)}, volume = {}, number = {}, pages = {100605}, doi = {10.1016/j.clinme.2026.100605}, pmid = {42264185}, issn = {1473-4893}, abstract = {Since 2021, Advanced Life Support (ALS) has no longer been a mandatory requirement of the UK Foundation Programme. Although the shift towards capability rather than certification was educationally defensible, in practice it has created marked national variation in how resuscitation preparedness is developed, evidenced and signed off. Foundation doctors now enter emergencies with unequal access to funded ALS training, simulation and supervised assessment, while supervisors are left to judge equivalence without a consistent national threshold. This matters not because patient-level harm has been neatly proven, but because high-stakes clinical capability should not depend on local opportunity or variable interpretation. A capability-based curriculum and a national minimum standard are not mutually exclusive. The Foundation Programme should therefore restore a national ALS requirement, or a formally recognised equivalent standard, alongside funded access, blended delivery and transparent national evaluation of uptake, exemptions and outcomes.}, }
@article {pmid42264545, year = {2026}, author = {Vishwakarma, H and Chauhan, A and Kaur, L and Awasthi, A}, title = {Nanotechnology-enabled targeting strategies for neurodegenerative disorders: role of functionalized nanoparticles.}, journal = {The Journal of pharmacy and pharmacology}, volume = {78}, number = {6}, pages = {}, doi = {10.1093/jpp/rgag060}, pmid = {42264545}, issn = {2042-7158}, abstract = {BACKGROUND: Neurodegenerative disorders comprise a diverse group of progressive neurological diseases characterized by the gradual loss of neuronal structure and function. Conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis arise from multifactorial mechanisms involving genetic susceptibility, environmental factors, and age-related cellular decline.<br><br>PATHOPHYSIOLOGY: Key pathogenic processes include oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, impaired axonal transport, Golgi fragmentation, and chronic neuroinflammation, all of which disrupt neuronal homeostasis and synaptic communication, ultimately leading to neuronal death. Hormonal imbalances further exacerbate these effects by promoting oxidative damage, inflammation, and metabolic dysfunction.<br><br>CHALLENGES IN THERAPY: Despite advances in understanding disease mechanisms, effective drug delivery remains challenging due to the restrictive nature of the blood-brain barrier.<br><br>Recent developments highlight the potential of nanoparticle-based drug delivery systems to overcome these limitations. Functionalized nanoparticles enhance blood-brain barrier penetration, improve targeting specificity, and enable controlled drug release. These systems can deliver neuroprotective agents, antioxidants, peptides, and gene therapies directly to affected brain regions. Thus, integrating disease pathophysiology with nanotechnology-based strategies offers a promising approach for improving therapeutic outcomes and advancing precision treatment in neurodegenerative disorders.}, }
@article {pmid42264722, year = {2026}, author = {He, S and Yu, H and Li, X and Chen, J and Liu, Z and Miao, D and Ren, M and Cui, H}, title = {Distribution of resistant Aegilops tauschii populations across China and its target-site resistance mechanism.}, journal = {Pesticide biochemistry and physiology}, volume = {221}, number = {}, pages = {107181}, doi = {10.1016/j.pestbp.2026.107181}, pmid = {42264722}, issn = {1095-9939}, abstract = {Aegilops tauschii is a notorious weed that poses a severe threat to wheat production. Recently, its resistance to mesosulfuron-methyl has been increasingly documented in some provinces of China. With Ae. tauschii rapidly expanding its distribution range throughout China, however, its nationwide resistance distribution and the underlying resistance molecular mechanisms remain poorly understood. To address this knowledge gap, 305 populations of Ae. tauschii were collected from eight major wheat-growing provinces of China to characterize their nationwide resistance profiles and target-site resistance mechanisms. Of the populations examined, 83 populations from Shanxi, Shaanxi, Henan, Hebei, Shandong, and Jiangsu provinces exhibited varying levels of resistance to mesosulfuron-methyl. Resistant populations were particularly widespread in Shanxi and Shaanxi compared with other regions. Forty-seven resistant populations were then selected for target-site mutation analysis. A Pro-197-Leu substitution in the acetolactate synthase (ALS) gene was identified in 14 resistant populations, whereas no known resistance-conferring amino acid alteration was detected in the remaining 33 populations. Resistant populations carrying the Pro-197-Leu mutation displayed a higher resistance level than resistant populations without ALS gene mutations. Furthermore, in vitro ALS activity assays showed that populations with the Pro-197-Leu substitution were highly resistant to mesosulfuron-methyl, with resistance index (RI) ranging from 32.95 to 33.12. In contrast, the RI values of resistant populations lacking target-site mutations were below 2.90. To the best of our knowledge, this study represents the first report of a target-site mutation (Pro-197-Leu) conferring resistance to mesosulfuron-methyl in Ae. tauschii.}, }
@article {pmid42264735, year = {2026}, author = {Rojano-Delgado, AM and Sohrabi, S and Santana, APDS and Palma-Bautista, C and Domínguez-Valenzuela, JA and Gherekhloo, J and Alcántara-de la Cruz, R and De Prado, R}, title = {Herbicide metabolism and EPSPS Pro-106-Ser substitution confer multiple resistance in Chenopodium spp. from Southern Spain.}, journal = {Pesticide biochemistry and physiology}, volume = {221}, number = {}, pages = {107132}, doi = {10.1016/j.pestbp.2026.107132}, pmid = {42264735}, issn = {1095-9939}, abstract = {Long-term herbicide programs in Mediterranean perennial systems have imposed sustained selection pressure on weed populations, promoting the evolution of multiple resistance. We investigated resistance mechanisms in Chenopodium album (Ca) and C. vulvaria (Cv) from southern Spain following more than two decades of glyphosate-based management. We aimed to (i) confirm resistance to atrazine, tribenuron-methyl (TM), glyphosate, and 2,4-D; (ii) distinguish between target-site and metabolic resistance; and (iii) characterize the biochemical and molecular basis of cross- and multiple-herbicide resistance. Screening assays revealed high survival (78-100%) of resistant (R) populations to acetolactate synthase (ALS)-, photosystem II (PSII)-, auxinic-, and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)-inhibiting herbicides. Dose-response assays confirmed resistance, with resistance indices (RI) of 6.7 and 5.1 for atrazine, 19.0 and 17.3 for TM, 7.0 and 13.9 for glyphosate, and 6.0 and 6.9 for 2,4-D in CaR and CvR, respectively. Radiolabelled and analytical metabolism assays demonstrated enhanced herbicide metabolism in R populations: atrazine (94-95% vs. 13-16% in S), TM (68-69% vs. 24-25%), 2,4-D (64-65% vs. 2-4%), and glyphosate (39-43% vs. 8-9%). Malathion partially reversed resistance to atrazine, TM, and 2,4-D, supporting cytochrome P450 (CYP450) involvement. In contrast, glyphosate metabolism was independent of CYP450 or glutathione S-transferases inhibition. Biochemical assays showed no differences in PSII or ALS sensitivity (I50 RI ≈ 1), whereas EPSPS inhibition assays revealed a tenfold increase in I50 in CvR. Sequencing identified a Pro-106-Ser substitution in EPSPS exclusively in CvR. Enhanced metabolism predominates in the R Chenopodium spp. populations, with coexistence of metabolic and target-site mechanisms in CvR, increasing the risk of further cross-resistance under continued herbicide reliance.}, }
@article {pmid42265364, year = {2026}, author = {Treittinger, K and Yang, S and Fischer, R and Dreisbach, G}, title = {The asymmetric list shift effect - flexible adaptation to new context demands?.}, journal = {Attention, perception &amp; psychophysics}, volume = {88}, number = {5}, pages = {}, pmid = {42265364}, issn = {1943-393X}, abstract = {The list-wide proportion congruency effect describes how the congruency effect varies depending on the frequency of incongruent trials within a block. Specifically, the congruency effect is larger in mostly congruent (MC) blocks compared to mostly incongruent (MI) blocks. Research has shown that adaptation to these blocks does not change symmetrically when transitioning between them: moving from MC to MI leads to a rapid decrease in the congruency effect while transitioning from MI to MC results in little or no increase (Abrahamse et al., 2013). We aimed to investigate this asymmetric list shift (ALS) effect in a within-participants design where all participants experienced both transitions (MC-MI and MI-MC). Throughout Experiments 1-3 using a color-word Stroop task, we identified various forms of practice - including trial-type, stimulus-specific learning, general RT decrease, and a decrease in congruency effects over time (see Schmidt, 2016) - that can either facilitate or obscure the ALS effect, depending on the order in which participants experienced the transitions. In Experiment 4, using a face-name version of the Stroop task, where we minimized practice-related confounding factors by employing more complex stimuli and used a new stimulus set in the second transition, an ALS effect was observed regardless of the order of transition and for frequency-unbiased (i.e., 50% congruent) items. The role of practice effects and implications for the (in)-flexibility of control adaptations will be discussed.}, }
@article {pmid42254864, year = {2026}, author = {Yokoi, S and Iguchi, Y and Katsuno, M}, title = {Human iPSC-derived motor neurons as a platform for elucidating TDP-43-related amyotrophic lateral sclerosis pathogenesis: a mini review.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1864964}, pmid = {42254864}, issn = {1662-5099}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a major pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). Heterozygous mutations in TDP-43 cause familial ALS, known as ALS10. TDP-43 is predominantly localized in the nucleus under physiological conditions. Not only ALS patients with TARDBP mutations but also the majority of sporadic ALS patients exhibit TDP-43 pathology, which is defined by nuclear clearance and cytoplasmic aggregation. The inclusion of cryptic exons in genes such as STMN2 and UNC13A has emerged as a hallmark of TDP-43 loss of function, as demonstrated in TDP-43 knockdown models and postmortem analyses. However, it is not yet clear how TDP-43 levels and location change from healthy to pathological conditions in ALS. Motor neurons derived from induced pluripotent stem cells (iPSCs) have been widely used in ALS research and provide a promising platform to investigate early-stage disease mechanisms. However, challenges remain in generating models that faithfully recapitulate ALS pathogenesis. In this review, we summarize recent advances in TDP-43-related iPSC-derived motor neuron models and discuss future perspectives for elucidating ALS pathogenesis. We propose that longitudinal analyses of TDP-43 dynamics and co-culture systems will be essential to better model early ALS pathogenesis.}, }
@article {pmid42255170, year = {2026}, author = {Gurumurthy, NP and Hurley, L and Nezami, BT and Gottfredson O'Shea, N}, title = {Behavior change techniques in mobile health interventions promoting recovery from substances: A synthesis of reviews and meta-analyses.}, journal = {Digital health}, volume = {12}, number = {}, pages = {20552076261458891}, pmid = {42255170}, issn = {2055-2076}, abstract = {OBJECTIVE: This synthesis of reviews and meta-analyses delves into the landscape of behavior change techniques (BCTs) employed in digital interventions designed to help individuals abstain from or reduce consumption of substances (including alcohol, tobacco, and illicit drugs). This review considers the "black box" problem in mHealth programs by using Michie et al.'s BCT taxonomy to describe BCTs that have been used in intervention literature and to explore potential active ingredients that may contribute to intervention effectiveness.<br><br>METHODS: We synthesize findings from 49 systematic reviews and meta-analyses. While individual studies often express inconclusiveness for the effectiveness of specific BCTs, this review uncovers promising avenues for future research. Our analysis focuses on mobile health (mHealth) just-in-time adaptive interventions (JITAIs), with a specific emphasis on substance use reduction.<br><br>RESULTS: Eleven BCTs were studied extensively in these reviews, including self-monitoring of behavior, feedback on behavior, goal setting, social support, prompts/cues, and behavior substitution. Our synthesis of evidence points to prompts/cues as particularly promising and highlights a handful of BCTs that demand further investigation, including self-monitoring, goal setting, and feedback on behavior.<br><br>CONCLUSIONS: This review identifies specific limitations in each step of review formulation and provides nuanced suggestions to enhance the efficacy of future research endeavors.}, }
@article {pmid42255926, year = {2026}, author = {}, title = {Correction to: C9orf72 poly(glycine-alanine) knock-in mice exhibit mild rotarod and proteomic changes consistent with amyotrophic lateral sclerosis/frontotemporal dementia.}, journal = {Brain communications}, volume = {8}, number = {3}, pages = {fcag208}, doi = {10.1093/braincomms/fcag208}, pmid = {42255926}, issn = {2632-1297}, abstract = {[This corrects the article DOI: 10.1093/braincomms/fcag087.].}, }
@article {pmid42256556, year = {2026}, author = {Xiao, X and Hao, G and Wan, P and Hou, W}, title = {Safety evaluation of Tofersen in amyotrophic lateral sclerosis based on the FAERS database.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1843630}, pmid = {42256556}, issn = {1664-2295}, abstract = {BACKGROUND: This study utilizes data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to conduct a post-marketing safety evaluation of Tofersen.<br><br>METHODS: A systematic search of the FAERS database was performed to identify adverse event (AE) reports from Q1 2023 to Q4 2025 was performed. Multi-dimensional disproportionality analyses were conducted using the ROR, PRR, BCPNN, and MGPS method.<br><br>RESULTS: A total of 409 Tofersen-related reports were identified, revealing significant signals across 22 System Organ Class (SOC) categories and 369 Preferred Terms (PTs). At the SOC level, the most prominent safety signals were observed in injury, poisoning and procedural complications, nervous system disorders, and musculoskeletal and connective tissue disorders. In contrast, ear and labyrinth disorders, as well as respiratory, thoracic and mediastinal disorders, were not listed in the current product labeling and may warrant further investigation. At the PT level, neurological procedural complication, CSF red blood cell count positive, CSF white blood cell count increased, and CSF cell count increased exhibited the strongest signals, primarily reflecting cerebrospinal fluid cytological and biochemical abnormalities, as well as procedural-related adverse events such as post-lumbar puncture syndrome, procedural pain, and procedural headache. Although central nervous system-related events (e.g., increased intracranial pressure, peroneal nerve palsy, papilloedema, and facial paralysis) and infectious or inflammatory events (e.g., radiculopathy, myelitis, aspiration pneumonia, and meningitis) were less frequently reported, their relatively high disproportionality signals warrant clinical attention and systematic monitoring. Notably, a newly identified signal of pulmonary embolism suggests a potential thromboembolic risk in specific patient populations.<br><br>CONCLUSION: These findings provide real-world evidence to inform the balance between the therapeutic potential and safety profile of Tofersen. Future clinical strategies should focus on mitigating central nervous system-related and procedure-related adverse events. Further mechanistic studies are crucial.}, }
@article {pmid42257176, year = {2026}, author = {Villasi, W and Frederic, R and Qureshi, S and Zheng, B and Torrente, MP and Fisher, RMA}, title = {Histone H3 Post-Translational Modification Changes are Linked to Manganese and Copper Exposure in Saccharomyces cerevisiae.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {42257176}, issn = {2578-9430}, abstract = {Prolonged exposures to heavy metals are risk factors for chronic diseases, such as Amyotrophic Lateral Sclerosis and Frontotemporal dementia (ALS/FTD). ALS/FTD comprises a fatal neurodegenerative disease continuum and is linked to disruptions in the levels of histone post-translational modifications (PTMs). Epigenetic mechanisms can connect environmental exposures to disease occurrences. Here, we examine the effects of manganese and copper exposure on the H3 PTM landscape in yeast. Manganese exposure decreases H3K9ac, H3K14ac, and H3S10ph levels. Copper exposure increases H3S10ph and H3K14ac levels and decreases H3K36me3 levels. This provides a basis for linking environmental exposure to biological mechanisms of disease.}, }
@article {pmid42257870, year = {2026}, author = {Nguyen, N and Lauinger, AR and Naik, A and Liu, R and Yolcu, Y and Arnold, PM}, title = {Clinical Research for the Use of 7 T Magnetic Resonance Imaging for Spinal Pathologies: a Scoping Review.}, journal = {Clinical neuroradiology}, volume = {}, number = {}, pages = {}, pmid = {42257870}, issn = {1869-1447}, abstract = {PURPOSE: Magnetic resonance imaging (MRI) at 7 T (7T) offers higher signal-to-noise ratio and improved spatial resolution compared to lower magnetic field strengths such as 1.5T and 3T, which may improve lesion detection and anatomical visualization for spinal cord pathology. This review summarizes current techniques and achievements in 7T spinal imaging and outlines associated technical barriers and future directions.<br><br>METHODS: A&#xa0;scoping review in accordance with PRISMA extension for scoping reviews guidelines was performed utilizing PubMed, Scopus, and Web of Science. Only studies related to 7T MRI of human subjects were included, after removing unrelated studies and those of non-human subjects.<br><br>RESULTS: Twenty-nine studies were included. Current literature supports 7T's superior resolution and signal-to-noise ratio in comparison to 1.5T and 3T MRI. These studies reported improved lesion detection and staging in multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS); however, the implications of results are limited by small sample sizes, technical heterogeneity, and inconsistent outcome measures. Additionally, the use of 7T spinal imaging remains limited by radiofrequency coil design, susceptibility artifacts, physiological noise, lack of FDA-clearance for spinal indications, and an absence of standardized imaging protocols. Future research aims to address these limitations.<br><br>CONCLUSION: Spinal cord imaging at 7T is challenging due to technical constraints and higher susceptibility to artifacts as a&#xa0;result of physiological noise (respiration, swallowing, and bulk movement). However, early studies' results using 7T imaging support improved ability, compared to 3T, to provide enhanced visualization of fine anatomical structures, such as nerve roots, and to improve spinal cord lesion detection.}, }
@article {pmid42257902, year = {2026}, author = {Horiuchi, K and Nakamura, S and Ishikawa, K and Nunomura, S and Yamada, K and Inoue, T and Oiwa, K and Fujii, S and Oshima, Y and Kudo, A and Yabe, I}, title = {Early respiratory decline around diagnosis and short-term post-landmark outcomes in amyotrophic lateral sclerosis: a 6-month landmark cohort study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {7}, pages = {}, pmid = {42257902}, issn = {1590-3478}, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), respiratory decisions rely on serial trends rather than a single value. We evaluated whether early respiratory decline around diagnosis provides prognostic information in a real-world landmark framework.<br><br>METHODS: This single-center retrospective cohort screened 94 consecutive patients diagnosed between April 2019 and December 2025. A 6-month landmark was used. Early decline was estimated from %FVC values between -&#x2009;30 and +&#x2009;180 days around diagnosis. The primary model included age and early %FVC decline; robustness analyses included time-varying Cox, piecewise Cox, RMST, included-vs-excluded comparison, death-only analysis, and slope-quality filtering.<br><br>RESULTS: Of 94 screened patients, 62 met baseline eligibility, 56 had calculable early slope, and 45 entered the landmark cohort; 28 post-landmark composite events occurred. In the Cox model, faster early %FVC decline was associated with higher hazard of death or invasive mechanical ventilation via tracheostomy (HR 1.33 per 1%/month faster decline, 95% CI 1.14-1.55, p&#x2009;<&#x2009;0.001). PH diagnostics suggested non-proportionality (%FVC p&#x2009;=&#x2009;0.031; NIV p&#x2009;=&#x2009;0.034 in the expanded model), so this HR was interpreted as an average follow-up association and complemented by PH-robust analyses. The signal was stronger early than late, remained consistent in a death-only analysis, and favored the slower-decline group by RMST at 24 and 36 months.<br><br>CONCLUSIONS: In this selected measurement-capable landmark cohort, early respiratory decline provided a clinically meaningful short-to-medium term prognostic signal for post-landmark adverse outcomes. External validation is required before broader generalization beyond measurement-capable landmark populations.}, }
@article {pmid42259179, year = {2026}, author = {Nakasako, J and Yaguchi, R and Terayama, A and Kuwahara, M and Nishimoto, Y}, title = {Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {488}, number = {}, pages = {126039}, doi = {10.1016/j.jns.2026.126039}, pmid = {42259179}, issn = {1878-5883}, abstract = {OBJECTIVE: Effective treatments for amyotrophic lateral sclerosis (ALS) remain limited, underscoring the need to identify robust biomarkers associated with disease severity and prognosis. This study investigated whether immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-glycolipid antibodies are associated with clinical manifestations of ALS, particularly decline in respiratory function.<br><br>METHODS: This was a retrospective observational cohort study of the patients with ALS. Among patients with definite or probable limb-onset ALS, 11 patients in the glycolipid IgG-positive group were compared with 15 patients in the IgG-negative group, and 5 patients in the glycolipid IgM-positive group were compared with 9 patients in the IgM-negative group, with adjustment for age. Associations between anti-glycolipid antibody status and respiratory function were assessed using Kaplan-Meier survival analysis and Cox proportional hazards models.<br><br>RESULTS: The time to decline of percent forced vital capacity (%FVC) below 80% and 60% was significantly shorter in the IgG-positive group than in the IgG-negative group (p&#xa0;=&#xa0;0.002 and p&#xa0;=&#xa0;0.025, respectively). Cox proportional hazards analysis demonstrated that IgG antibody positivity was an independent risk factor for earlier decline in %FVC to 80%.<br><br>INTERPRETATION: These findings suggest that anti-glycolipid IgG antibodies may be associated with respiratory function decline in ALS. Larger comprehensive studies will be required to validate these results and to elucidate the underlying pathophysiological mechanisms.}, }
@article {pmid42259250, year = {2026}, author = {Creel, SC}, title = {A note of caution on tone language advantages for music.}, journal = {Current biology : CB}, volume = {36}, number = {11}, pages = {R467-R469}, doi = {10.1016/j.cub.2026.04.009}, pmid = {42259250}, issn = {1879-0445}, abstract = {Liu et al.[1] reported recently in Current Biology a large-scale citizen science replication of the tone-language advantage for musical pitch perception. Their 493,100 volunteers spoke 54 languages, including 19 tone languages, those in which a word's pitch pattern contributes to its meaning. For example, Mandarin ma with high pitch means 'mother', while ma with dipping pitch means 'horse'. Previous studies reported tone language advantages, but with far smaller and less linguistically diverse samples (mostly East Asian tone languages). I applaud the authors' exploration of diverse tone languages with disparate tonal properties, including varying numbers, types, and linguistic uses of tones, plus varying cultural factors. While I do not dispute the overall tone language advantage, I take issue with Liu et al.'s[1] inference that the effect is consistent across the varied tone languages tested: because of the properties of the models they used to estimate individual-language effects, their more-diverse tone languages spuriously appear to pattern consistently, when in actuality the data are too noisy to draw strong conclusions about tone languages as a unified group.}, }
@article {pmid42246871, year = {2026}, author = {Wang, Q and Zhou, X and Zhao, W and Du, H and Zhu, P}, title = {Three Unaddressed Methodological Concerns in Chen Et al.'s Sarcopenia Study: Physical Activity Weighting, Muscle Mass Estimation, and Time-Varying Exposure.}, journal = {Geriatrics &amp; gerontology international}, volume = {26}, number = {6}, pages = {e70587}, doi = {10.1111/ggi.70587}, pmid = {42246871}, issn = {1447-0594}, }
@article {pmid42247870, year = {2026}, author = {Aprile, FA and Pastore, A}, title = {Ribonucleic acid as an active driver of protein aggregation in neurodegeneration.}, journal = {Current opinion in structural biology}, volume = {99}, number = {}, pages = {103298}, doi = {10.1016/j.sbi.2026.103298}, pmid = {42247870}, issn = {1879-033X}, abstract = {Neurodegeneration has traditionally been largely attributed to protein aggregation, yet ribonucleic acid (RNA) has emerged as an active driver of pathology. Expanded repeat RNAs, misregulated RNA-binding proteins, and aberrant RNA-protein interactions can directly or indirectly trigger neuronal dysfunction, although the distinction between the two mechanisms might, in some cases, be loose. RNA modulates prion-like aggregation, scaffolds liquid-liquid phase separation, and either promotes or inhibits protein assembly, depending on RNA sequence and structure. The aim of this review is to discuss our current understanding of RNA's dual role-as a facilitator of aggregation or as a potential therapeutic target-revealing new mechanistic insights into diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinocerebellar ataxias. We highlight RNA metabolism as a central determinant of neuronal vulnerability.}, }
@article {pmid42248860, year = {2026}, author = {Ball, HE and Woods, AC and Wong, YC}, title = {TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-74009-9}, pmid = {42248860}, issn = {2041-1723}, support = {DP2GM146322//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).}, }
@article {pmid42248993, year = {2026}, author = {Gad, AG and Kelani, KM and Mahmoud, AM and Arafa, RM and Abbas, AEF}, title = {Fedorov algorithm-optimized chemometric spectrophotometry for cefepime-tazobactam microanalysis in plasma and pharmaceuticals with integrated MA and NQS sustainability assessment.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42248993}, issn = {2045-2322}, abstract = {A green, sustainability-oriented chemometric-assisted UV spectrophotometric platform was developed for the simultaneous determination of Cefepime (CFPM) and Tazobactam (TAZO) in pharmaceutical formulations and human plasma. Water served as the sole diluent, eliminating hazardous organic solvents and substantially reducing the environmental impact of the analytical procedure. Calibration and validation sets were efficiently constructed using the Fedorov exchange algorithm within Brereton's multilevel design framework, yielding 25 calibration and 13 validation mixtures and reducing experimental workload by approximately 70% compared with conventional designs. Three complementary chemometric models were evaluated: Principal Component Regression (PCR), Firefly Algorithm-assisted Partial Least Squares (FA-PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Among them, MCR-ALS demonstrated superior predictive performance, with correlation coefficients exceeding 0.9998 for both analytes, minimal systematic bias confirmed by Elliptical Joint Confidence Region analysis, and high robustness across pharmaceutical and plasma matrices. Limits of detection were 0.0487 and 0.0396 µg mL[-1], while limits of quantification were 0.1476 and 0.1200 µg mL[-1] for CFPM and TAZO, respectively. The method was validated in accordance with ICH guidelines and successfully applied to CEFE-MAX™ powder for injection and fortified human plasma. Matrix effect evaluation showed negligible signal suppression (- 2.35% to - 1.27%), indicating strong matrix tolerance and calibration transferability. Comparative benchmarking against reported HPLC-UV, LC-MS/MS, capillary zone electrophoresis, and UV spectrophotometric methods demonstrated that the proposed approach achieves an optimal balance of sensitivity, simplicity, and environmental sustainability. Sustainability assessment using the Multi-Color Assessment (MA), carbon footprint analysis, and the Need-Quality-Sustainability (NQS) index yielded a Whiteness Score of 83.6%, an NQS score of 90, and a low carbon footprint of 0.032 kg CO2-eq per analysis. Overall, the developed platform provides a rapid, cost-effective, and environmentally responsible alternative for routine quality control and preliminary therapeutic monitoring of the CFPM-TAZO combination.}, }
@article {pmid42250142, year = {2026}, author = {Jalaiei, A and Kiani Darabi, AH and Sakkaki, E and Rezazadeh, M and Ghafouri-Fard, S}, title = {Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42250142}, issn = {1573-4978}, abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.}, }
@article {pmid42250707, year = {2026}, author = {Hosseinpoor, Z and Seyedalipour, B and Behjou, NK and Hosseinkhani, S and Baziyar, P}, title = {Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {152922}, doi = {10.1016/j.ijbiomac.2026.152922}, pmid = {42250707}, issn = {1879-0003}, abstract = {The aberrant aggregation of human superoxide dismutase 1 (hSOD1) into β-sheet-rich amyloid fibrils is a crucial process in the pathogenesis of amyotrophic lateral sclerosis (ALS), enhancing motor neuron degeneration and disease progression. The P66R mutation in SOD1 destabilizes local structure and promotes β-sheet-driven fibrillation, which makes it a suitable model for exploring approaches for reducing pathogenic aggregation. Here, we evaluate silymarin, a polyphenolic compound with known antioxidant and neuroprotective properties, for its potential to inhibit P66R-hSOD1 aggregation. ThT fluorescence and transmission electron microscopy analyses demonstrate a significant decrease in amyloid fibril formation in the presence of silymarin; in addition, FTIR spectroscopy confirms the suppression of β-sheet formation. Fluorescence quenching and ANS binding assays indicate a moderate-affinity binding between silymarin and the mutant protein, along with a reduction in surface hydrophobicity. Hemolysis assays confirm its protective effect against membrane damage induced by aggregates, while molecular docking and dynamic simulations indicate that silymarin stabilizes aggregation-prone areas with hydrogen bonding and hydrophobic interactions, thereby promoting compact conformations and reducing solvent-exposed surfaces. The findings identified silymarin as an effective anti-amyloidogenic agent that reduces β-sheet accumulation and fibril formation while also decreasing cytotoxicity, highlighting its potential as a therapeutic candidate for ALS.}, }
@article {pmid42251349, year = {2026}, author = {Masrori, P and Amado, DA}, title = {RAN translation as a dominant pathogenic axis in C9ORF72-associated ALS and FTD models.}, journal = {Molecular neurodegeneration}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13024-026-00959-9}, pmid = {42251349}, issn = {1750-1326}, }
@article {pmid42251967, year = {2026}, author = {Manchinu, MF and Congiu, M and Massidda, M and Borghero, G and Marongiu, J and Marzi, I and Maschio, A and Rallo, V and Serra, M and Porcedda, C and Etzi, M and Palmas, MF and Angius, A and Sogos, V and Pateri, MI and Steri, M and Coroneo, V and de Simone, A and Cossu, G and Chiti, F and Carta, AR}, title = {PBMC DEG/miRNA biomarkers of TDP-43 pathology in ALS.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107473}, doi = {10.1016/j.nbd.2026.107473}, pmid = {42251967}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) lacks reliable, disease-specific, and minimally invasive biomarkers, representing a major barrier to early diagnosis and patient stratification. The primary aim of this translational pilot study was to identify a disease-specific, TDP-43-related, gene-microRNA (miRNA) signature in peripheral blood mononuclear cells (PBMCs) of ALS patients with potential diagnostic value. To this end, we first identified differentially expressed disease-specific genes (dsDEGs) using a TDP-43-based rat model of ALS, generated by stereotaxic infusion of full-length (FL) TAR DNA-binding protein 43 (TDP-43) into the motor cortex. Transcriptomic profiling of the motor cortex revealed candidate dsDEGs, which were subsequently validated by RT-qPCR in motor cortex, spinal cord, and PBMCs from the same animals. To assess translational relevance, expression levels of these dsDEGs were analyzed in PBMCs from early- to mid-stage ALS patients and matched healthy controls, while disease specificity was evaluated using Parkinson's disease (PD) samples. In parallel, conserved miRNAs predicted to target the identified dsDEGs were examined in both rat and human PBMCs. Five dsDEGs, Mctp1, Penk, Mt2A, Drd1, and Rasgrp2, were consistently dysregulated across central and peripheral tissues in the TDP-43 rat model. RT-qPCR analysis of human PBMCs confirmed significant and selective dysregulation of these genes in ALS, but not in PD, supporting disease specificity. Moreover, exposure of human neuroblastoma cells and healthy PBMCs to TDP-43 recapitulated the ALS-like expression changes. Computational and experimental analyses identified seven conserved miRNAs targeting these dsDEGs, of which four were significantly downregulated in ALS PBMCs, supporting a coordinated regulatory network. Receiver operating characteristic (ROC) analyses demonstrated strong discriminative performance for both the gene signature (AUC 0.87-1.00) and the associated miRNAs (AUC 0.95-1.00). Together, these findings define a novel PBMC-based gene-miRNA signature that mirrors central ALS pathology and shows high diagnostic accuracy and disease specificity, highlighting its potential as a minimally invasive biomarker for ALS.}, }
@article {pmid42252093, year = {2026}, author = {Arlt, FA and Miske, R and Appeltshauser, L and Zinnow, V and Borowski, K and Stenzel, W and Radbruch, H and Meisel, A and Ruprecht, K and Endres, M and Blau, I and Kirchner, M and Mertins, P and Sanchez-Sendin, E and Wernick, S and Pressler, H and Stascheit, F and Linke, J and Hümmert, S and Werner, HB and Wibisono, EA and Doppler, K and Komorowski, L and Spiliotis, ET and Dubey, D and Zeckeridou, A and Pittock, SJ and Mills, JR and McKeon, A and Scharf, M and Prüss, H}, title = {Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag183}, pmid = {42252093}, issn = {1460-2156}, abstract = {Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibers. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays, and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n=86, Guillain-Barré syndrome n=37, multifocal motor neuropathy n=18, diabetic neuropathy n=30, other inflammatory neuropathies n=10), amyotrophic lateral sclerosis (n=50), multiple sclerosis (n=50), and healthy controls (n=50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over four years. Among 3,543 total samples tested, three patients (two male, one female) - diagnosed with the LMND variant of amyotrophic lateral sclerosis (ages 65, 72, and 79, respectively) - showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes, and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ("incisuropathy"). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over three years. The other two patients died of rapid disease progression: One of them received no immunotherapy while the other had ineffective treatments with single administrations of IVIG and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome, and responses to immunotherapy in larger cohorts.}, }
@article {pmid42252583, year = {2026}, author = {Melone, M and Di Palma, M and Scimemi, A and Conti, F}, title = {Organization of Astrocytic GLT-1 at Cortical Inhibitory Synapses.}, journal = {Glia}, volume = {74}, number = {8}, pages = {e70180}, doi = {10.1002/glia.70180}, pmid = {42252583}, issn = {1098-1136}, support = {PRIN2022BZWEKA//Italian Ministry of University and Reearch/ ; R56NS12955601/NH/NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/ultrastructure ; Animals ; *Excitatory Amino Acid Transporter 2/metabolism ; *Synapses/metabolism/ultrastructure ; Humans ; *Cerebral Cortex/metabolism/ultrastructure/cytology ; Rats ; Male ; Female ; Rats, Sprague-Dawley ; Glutamic Acid/metabolism ; *Neural Inhibition/physiology ; }, abstract = {Glutamate spillover from excitatory synapses modulates neighboring inhibitory synapses, yet the ultrastructural organization of the major glutamate transporter GLT-1 at these sites remains poorly defined. Using quantitative pre-embedding electron microscopy in rat and human cortex, we found that GLT-1-positive astrocytic leaflets (ALs) were frequently juxtaposed to morphologically identified symmetric synapses, with similar prevalence across axo-somatic, proximal axo-dendritic, and distal axo-dendritic subtypes. Because inhibitory synapses are embedded in a dense excitatory neuropil, we applied distance-based phenotyping relative to the nearest asymmetric synapse to define symmetric-associated GLT-1+ ALs. Within this population, distal axo-dendritic symmetric synapses showed shorter AL-to-synaptic-edge distances and were embedded in a tighter local excitatory microenvironment. Post-embedding immunogold further showed that GLT-1 was enriched at the plasma membranes of ALs and localized extrasynaptically relative to symmetric synapses. Consistently, symmetric-associated membrane GLT-1 and closely spaced GLT-1/α2 couples (with an interdistance ≤ 50 nm) were preferentially localized within 1000 nm of distal symmetric synapses compared to proximal. Similar organizational features of membrane GLT-1/α2 couples were observed in human cortex. These findings identify a subtype-dependent extrasynaptic astrocytic GLT-1 organization at cortical inhibitory synapses and provide a morphological framework for glutamate-dependent modulation of inhibitory signaling.}, }
@article {pmid42252587, year = {2026}, author = {Jin, H}, title = {PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.6c00338}, pmid = {42252587}, issn = {1948-7193}, abstract = {Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.}, }
@article {pmid42253115, year = {2026}, author = {Orzechowski, K and Wasiluk, M and Milewska, W and Kowalska, N and Chuang, YT and Cao, JY and Wang, CT and Neumann, A and Strzeżysz, O and Kozanecka-Szmigiel, A and Konieczkowska, J and Schab-Balcerzak, E and Lewandowski, W and Woliński, TR}, title = {Synergistic Effects of Nanoparticles and Surface Anchoring on Fine-Tuning the Photonic Bandgap in Blue Phase Liquid Crystals.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.6c01127}, pmid = {42253115}, issn = {1936-086X}, abstract = {Precise control over the photonic bandgap in Blue Phase Liquid Crystals (BPLCs) remains challenging due to the inherent limitations of existing tuning methods. Here, we present a 2-fold approach that synergistically combines internal and external effectors to enable controlled, fine modulation of the photonic bandgap across a wide spectral range of 200 nm. Internally, nanoparticles (NPs) embedded within the BPLC lattice enhance the thermal stability of the blue phase and reduce the cubic unit cell size, thereby shifting the reflection bandgap toward shorter wavelengths. Externally, the chemical structure of homogeneous alignment layers (ALs) affects the spectral position of the Bragg reflection. By systematically varying four ALs and three NP doping levels (0, 0.5, and 2 wt %), a cooperative influence of both effectors on spectral tuning is observed. These interactions are qualitatively explained by contact-angle measurements and chemical interactions at the LC-AL and LC-NP interfaces. Kossel diagram analysis, together with a factor based on the total tuning range and associated statistical descriptors, is used to confirm and quantify Bragg wavelength shifts. The results demonstrate that combined internal and external control provides an effective strategy for adjusting the optical response and thermal behavior of BPLCs, supporting their application in photonic devices.}, }
@article {pmid42253371, year = {2026}, author = {Chen, X and Mo, Y and Jiang, H}, title = {NEK1 variants and reduced protein levels in Chinese ALS patients: a descriptive study.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1831861}, pmid = {42253371}, issn = {1663-4365}, abstract = {OBJECTIVE: NIMA-related kinase 1 (NEK1) have been implicated in amyotrophic lateral sclerosis (ALS). But genetic spectrum and clinical presentation have not been systematically defined.<br><br>METHODS: We screened 378 ALS patients and identified NEK1 variant carriers. Clinical records were reviewed retrospectively to characterise phenotypes. Leukocytes were isolated after routine testing and NEK1 protein abundance was quantified by western blot to assess the relationship between NEK1 protein levels and the rate of clinical progression. In parallel, we conducted a structured narrative review of published NEK1-ALS cases based on a systematic search of PubMed, Embase, and Web of Science. We extracted genetic and clinical information to summarise the variant spectrum, co-mutation profiles, and phenotype differences across populations.<br><br>RESULTS: NEK1 variants were identified in 8 of 378 patients (2.12%). Protein analysis showed lower peripheral NEK1 levels among carriers than among controls in this small exploratory sample. An exploratory analysis further suggested that lower systemic NEK1 protein levels may be associated with faster disease progression; however, because these measurements were obtained from peripheral leukocytes at highly heterogeneous sampling times and without adjustment for major clinical confounders, they should be interpreted strictly as descriptive observations and do not support biomarker claims. While phenotypic heterogeneity and population-specific variant distributions were observed, these findings remain descriptive due to the small sample size.<br><br>CONCLUSION: This regional case series provides a descriptive overview of NEK1 variants in a Chinese ALS cohort and offers preliminary exploratory evidence consistent with reduced peripheral NEK1 protein levels in variant carriers. The observed inverse relationship between lower measured protein levels and faster clinical decline should be regarded as hypothesis-generating only. Given the small sample size, highly heterogeneous sampling times, use of peripheral leukocytes, and lack of adjustment for major clinical confounders, these protein data do not support biomarker claims at this stage. Validation in larger, prospective multi-center cohorts with standardized longitudinal sampling is required.}, }
@article {pmid42253609, year = {2026}, author = {Lajoie, I and Kalra, S and Dadar, M}, title = {Data-driven subtyping and staging of ALS: A multicenter, longitudinal, deformation-based morphometry study.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {4}, number = {}, pages = {}, pmid = {42253609}, issn = {2837-6056}, abstract = {Amyotrophic lateral sclerosis (ALS) is clinically and biologically heterogeneous, yet data-driven imaging subtyping approaches have rarely been validated longitudinally or linked to clinical and survival outcomes. We aimed to identify and validate distinct ALS subtypes and disease stages using deformation-based morphometry (DBM) and the Subtype and Stage Inference (SuStaIn) model, and to characterize their cross-sectional and longitudinal imaging, clinical, cognitive, and survival profiles. Data from 198 ALS patients and 144 healthy controls in the Canadian ALS Neuroimaging Consortium (CALSNIC) multicenter cohort were analyzed. Baseline regional DBM w-scores from 14 ALS-relevant regions served as input to SuStaIn to infer subtypes and stages. Longitudinal consistency of subtype and stage assignments (e.g. adherence to the expected disease evolution) was assessed using follow-up visits. Imaging and clinical trajectories were compared across subtypes using linear mixed-effects models incorporating stage and elapsed time. Associations between longitudinal variables and SuStaIn stage were estimated using mixed models, while baseline clinical and cognitive differences were assessed with ordinary least squares regression. Survival differences were evaluated using Kaplan-Meier curves and log-rank tests. SuStaIn identified one normal-appearing group (S0) and three ALS atrophy subtypes. S0 showed no baseline atrophy but exhibited longitudinal motor decline and the most favorable survival (log-rank p < 0.05 to p < 0.01). S1 exhibited classical motor/corticospinal tract-dominant degeneration, greater lower motor neuron burden, and intermediate survival. S2 showed limbic-onset atrophy progressing toward motor pathways, with preserved cognition and a milder course. S3 demonstrated extensive fronto-parietal and striatal atrophy, longitudinal motor-thalamic degeneration, and the shortest survival. Subtype and stage assignments demonstrated high longitudinal consistency (>90%). SuStaIn stage was strongly associated with widespread brain atrophy (and ventricular expansion), with the strongest effects in limbic-subcortical regions. Stage also correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) decline and forced vital capacity (FVC) reduction, indicating that stage reflects disease-linked progression. This study establishes a robust, longitudinally validated model of ALS heterogeneity, showing that SuStaIn-derived subtypes define distinct disease trajectories, whereas the normal-appearing group reflects an early, structurally preserved state with a more favorable survival profile. By integrating probabilistic staging with longitudinal modeling, these findings clarify dynamic subtype-specific progression patterns and support the use of SuStaIn for biologically informed patient stratification, prognostication, and clinical trial enrichment in ALS.}, }
@article {pmid42253794, year = {2026}, author = {Melby, SR and Asok Kumar, JN and Bigus, ER and Kellis, S}, title = {Clinical evaluation of communication brain computer interfaces in amyotrophic lateral sclerosis: a landscape analysis.}, journal = {Frontiers in human neuroscience}, volume = {20}, number = {}, pages = {1771146}, pmid = {42253794}, issn = {1662-5161}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that leads to severe motor impairment, including loss of communication ability, and ultimately death. Communication brain computer interfaces (cBCIs) have the potential to restore communication without reliance on motor function, thereby improving quality of life, independence, and palliative care. However, standardized methods to evaluate cBCI efficacy necessary for clinical implementation are not yet established.<br><br>METHODS: We conducted a systematic literature review, semi structured interviews with key opinion leaders (KOLs), and a clinical assessment review panel to (1) identify clinical outcome assessments (COAs) relevant to cBCIs in ALS, (2) obtain expert feedback, and (3) synthesize the current clinical and scientific landscape.<br><br>RESULTS: A total of 21 COAs were identified as potentially relevant and may serve as a foundation for cBCI specific measures. However, no existing COA was found to comprehensively capture the clinical benefit or functional impact of cBCIs in ALS.<br><br>DISCUSSION: Current COAs are insufficient to evaluate cBCIs in ALS, highlighting a critical gap. Development of cBCI specific outcome measures is needed to support clinical validation, regulatory evaluation, and adoption.}, }
@article {pmid42253845, year = {2026}, author = {Maslać, I and Palić, B and Kljakić, M and Puljić, M and Opančar, M and Kljakić, M and Opančar, B}, title = {Impact of dispatcher-assisted cardiopulmonary resuscitation, advanced life support training, and physician experience on out-of-hospital cardiac arrest outcomes in Mostar: a 10-year retrospective cohort study.}, journal = {Resuscitation plus}, volume = {28}, number = {}, pages = {101253}, pmid = {42253845}, issn = {2666-5204}, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a major public health challenge, with survival to hospital discharge rarely exceeding 10%. This study evaluated the association of dispatcher-assisted CPR (DA-CPR), advanced life support (ALS) training, and physician experience with OHCA outcomes in Mostar, Bosnia and Herzegovina, a resource-limited emergency medical service (EMS) system.<br><br>METHODS: We conducted a retrospective cohort study encompassing all OHCA cases recorded in the Mostar region between 2013 and 2022. Dispatcher-assisted CPR was formally implemented in early 2018. Accordingly, patients were stratified into two groups: the pre-implementation period (2013-2017) and the post-implementation period (2018-2022). The primary outcome was return of spontaneous circulation (ROSC) and the secondary outcome was survival to hospital discharge.<br><br>RESULTS: A total of 308 OHCA cases were included. ROSC was achieved in 88 patients (28.6%), and 14 patients (4.5%) survived to hospital discharge. Following DA-CPR implementation, ROSC increased from 22.7% to 33.5%. In adjusted logistic regression DA-CPR (OR&#xa0;=&#xa0;1.857, 95% CI 1.075-3.208) and ALS-trained physician involvement (OR&#xa0;=&#xa0;1.802, 95% CI 1.045-3.105) were independently associated with ROSC. Physician experience was not associated with ROSC or survival to hospital discharge, and no examined exposures were associated with survival to hospital discharge.<br><br>CONCLUSIONS: Dispatcher-assisted CPR and ALS-trained physician involvement were associated with higher odds of ROSC, while none of the examined variables showed an association with survival to hospital discharge. Early resuscitation gains did not translate into final outcomes in this resource-limited EMS system. Improving survival will require coordinated system strengthening, particularly public-access defibrillation and standardized post-resuscitation care.}, }
@article {pmid42254255, year = {2026}, author = {Beniwal, SS and Rawat, A and Sharma, N and Calderón, DC and Mwaanga, C and Mora, VA and Saini, P and da Costa, REAR and Mushir Ali, AS and Kumar, A and Dwivedi, A and Mehta, SP and Patel, DR and Danda, P}, title = {Translating potential into practice: the evolving landscape of neural stem cell therapeutics in clinical applications.}, journal = {Annals of medicine and surgery (2012)}, volume = {88}, number = {6}, pages = {3284-3295}, pmid = {42254255}, issn = {2049-0801}, abstract = {BACKGROUND: Neural stem cell (NSC) therapeutics have emerged as a promising approach for addressing neurological disorders due to their inherent ability to self-renew, differentiate into neural lineages, and secrete neurotrophic factors.<br><br>METHODS: This narrative review explores the evolving clinical landscape of NSC applications, highlighting their therapeutic potential in neurodegenerative diseases, ischemic stroke, and spinal cord injuries.<br><br>FINDINGS: Recent clinical advancements demonstrate the safety and preliminary efficacy of NSC-based therapies in conditions like Parkinson's disease and amyotrophic lateral sclerosis. NSCs' capacity to promote neuroplasticity and tissue restoration underscores their potential in reversing synaptic and neuronal damage. Despite these advancements, significant challenges remain. Ethical considerations, particularly concerning cell sourcing and patient consent, must be carefully navigated. Technical barriers, including cell delivery, survival, and long-term integration, require innovative solutions. Furthermore, safety concerns such as tumor formation and immune rejection necessitate rigorous preclinical and clinical assessments. Regulatory challenges, including the standardization of manufacturing processes and international harmonization, are essential for widespread adoption.<br><br>CONCLUSION: Looking ahead, the integration of precision medicine, advanced biomaterials, and patient-specific-induced pluripotent stem cells offers promising approaches to enhance NSC therapeutics. Collaborative efforts between researchers, clinicians, and regulatory agencies are crucial for overcoming existing barriers and translating NSC research into clinical practice, offering new hope for patients with complex neurological conditions.}, }
@article {pmid42245509, year = {2026}, author = {Wang, Z and Li, L and Dong, Y and Zhang, Y}, title = {The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1820111}, pmid = {42245509}, issn = {1664-302X}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.}, }
@article {pmid42246025, year = {2026}, author = {Pu, H}, title = {Editorial: Regulated cell death and neurological diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1842251}, pmid = {42246025}, issn = {1662-4548}, }
@article {pmid42015194, year = {2026}, author = {Luo, J and Li, K and Yang, R and Tang, M and Ge, J}, title = {Whole-exome sequencing identifies PRSS56 variants in Chinese patients with microphthalmia.}, journal = {BMC medical genomics}, volume = {19}, number = {1}, pages = {}, pmid = {42015194}, issn = {1755-8794}, support = {A1515010914//Guangdong Basic and Applied Basic Research Foundation/ ; 82271083//National Natural Science Foundation of China/ ; 2018YFA0108304//National Key Research and Development Program of China/ ; 2025QZSPT46//State Key Laboratory of Ophthalmology/ ; }, abstract = {PURPOSE: This study aimed to elucidate the genetic and clinical profiles of Chinese patients with microphthalmia harbouring PRSS56 variants and investigate the genotype‒phenotype correlation.<br><br>METHODS: Whole-exome sequencing (WES) was performed in patients with microphthalmia and available family members to assess coding regions and adjacent intronic splice boundaries for variant detection and downstream interpretation. The axial lengths (ALs) of all the probands and available family members were measured. The genotype&#x2012;phenotype correlation was explored by statistical analysis, and protein structure prediction was analysed in silico.<br><br>RESULTS: Seven PRSS56 variants were detected across four of the seven families, including two novel candidate variants (c.175G&#x2009;>&#x2009;A:p.E59K and c.1030&#xa0;C&#x2009;>&#x2009;A:p.P344T) and five previously reported variants. Variant p.Q356Pfs152 was found in two unrelated families and was the most frequent. The mutational spectrum frequency in the Chinese population differed from that in other ethnic groups worldwide. The average AL was 17.82&#x2009;&#xb1;&#x2009;1.51&#xa0;mm. In an exploratory pooled analysis combining the current cohort with previously published cases, eyes with biallelic LoF variants showed shorter ALs than eyes with missense variants. Variants p.G107V and p.E396K, which were reported exclusively in Chinese microphthalmia cases, were predicted to destabilize the PRSS56 protein.<br><br>CONCLUSIONS: Among nine individuals from seven families, seven PRSS56 variants were identified in four families, underscoring the significant genetic diversity within the Chinese population. The reported variant p.Q356Pfs*152 had the highest frequency in our cohort. Our findings expand current understanding of PRSS56-associated microphthalmia and provide valuable information for prenatal diagnosis and future therapeutic strategies.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-026-02376-9.}, }
@article {pmid42243993, year = {2026}, author = {Hsieh, WC and Lin, CY and Wu, HC and Weng, EF and Wang, SM}, title = {Hyperoside protects against poly-GR-mediated neurodegeneration via regulation of mitochondrial fission and oxidative stress in C9orf72-associated ALS.}, journal = {Chinese medicine}, volume = {21}, number = {1}, pages = {}, pmid = {42243993}, issn = {1749-8546}, support = {MOST 111-2628-B-039- 006-MY3//National Science and Technology Council/ ; CMU114-MF-04//China Medical University, Taiwan/ ; }, abstract = {BACKGROUND: Arginine-rich poly-glycine-arginine (poly-GR), a toxic dipeptide repeat protein generated from C9orf72 hexanucleotide repeat expansion, drives mitochondrial dysfunction, oxidative stress, and neuronal loss in amyotrophic lateral sclerosis (ALS). Hyperoside, a bioactive flavonoid, exhibits antioxidant and cytoprotective properties, but its therapeutic relevance to C9orf72-associated ALS remains unclear.<br><br>PURPOSE: To determine whether hyperoside attenuates poly-GR-induced mitochondrial and oxidative injury and improves neuronal survival in cellular and animal models of C9orf72-ALS.<br><br>METHODS: A combined in vitro and in vivo experimental study using motor neuron-like cells and an AAV-mediated neonatal mouse model of poly-GR toxicity. NSC34 cells expressing EGFP-GR50 were analyzed for mitochondrial morphology, membrane potential, ROS generation, antioxidant signaling, and apoptosis using confocal microscopy, CellROX/MitoTracker assays, Western blot analysis, and viability testing. For in vivo assessment, neonatal mice received intracerebroventricular AAV9-EGFP-GR50 followed by intraperitoneal hyperoside (10&#xa0;mg/kg). Survival, cerebral hemisphere length, and cortical NeuN&#x207a; neuron numbers were quantified.<br><br>RESULTS: Poly-GR expression induced pronounced mitochondrial fragmentation, reduced membrane potential, elevated ROS, and suppressed Nrf2/HO-1/GPx4 signaling, accompanied by increased Drp1 and reduced Opa1 expression. Hyperoside reversed these abnormalities by restoring mitochondrial integrity, normalizing the Drp1/Opa1 balance, enhancing Nrf2 nuclear accumulation, and increasing the expression of HO-1 and GPx4. Hyperoside also reduced cleaved caspase-3 and corrected the Bax/Bcl-2 ratio, improving cell viability under basal and oxidative stress conditions. In vivo, hyperoside modestly prolonged survival, increased cerebral hemisphere length, and significantly preserved cortical neuronal numbers in AAV9-EGFP-GR50 mice.<br><br>CONCLUSION: Hyperoside mitigates poly-GR-induced neurotoxicity by alleviating excessive mitochondrial fission, strengthening Nrf2-dependent antioxidant defenses, and suppressing apoptosis. These findings support hyperoside as a promising multi-target therapeutic candidate for C9orf72-associated ALS.}, }
@article {pmid42244138, year = {2026}, author = {Subbotin, D and Voskanyan, A and Borovikov, A and Marakhonov, A and Bobreshova, A and Rosales-Sabino, M and Murtazina, A}, title = {FLNC Complex Structural Variant Causing Distal Myopathy Identified by Family-Based Genome Sequencing.}, journal = {American journal of medical genetics. Part A}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajmg.a.70223}, pmid = {42244138}, issn = {1552-4833}, support = {25-65-00031//Russian Science Foundation/ ; }, abstract = {Distal myopathies (DM) are clinically and genetically heterogeneous neuromuscular disorders, and identifying a molecular genetic cause may remain challenging in a subset of cases. Moreover, DM may be misdiagnosed as hereditary neuropathies due to overlapping clinical features. Here, we report a novel structural variant in FLNC associated with DM identified through genome sequencing (GS). Two affected relatives initially presented independently with referral diagnoses of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Clinical re-evaluation led to a change of the diagnosis to DM. Muscle MRI revealed a consistent pattern of selective muscle involvement characteristic of DM, enabling identification of six affected individuals within the family. GS was performed in seven family members, including six affected individuals and one unaffected relative. The analysis identified an insertion of two inverted fragments derived from the adjacent intron 2 into exon 3 of the FLNC gene. This complex rearrangement was accompanied by short non-templated nucleotide insertions at the junctions and a 3-bp exonic deletion at the insertion site, ultimately resulting in a frameshift. The structural variant was segregated with disease and was confirmed by Sanger sequencing and one Oxford nanopore long-read sequencing. Our findings expand the mutational spectrum of FLNC-associated disorders and highlight the importance of GS combined with a detailed clinical examination for the diagnosis of DM.}, }
@article {pmid42244301, year = {2026}, author = {Pu, H and Liu, Y and Xu, Z and Fang, J and Song, T and Qin, C and Lu, J and Luo, Y}, title = {Synergistic Control and Resource Utilization of Carbonyl Sulfur (COS) and Hydrogen Sulfide (H2S) over Oxidized K-Mo Materials.}, journal = {Environmental science &amp; technology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.est.6c05690}, pmid = {42244301}, issn = {1520-5851}, abstract = {Carbonyl sulfide (COS) and hydrogen sulfide (H2S) coexist extensively in industrial waste gases, yet conventional technologies typically address them separately, leaving synergistic control and resource utilization as ongoing challenges. This study presents a novel approach for the synergistic catalytic transformation of COS/H2S into high-value-added methyl mercaptan (CH3SH). Activity results revealed that the oxidized K-Mo/Al-O catalyst, unexpectedly active, outperforms the common sulfided K-Mo/Al-S catalyst. Characterizations suggested that K-Mo/Al-O undergoes in situ reconstruction into the K-intercalated 1T-MoS2 phase (KxMoS2), subsequently transforming into the K-decorated 2H-MoS2 phase (K/MoS2). Structure-activity relationship confirmed KxMoS2 as the key metastable active phase for the generation of CH3SH, where potassium species acted as the primary active site, while Mo oxide/sulfide species played an assistant role. Temperature-programmed surface reaction of reactants (COS/H2/H2S-TPSR) and in situ diffuse reflectance infrared spectroscopy (in situ DRIFTS) elucidated that the reaction mechanism strongly depends on both reaction temperature and the active phase types, i.e., K2MoO4 precursor follows an Eley-Rideal (E-R)-type direct COS hydrogenation pathway, KxMoS2 exhibits a dual-path E-R mechanism (direct COS hydrogenation at low temperature and indirect hydrogenation at medium temperature), and K/MoS2 primarily follows indirect COS hydrogenation at medium temperatures. This work paves a new avenue for synergistic resource utilization of multicomponent sulfur pollutants.}, }
@article {pmid42237814, year = {2026}, author = {Kulkarni, NP and Thulasidharan, A and Soory, A and Goel, P and Sarkar, S and Kelkar, V and Ratnaparkhi, GS}, title = {Fos regulates age-dependent neuroinflammation in VAPBALS.}, journal = {Disease models &amp; mechanisms}, volume = {}, number = {}, pages = {}, doi = {10.1242/dmm.052810}, pmid = {42237814}, issn = {1754-8411}, support = {2023/SL03//EMSTAR/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor function. We have developed a Drosophila model of ALS8 (VAPBP58S) using CRISPR/Cas9 genome editing. VAPB is an ER-based adapter protein associated with and regulating intracellular membrane:membrane contact sites. VAPB P58S flies show progressive age-dependent motor deficits and a shortened lifespan, paralleling features of the human disease. VAPBP58S brains exhibit age-dependent neuroinflammation, as measured by whole-transcriptome quantitative mRNA sequencing, suggesting a broad, low-grade enhancement of signalling across multiple immune pathways (Toll, IMD, Jak-STAT, and Jun-kinase). We implicate glial cells in the brain as the site of brain inflammation and identify Drosophila Fos (Kayak) as a key modulator of age-dependent inflammation. In accordance, we find that overexpression of wild-type kayak or its dominant-active variant kayakK357R in glia reduces inflammation and, concomitantly, improves motor function. In contrast, knockdown of glial kayak accelerates age-dependent deterioration of motor function and enhances neuroinflammation. Our study underscores the roles of glial-modulated brain inflammation in dictating ALS8 progression and identifies kayak as a central negative regulator of neuroinflammation in disease.}, }
@article {pmid42237817, year = {2026}, author = {Biondi, A and Gray, E and Aggreh, M and Jones, E and Collingwood, A and Knox, L and Bredin, A and Setters, D and Talbot, K and Al-Chalabi, A}, title = {The Motor Neuron Disease Register for England, Wales, and Northern Ireland: Protocol for a Population Register.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e86458}, pmid = {42237817}, issn = {1929-0748}, abstract = {BACKGROUND: Despite the existence of several regional registries in the United Kingdom, gaps in geographic coverage have limited the ability to produce accurate national estimates of incidence, prevalence, and regional variation for motor neuron disease (MND). To address these challenges, a comprehensive national register encompassing England, Wales, and Northern Ireland was established to support epidemiological studies, health care planning, and clinical research.<br><br>OBJECTIVE: The primary objective of the MND Register is to provide a centralized research database aggregating clinical and demographic data to facilitate high-quality research. Secondary objectives include estimating disease incidence and prevalence, identifying regional differences in care and survival, evaluating potential disease clustering, and supporting data linkage and clinical trial recruitment.<br><br>METHODS: Eligible patients are those aged 16 years or older with a confirmed MND diagnosis made by a consultant neurologist. Data are collected prospectively and retrospectively through standardized templates, available via Microsoft Access, Microsoft Excel, or the REDCap (Research Electronic Data Capture; Vanderbilt University) web platform, and include up to 34 demographic and clinical variables. Additional self-reported data can be contributed through the Telehealth in MND-Research platform. All data are securely stored in the King's College London Trusted Research Environment, undergo standardized preprocessing, and may be linked to National Health Service and national datasets for epidemiological analyses.<br><br>RESULTS: The register includes data on over 11,000 individuals with MND, of whom nearly 7000 are currently alive. Postcode data are available for more than 4300 patients, enabling future geospatial analyses. By October 2025, 60 clinical sites were participating in the register, with around 50 actively submitting data.<br><br>CONCLUSIONS: The MND Register represents one of the largest national registries for MND worldwide, providing a robust foundation for epidemiological modeling, clinical research, and health care planning. Ongoing efforts to expand prospective data collection, improve completeness, and integrate digital tools will further enhance its impact and support national and international MND research collaborations.}, }
@article {pmid42238865, year = {2026}, author = {Bouras, A and Adio, AA and Kumar, R and Phadke, R and Rice, SW and Mody, K and Ndu, A}, title = {Primary Tibiotalocalcaneal Nailing vs Open Reduction and Internal Fixation for Fragility Ankle Fractures in Older Adults: A Markov Model.}, journal = {Foot &amp; ankle orthopaedics}, volume = {11}, number = {2}, pages = {24730114261450956}, pmid = {42238865}, issn = {2473-0114}, abstract = {BACKGROUND: Fragility ankle fractures are common in the elderly population. The cost-effectiveness of primary tibiotalocalcaneal (TTC) nailing compared with open reduction and internal fixation (ORIF) in this population remains unclear.<br><br>METHODS: We constructed a Markov cohort model with a 4-year time horizon to compare TTC nailing vs ORIF for fragility ankle fractures in patients aged 75 years and older. All complication rates were derived from the McDonald et al's (2025) systematic review and meta-analysis. Costs were in 2024 US dollars with 3% annual discounting for costs and outcomes. Probabilistic and deterministic sensitivity analyses were performed.<br><br>RESULTS: In the base case, ORIF yielded 3.210 quality-adjusted life years (QALYs) (95% credible interval [CrI] 2.785-3.584) at $30 091 (95% CrI $21 426-$40 852) compared with 3.207 QALYs (95% CrI 2.783-3.581) at $33 583 (95% CrI $23 741-$45 447) for TTC nailing. ORIF dominated incremental cost (+$3492, 95% CrI -$11 467 to +$18 273) and incremental QALYs (-0.003, 95% CrI -0.009 to +0.002). The cost differential was driven by the $3000 higher index procedure cost for TTC, partially offset by lower superficial infection (2.1% vs 10.2%). Probabilistic sensitivity analysis demonstrated 33% probability of cost-effectiveness at $100 000/QALY. All 4 scenario analyses confirmed that ORIF dominated.<br><br>CONCLUSION: Under McDonald's pooled estimates, TTC nailing is dominated by ORIF for fragility ankle fractures in older adults. The lower superficial infection rate with TTC does not offset its higher procedure cost and higher rates of nonunion and hardware failure. These findings support ORIF as the preferred strategy from a cost-effectiveness standpoint, although the small incremental differences should be considered alongside clinical factors when selecting treatment.<br><br>LEVEL OF EVIDENCE: Level IV, economic modeling.}, }
@article {pmid42239172, year = {2026}, author = {Matthews, AM and Whiteley, AM}, title = {The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.21.727000}, pmid = {42239172}, issn = {2692-8205}, abstract = {UNLABELLED: Retroelements, including retrotransposons, endogenous retroviruses, and their fragments, as well as rare co-opted or domesticated retroelements, can contribute to neurodegenerative disorders and aging through modulation of gene expression and induction of neuroinflammation. Paternally Expressed Gene 10 (PEG10) is a retroelement-derived human gene that has recently been identified as a putative driver of Amyotrophic Lateral Sclerosis (ALS) and Angelman's Syndrome. PEG10 has been reported to bind nucleic acid and undergoes a complex self-processing pathway that results in gene expression changes when the protein accumulates in cells. Here, we report that PEG10 has selectivity for binding U/G-rich RNAs and influences widespread gene expression changes. PEG10 overexpression mimics the loss of TDP-43 in broad changes to gene expression, including dysregulation of mRNA splicing pathways. Specific changes to mRNA splicing were largely unique between TDP-43 knockdown and PEG10 overexpression, as classic TDP-43 targets including STMN2 were not altered by PEG10. Instead, we identified a unique role for PEG10 in regulating splicing of neuregulin 3 (NRG3) , a ligand for the neuronal receptor ERBB4. In SH-SY5Y cells and in human neurons overexpressing PEG10, NRG3 protein levels were decreased along cellular processes, suggesting that these cells are less competent at signaling through the NRG3/ERBB4 axis. Using human patient data, we observed similar changes to NRG3 splicing in UBQLN2 -mediated ALS, where PEG10 is accumulated, as well as in some cases of sporadic ALS. In conclusion, the retroelement-derived gene PEG10 plays an unexpected role in regulating splicing of neuronal transcripts, which mimics some of the transcript changes observed in human ALS patient samples. Ultimately, this work has implications for the study of PEG10, and mRNA splicing in neurological diseases associated with elevated PEG10 abundance.<br><br>HIGHLIGHTS: PEG10 NC expression influences abundance of transcripts implicated in ALS PEG10 NC expression leads to an exon skipping event in neuregulin 3 (NRG3) NRG3 expression is decreased along dendrites of PEG10 NC expressing human neuronsExpression of PEG10 NC mimics changes observed in human ALS.}, }
@article {pmid42239283, year = {2026}, author = {Reedich, E and Chen, YT and Imhoff-Manuel, R and Li, D and Manuel, M}, title = {Chronic diazepam reveals excessive homeostatic gain in SOD1 [G93A] mouse spinal motoneurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.16.725609}, pmid = {42239283}, issn = {2692-8205}, abstract = {Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1 [G93A] mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1 [G93A] mice modulate excitability differently than wild type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1 [G93A] versus wild type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1 [G93A] motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.}, }
@article {pmid42240799, year = {2026}, author = {Saadat, A and Jasińska, M and Cedro, B and Piekarska, A and Flis, DJ and Ziółkowski, W and Pyza, E}, title = {Synaptic Plasticity Changes in the Somatosensory Cortex During Amyotrophic Lateral Sclerosis Progression and After Swim Training in SOD1-G93A Mice.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42240799}, issn = {1559-1182}, abstract = {Somatosensory cortex hyperexcitability is present in the pre-symptomatic stage of amyotrophic lateral sclerosis (ALS) as evidenced by brain recordings, but its synaptic basis remains unclear. We examined synaptic plasticity, the density of asymmetric (putative excitatory) and symmetric (putative inhibitory) synapses, dendritic spine morphology, and the putative excitatory/inhibitory (E/I) ratio in the B2 barrel of the somatosensory cortex in female mice of an ALS mouse model. Transgenic mice, B6SJL-Tg (SOD1*G93A)1Gur/J, were used as the ALS model, and wild-type (WT) B6SJL/F1 mice served as controls. ALS mice were allocated to experimental groups based on disease stage (pre-symptomatic, onset, or terminal) and training condition (swim-trained or untrained). Swim training was applied after the first onset of symptoms (clinical score 1). We analyzed and quantified the density of asymmetric (putative excitatory) and symmetric (putative inhibitory) synapses and E/I ratios using serial electron micrographs to understand how these parameters change during disease progression and whether swim training influences this process. Our results showed stage-dependent alterations in asymmetric (putative excitatory) and symmetric (putative inhibitory) synaptic architecture in ALS. The obtained data showed an increase in the excitatory synaptic density in the presymptomatic ALS mice. This finding is consistent with previous reports of early cortical hyperexcitability and may reflect structural alterations associated with an initial increase in excitatory synapses before disease onset. Importantly, we report here an increase in inhibitory synapses at disease onset. TEM-based synaptic density quantification revealed reduced excitatory synapse density in the B2 barrel of the somatosensory cortex of trained ALS mice compared to WT controls, alongside a trend toward a reduced putative excitatory/inhibitory synaptic ratio. However, as no significant differences were detected between trained and untrained ALS mice, the contribution of swim training to these alterations remains unclear. Notably, swim training was not associated with detectable adverse effects on somatosensory cortex ultrastructure, excitatory synapse density, or the putative excitatory/inhibitory ratio, supporting previous observations that swim training is well tolerated under these experimental conditions. To our knowledge, these results provide the first TEM-based ultrastructural characterization of synaptic architecture in swim-trained SOD1-G93A mice, although further studies are needed to establish the underlying mechanisms and therapeutic relevance in ALS.}, }
@article {pmid42241089, year = {2026}, author = {Alister, M and Ransom, KJ and Perfors, A}, title = {When a helpful bias is unhelpful: Limitations in reasoning about random and deliberately misleading evidence.}, journal = {Journal of experimental psychology. General}, volume = {}, number = {}, pages = {}, doi = {10.1037/xge0001939}, pmid = {42241089}, issn = {1939-2222}, support = {//Australian Defence Science and TechnologyGroup/ ; //Australian Government/ ; }, abstract = {Social information aids learning: By making assumptions about other people's knowledge and intentions, people can draw strong and accurate inferences from limited data. In this study, we systematically tested people's ability to reason from information providers with different intentions. The task was an adaptation of Shafto et al.'s (2014) rectangle game, where learners guessed a rectangle's size and location based on provided clues. We examined reasoning based on information from four types of providers: a helpful provider, a provider who sampled randomly, and two misleading providers (who could mislead but not lie). We also varied whether people were given a cover story describing the provider in advance or whether they could infer how helpful a provider was based on what the provider shared. Participants learned efficiently from helpful providers, aligning closely with the predictions of a normative Bayesian model, even without a cover story. However, while people usually recognized unhelpful providers, they struggled to identify and respond appropriately to misleading strategies. Overall, our results suggest a helpful bias: In our task, participants assumed helpful intent unless given explicit feedback, and even then, they did not fully adjust in line with Bayesian predictions. People also struggled to overcome this bias when learning from randomly sampled information, especially when they had experience being an information provider themselves (Experiment 3). (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42241188, year = {2026}, author = {Chikktimmegowda, D and Keerthipriya, MS and Vengalil, S and Nashi, S and Baskar, D and Mol, JJ and Joseph, S and Aishwarya, SY and Binesha, PB and Kumar, BD and Chandrika, H and Mehta, M and Roshan, A and Belur, YK and Nalini, A and Thomas, PT}, title = {The Unfinished Breath: Caregiver Perceptions of Terminal Events and Gaps in Amyotrophic Lateral Sclerosis Care in India.}, journal = {Annals of Indian Academy of Neurology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aian.aian_1234_25}, pmid = {42241188}, issn = {0972-2327}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a high symptom burden and limited survival. Little is known about the terminal phase experiences, symptom prevalence, and end-of-life care patterns of people with ALS (PALS) in India. This study aimed to assess terminal events and caregiver-reported outcomes in PALS to identify gaps in ALS care delivery in India.<br><br>METHODS: A cross-sectional telephonic survey was conducted among bereaved caregivers of PALS enrolled in the Neuropalliative and Supportive Care project between December 2021 and May 2024. A structured, validated questionnaire was used to collect data on demographics, terminal-phase symptoms, medical interventions, and the nature of death as perceived by primary caregivers. Descriptive statistics and appropriate statistical analyses were performed.<br><br>RESULTS: A total of 130 caregivers participated in the survey; the majority (57.7%) were sons or daughters. Among the 130 PALS, 76 (58.5%) were men; 56.2% had limb onset and 43.8% had bulbar onset. The mean age at death was 53.5 &#xb1; 11.4 years. Most patients (57.7%) died at home, and 29.2% experienced sudden death. Patients who died in the hospital were more likely to be on invasive mechanical ventilation (P < 0.001). The most common terminal symptoms were breathlessness (79.2%), excessive oral secretions (54.6%), followed by anxiety or restlessness (44.6%). Only 20% received bilevel positive airway pressure, and 25.4% were on percutaneous endoscopic gastrostomy. A significant association was found between bulbar onset and assisted feeding (P = 0.002).<br><br>CONCLUSIONS: This study highlights the need for proactive, community-integrated palliative care services and emphasizes the urgency of early intervention and caregiver support to improve end-of-life experiences in PALS in India.}, }
@article {pmid42242586, year = {2026}, author = {Wong, B and Payne, M and Silva, A and Kurniawan, E and Eidman, AS and Pizzo, D and Rajupalem, R and Lenk, GM and Paulo, JA and Khan, T and Eskelinen, EL and Gygi, SP and Brown, NG and Meisler, MH and Mendiola, AS and Gassaway, BM and Ferguson, CJ}, title = {Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107467}, doi = {10.1016/j.nbd.2026.107467}, pmid = {42242586}, issn = {1095-953X}, abstract = {Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits Fig. 4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4 J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig. 4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig. 4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.}, }
@article {pmid42233796, year = {2026}, author = {Nolan, HA and Dunford, L}, title = {A qualitative exploration of medical educators' familiarity and perspectives regarding trauma-informed approaches in medical education.}, journal = {Medical teacher}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/0142159X.2026.2681193}, pmid = {42233796}, issn = {1466-187X}, abstract = {INTRODUCTION: Evidence demonstrates profound impacts of trauma, on both physical and mental health across the lifespan, making trauma a significant public health issue. Current understanding of traumatic events acknowledges origins from social, structural, as well as interpersonal sources. Trauma-informed approaches (TIAs) provide a framework for interactions with those affected, and advocate for accommodation of trauma impacts throughout individual practice, and in organisations and systems to prevent retraumatisation. While TIAs are increasingly recommended in healthcare policy, evidence suggests these are not consistently incorporated in medical education. Educators are key stakeholders in embedding this practice, yet their perspectives have not been evaluated, representing a critical knowledge gap.<br><br>METHODS: We applied Brown et&#xa0;al.'s proposed Trauma-Informed Medical Education (TIME) framework (2021) that integrates trauma-informed principles throughout educational content and context as a conceptual model in this qualitative exploration of educator knowledge and practice. Educators at UK medical schools were invited to participate in semi-structured interviews exploring familiarity with TIAs, benefits and drawbacks. Data were analysed using reflexive thematic analysis.<br><br>RESULTS: Twenty-three educators from 16 medical schools were interviewed. Knowledge, routes to familiarisation and practice varied considerably among participants, who broadly recognised need for and value of TIAs. Practice often mirrored trauma-informed principles. Motivations related to person-centred care, inclusive education, and learner wellbeing, with concerns regarding avoidance of distressing content. Compatibility of TIME recommendations with education and healthcare contexts was discussed, with facilitators, and more commonly, barriers identified.<br><br>DISCUSSION: Variable knowledge, opportunistic familiarisation, and individually determined practice indicate the need for more precise understanding of evidence regarding trauma sources and impacts and TIAs amongst education stakeholders at all levels to harness benefits. Wider contextual factors are not addressed in the current framework. Greater consideration of contextual factors and more cohesive approaches across medical education, alongside stakeholder engagement, are needed to meet healthcare policy intentions.}, }
@article {pmid42234085, year = {2026}, author = {Rinner, C}, title = {Ethical justification of coercive public health policies must be premised upon their safety and efficacy.}, journal = {Monash bioethics review}, volume = {}, number = {}, pages = {}, pmid = {42234085}, issn = {1836-6716}, support = {NFRFR-2022-00305//New Frontiers in Research Fund/ ; }, abstract = {This commentary on Johnson et al. (2025) argues that ethical justification of a public health policy is void if the underlying intervention has not been shown, beyond reasonable doubt, to be effective, necessary, proportionate, and safe. I respond to Johnson et al.'s (2025) explorations with examples of coercive policies during the COVID-19 crisis. Frequently, the scientific evidence underpinning pandemic response measures has shifted, weakening or nullifying their original purpose. Such measures can no longer be ethically justified, and contemporary concerns regarding lockdown and mask policies as well as vaccination requirements were not properly considered by public health authorities.}, }
@article {pmid42234776, year = {2026}, author = {Guo, C and Chen, K and Vatsavayai, S and Akiyama, T and Liu, C and Zeng, Y and Sianto, O and Yang, E and Bombosch, J and Powell, R and Zhen, S and Mekhoubad, S and Morrie, RD and Miller, G and Ilic, D and Boll, M and Parnell, E and Penzes, P and Lipstein, N and Green, EM and Petrucelli, L and Seeley, WW and Gitler, AD}, title = {Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.}, journal = {Science translational medicine}, volume = {18}, number = {852}, pages = {eaeb8517}, doi = {10.1126/scitranslmed.aeb8517}, pmid = {42234776}, issn = {1946-6242}, abstract = {TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7, and KCNQ2. Using human stem cell-derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.}, }
@article {pmid42235092, year = {2026}, author = {Wolff, AW and Leha, A and Koch, JC and Demleitner, AF and Neuwirth, C and Friede, T and Weber, M and Lingor, P}, title = {Effects of fasudil on disease spreading in ALS - A MUNIX-based post-hoc analysis of the ROCK-ALS trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {4}, pages = {e00936}, doi = {10.1016/j.neurot.2026.e00936}, pmid = {42235092}, issn = {1878-7479}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the spread of muscle weakness across body regions. ROCK-ALS was a multicenter, placebo-controlled phase 2 trial assessing the safety, tolerability, and efficacy of the Rho kinase inhibitor fasudil in ALS patients. A key exploratory objective was to evaluate fasudil's effect on the spread of muscle weakness using the Motor Unit Number Index (MUNIX), an established, quantitative electrophysiological biomarker of lower motor neuron integrity. MUNIX was assessed in 10 muscles at baseline, day 26, day 90, and day 180. In the present post-hoc analysis, correlations were assessed between baseline serum biomarkers-neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)-and baseline clinical measures (ALSFRS-R, slow vital capacity, and MUNIX-10 sum scores) as well as their monthly rates of change, to explore potential prognostic relationships. For the analysis of disease spreading, muscles were classified as newly affected based on MUNIX decline relative to contralateral values or prior measurements, using thresholds of ≥10%, ≥20%, or ≥30%. Out of 118 participants included in the intention-to-treat population, 78 had full MUNIX datasets at baseline, and 67 had at least one follow-up. Baseline MUNIX-10 sum scores correlated with subsequent ALSFRS-R decline, suggesting prognostic value. Additionally, at day 90, fasudil significantly reduced the number of newly affected muscles compared to placebo in a dose-dependent manner over different thresholds. This supports MUNIX as a sensitive biomarker for monitoring disease spreading and demonstrates that fasudil may attenuate the progression of lower motor neuron involvement in ALS. Trial registration number: NCT03792490 (ClinicalTrials.gov); 2017-003676-31 (Eudra-CT).}, }
@article {pmid42235125, year = {2026}, author = {Talbot, K}, title = {Celebrating a breakthrough for amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {6}, pages = {1799-1800}, doi = {10.1093/brain/awag174}, pmid = {42235125}, issn = {1460-2156}, }
@article {pmid42235808, year = {2026}, author = {De Mori Bajolin, F and Tavazzi, E and Bianchi, AM and Mendez, MO}, title = {Robust end-to-end stratification of amyotrophic lateral sclerosis patients via recurrent variational autoencoder and consensus clustering.}, journal = {Journal of biomedical informatics}, volume = {180}, number = {}, pages = {105059}, doi = {10.1016/j.jbi.2026.105059}, pmid = {42235808}, issn = {1532-0480}, abstract = {OBJECTIVE: This study aims to develop a data-driven methodology for stratifying Amyotrophic Lateral Sclerosis (ALS) patients based on longitudinal disease progression patterns, using a novel deep learning framework that combines a Recurrent Variational Autoencoder (RVA) with consensus clustering to identify clinically meaningful subgroups.<br><br>METHODS: The RVA integrates Peephole Long Short-Term Memory networks within the Variational Deep Embedding (VaDE) architecture to simultaneously learn latent representations and cluster assignments from multivariate time-series data. The approach incorporates hyperparameter optimization via prediction strength with two-fold cross-validation, consensus clustering, and internal validation metrics (Silhouette Coefficient, Davies-Bouldin index, Calinski-Harabasz index) for optimal cluster selection. The methodology was validated on simulated data and applied to 3076 ALS patients from the PRO-ACT dataset, using ALSFRS-R total scores, domain subscores, and MiToS staging from the first six months of observation.<br><br>RESULTS: Simulation experiments demonstrated that consensus clustering consistently outperformed single-model predictions across all noise levels. Applied to the PRO-ACT real data, the framework identified five distinct patient subgroups. These clusters exhibited distinct progression patterns and statistically significant differences in baseline clinical features, disease onset characteristics, and survival outcomes, with median survival ranging from 12.8 months to 27.5 months.<br><br>CONCLUSION: The proposed deep learning framework effectively captures the heterogeneous nature of ALS progression and identifies clinically relevant patient subgroups using routine clinical assessments. The stratification provides a foundation for personalized prognosis, optimized clinical trial design, and tailored therapeutic strategies, representing a practical tool for improving ALS patient management.}, }
@article {pmid42236740, year = {2026}, author = {Moro-Velazquez, L and Wang, H and Gunzler, A and Rao, M and Butala, AA and Clawson, L and Ravichandran, V}, title = {HeyJay! A corpus of atypical speech for spoken language understanding and automatic speech recognition.}, journal = {Scientific data}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41597-026-07497-5}, pmid = {42236740}, issn = {2052-4463}, support = {No grant number//JHU+Amazon ai2ai faculty award/ ; }, abstract = {Speech technologies, such as automatic speech recognition or spoken language understanding, are not usually adapted to atypical speech, i.e., the speech of people with dysarthria, dysphonia, or another type of speech impairment. That prevents atypical speakers from leveraging speech assistants or other human-machine-interaction-powered platforms, which could make their lives easier or increase their independence. In this article, we present HeyJay!, a new corpus of atypical speech in English language from participants with neurodegenerative disorders, including Parkinson's Disease, or Amyotrophic Lateral Sclerosis. The current corpus version comprises 8,669 utterance recordings, including supervised transcriptions and intent annotations. In this study, we demonstrate the validity of the corpus by applying it to automatic speech recognition, spoken language understanding, and data augmentation tasks. Additionally, the dataset includes speech quality ratings for each participant, performed by expert speech and language pathologists. This corpus, the first one with intent annotation of atypical speech that is publicly available, is intended to create more fair speech technologies for atypical speakers by adapting and improving the state of the art, and to facilitate further research in the field.}, }
@article {pmid42236747, year = {2026}, author = {Yang, J and Li, J and Hou, X and Zheng, Y and Zhao, Z and Zhou, T and Jing, T and Kong, J and Zhang, G and Guo, Y}, title = {Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.}, journal = {npj aging}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41514-026-00424-3}, pmid = {42236747}, issn = {2731-6068}, support = {CSTB2023NSCQ-BHX0119//the Postdoctoral Science Founation Project of the Chongqing Natural Science Foundation/ ; C2024405023//the Natural Science Foundation of Hebei Province/ ; }, abstract = {Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.}, }
@article {pmid42237051, year = {2026}, author = {Tooley, KM and Dawkins, PC}, title = {A lack of robust cross-domain structural priming effects.}, journal = {Memory &amp; cognition}, volume = {}, number = {}, pages = {}, pmid = {42237051}, issn = {1532-5946}, abstract = {Structural priming effects within language (e.g., Bock, 1986) have guided theory and research on structural representation for several decades. Structural priming has also been observed across domains, such as from mathematics to language (e.g., Scheepers et al., 2011), suggesting highly abstract structural representation within the global cognitive system. Experiment 1 investigated how this effect is impacted by a mathematical structural prime that lacks an overt operator, as is the case with exponents. A weak numerical trend toward a math-to-language priming effect was not found to be statistically significant. Experiments 2-3 sought to replicate Scheepers et al.'s (2011) original math to language priming effects in online and in-person settings, respectively. Separately and combined, these experiments failed to yield significant math to language priming effects, despite robust sample sizes. Bayes factor estimates suggest a null effect was more likely than a priming effect in the combined dataset. These results highlight the fact that cross-domain structural priming is understudied and underspecified, leading to difficulty planning and implementing the types of studies needed to establish when and how abstract structural representations persist across cognitive domains. Recommendations for future research include increasing item numbers and exploring methodologies that measure processing as well as behavioral responses.}, }
@article {pmid42237462, year = {2026}, author = {Iftesum, M and Sahoo, GR and Sheikh, E and Srivastava, M and Roy, S and Shukla, HD and Biswal, NC and Gartia, MR}, title = {Machine Learning-Integrated Raman Spectroscopy Identifies Race-Associated Biochemical Signatures in Prostate Cancer.}, journal = {Journal of biophotonics}, volume = {19}, number = {6}, pages = {e70293}, doi = {10.1002/jbio.70293}, pmid = {42237462}, issn = {1864-0648}, support = {R35GM150564/GM/NIGMS NIH HHS/United States ; R24GM146107/GM/NIGMS NIH HHS/United States ; R35GM151218/GM/NIGMS NIH HHS/United States ; 2045640//National Science Foundation/ ; }, abstract = {Black men experience disproportionately higher prostate cancer incidence and mortality, yet the underlying biochemical contributors remain unclear. In this study, we integrate Raman spectroscopy with advanced multivariate and machine-learning methods to characterize molecular differences in clinical formalin-fixed, paraffin-embedded (FFPE) prostate tissues from Black and White patients. Raman spectra were corrected using ICA-PLS, wavelet-denoised, and unmixed with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to quantify cellular components. Random forest (RF) models were trained on denoised spectra to classify cancer versus control tissues. MCR-ALS revealed elevated protein, collagen, lipid, and nucleic acid signatures in tumors from Black patients, aligning with clinically observed aggressive disease phenotypes. RF classification achieved > 90% accuracy, 95% sensitivity, 85% specificity, and an AUC > 0.96, demonstrating robust diagnostic performance. These findings show that Raman spectroscopy integrated with computational analysis provides a powerful label-free approach to probe biochemical drivers of racial disparities in prostate cancer.}, }
@article {pmid42237527, year = {2026}, author = {Zoubi, M and Weydt, P and Kobeleva, X}, title = {Attentional Function in Patients With Amyotrophic Lateral Sclerosis is Moderated by Age and Education.}, journal = {Brain and behavior}, volume = {16}, number = {6}, pages = {e71511}, doi = {10.1002/brb3.71511}, pmid = {42237527}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Female ; Male ; *Executive Function/physiology ; Middle Aged ; *Attention/physiology ; Aged ; Educational Status ; Age Factors ; Reaction Time/physiology ; Neuropsychological Tests ; Adult ; }, abstract = {PURPOSE: Besides motor brain regions, amyotrophic lateral sclerosis (ALS) affects non-motor regions such as front temporal regions, affecting various cognitive domains.<br><br>METHOD: We performed a behavioral study using the attention network test (ANT) to examine two components of attention (alerting, executive condition) and two degrees of difficulty (conflict condition) in 27 patients with ALS with no reported symptoms suggestive of cognitive impairment and 26 matched control participants.<br><br>FINDINGS: Using a modified ANT that accounted for ALS-induced motor impairment by focusing on relative reaction times, we could demonstrate its feasibility even in severely paralyzed patients. Relative reaction time differences were comparable to controls, demonstrating the task's ability to correct for motor bias. When focusing on relative reaction times, in both groups we found intact executive and conflict effects. Furthermore, ALS patients had comparable task accuracies when reacting to congruent and incongruent easy targets. However, the task accuracy of ALS patients was significantly lower compared to controls when reacting to the incongruent hard target. This effect was enhanced by the interaction effect of ALS diagnosis and age.<br><br>CONCLUSION: Our results suggest a significant interaction between age and ALS pathology, potentially leading to a breakdown of cognitive resources at higher levels of executive demand. We hypothesize that subclinical executive vulnerability in ALS patients becomes apparent when additional detrimental factors, such as aging, are present in patients. While we did not test co-pathologies in our cohort, co-occurring neurodegenerative or vascular processes might have contributed to this result. Our findings highlight the importance of cognitive screening for ALS patients above 60 years, even in the absence of subjective and collateral history of cognitive impairment.}, }
@article {pmid42237658, year = {2026}, author = {Vesevick, DR and Ghosh, S and Kalmes, A and Ozdinler, PH and Gautam, M}, title = {Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70289}, pmid = {42237658}, issn = {1097-4598}, support = {//Revalesio/ ; //Queen B Foundation/ ; //A Long Swim/ ; }, abstract = {INTRODUCTION: TDP-43 pathology is broadly observed in the cerebral cortex of patients with amyotrophic lateral sclerosis (ALS). RNS60, an experimental treatment for acute ischemic stroke and ALS, enhanced mitochondrial biogenesis and function in other preclinical models. We investigated whether RNS60 improved mitochondrial stability and upper motor neuron (UMN) health in a TDP-43 mouse model of ALS.<br><br>METHODS: prpTDP-43[A315T]-UeGFP mice, in which UMNs express green fluorescent protein (eGFP), and WT-UeGFP mice were treated with RNS60 or placebo intraperitoneally every other day from post-natal day (P) 30 until P90. Astrogliosis and microgliosis in brain and spinal cord were quantified by immunocytochemistry. Mitochondrial ultrastructure was studied via electron microscopy, and mitochondrial function was assessed using flow cytometry. Neuromuscular junction (NMJ) integrity was assessed in gastrocnemius, tibialis, and diaphragm muscles.<br><br>RESULTS: RNS60 treatment reduced defective mitochondria in UMNs (prpTDP-43[A315T]&#x2009;+&#x2009;vehicle: 53.2%&#x2009;&#xb1;&#x2009;0.71%; prpTDP-43[A315T]&#x2009;+&#x2009;RNS60: 19.6%&#x2009;&#xb1;&#x2009;1.4%, p&#x2009;=&#x2009;0.0001) and spinal motor neurons (prpTDP-43[A315T]&#x2009;+&#x2009;vehicle: 70.1%&#x2009;&#xb1;&#x2009;0.4.48%; prpTDP-43[A315T]&#x2009;+&#x2009;RNS60: 33.5%&#x2009;&#xb1;&#x2009;4.43%, p&#x2009;=&#x2009;0.001). It increased mitochondrial membrane polarization (prpTDP-43[A315T]-UeGFP&#x2009;+&#x2009;vehicle: 7184&#x2009;&#xb1;&#x2009;1689 mean intensity; prpTDP-43[A315T]-UeGFP+RNS60: 22120&#x2009;&#xb1;&#x2009;4818 mean intensity, p&#x2009;=&#x2009;0.032), reduced the extent of astrogliosis and microgliosis in motor cortex and spinal cord, protected UMNs compared to placebo, and enhanced the proportion of intact NMJs in leg and diaphragm muscles (prpTDP-43[A315T]-UeGFP&#x2009;+&#x2009;vehicle: 29.6%&#x2009;&#xb1;&#x2009;3.6%; prpTDP-43[A315T]-UeGFP&#x2009;+&#x2009;RNS60: 64.3%&#x2009;&#xb1;&#x2009;4.4%, p&#x2009;=&#x2009;0.0002).<br><br>DISCUSSION: These results suggest that RNS60 treatment promotes motor neuron health in ALS by protecting mitochondrial structure and function, preserving NMJ integrity, and reducing gliosis.}, }
@article {pmid42227145, year = {2026}, author = {Kumar, V and Kashif, M and Singh, V and Rawat, RS and Khan, A and Sarkar, GC and Majood, M}, title = {Therapeutic targeting of DNA repair pathway dysregulation in aging, cancer, and neurodegeneration.}, journal = {Expert opinion on therapeutic targets}, volume = {}, number = {}, pages = {}, doi = {10.1080/14728222.2026.2683686}, pmid = {42227145}, issn = {1744-7631}, abstract = {INTRODUCTION: Genome maintenance is increasingly recognized as a shared vulnerability across aging, cancer, and neurodegeneration, yet the therapeutic implications of pathway-specific dysregulation of DNA repair remain incompletely defined.<br><br>AREAS COVERED: This review integrates recent mechanistic and translational literature on how base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, canonical non-homologous end joining, and alternative end joining are remodeled across these conditions. We discuss how oxidative stress, replication stress, telomere dysfunction, mitochondrial injury, and persistent DNA damage response signaling drive senescence and inflammation; how tumor cells exploit repair rewiring to survive genotoxic stress and acquire resistance; and how post-mitotic neurons are limited by restricted repair redundancy. We also summarize biomarkers for repair-state stratification and emerging strategies targeting PARP, ATR, ATM, DNA-PK, POLQ, and cGAS-STING.<br><br>EXPERT OPINION: Clinical translation will depend less on single-gene alterations than on defining context-specific repair states and pathway dependencies. Such stratification should enable rational combinations that either restore repair fidelity in aging and neurodegeneration or exploit repair addiction in cancer.}, }
@article {pmid42227472, year = {2026}, author = {Amin, MA and Zehravi, M and Sweilam, SH and Darwin, R and Gupta, JK and Bhargav, E and Dharmamoorthy, G and Kumar, VV and Rao, AA and Suliman, M and Periyasamy, T and Emran, TB}, title = {Fisetin and Neurodegeneration: From Preclinical Studies to Potential Clinical Applications.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273427644251204045253}, pmid = {42227472}, issn = {1996-3181}, abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, pose significant challenges due to their gradual deterioration and limited available treatments. Fisetin, a naturally occurring flavonoid, has gained attention for its neuroprotective properties. This review explores the therapeutic potential of fisetin in NDs, focusing on its molecular processes and signaling pathways. Additionally, fisetin exhibits significant protective properties, particularly in reducing oxidative stress, neuroinflammation, and apoptosis. It enhances neuronal survival and reduces neuroinflammation by regulating key pathways, such as Nrf2/ARE, PI3K/Akt, and NF-κB. It also has anti-inflammatory, anti-apoptotic, and antioxidant actions. It stimulates autophagic processes, aiding in the removal of harmful protein aggregates, like tau tangles and amyloid plaques, which are hallmarks of NDs. Fisetin, as demonstrated through behavioral evaluations in animal models, has been found to improve motor coordination, synaptic plasticity, and cognitive function. Furthermore, fisetin's potential as a neuroprotective drug is emphasized by its role in enhancing autophagy and reducing tau and amyloid pathology. Research has shown its efficacy in enhancing neural resilience, synaptic plasticity, and cognitive function in both preclinical and in vitro settings. However, clinical translation remains limited due to challenges in pharmacokinetics and bioavailability, despite robust experimental evidence. Further clinical trials are needed to evaluate the safety and efficacy of fisetin, especially in early-stage NDs, explore potential synergistic effects, and understand the molecular interactions. The review demonstrates fisetin's therapeutic potential, recent research, and future strategies for NDs, highlighting bioavailability limitations and the need for new formulations or delivery systems.}, }
@article {pmid42227825, year = {2026}, author = {Watson, MD and Lee, JC}, title = {Site-Specific Raman Probes Reveal Droplet Aging and Residue-Level Fibril Polymorphism in TDP-43CTD.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.6c07727}, pmid = {42227825}, issn = {1520-5126}, abstract = {The C-terminal domain of TAR DNA-binding protein 43 (TDP-43CTD) drives both liquid-liquid phase separation (LLPS) and amyloid formation. Understanding how TDP-43CTD droplets convert into amyloid aggregates, a process implicated in amyotrophic lateral sclerosis and frontotemporal dementia, requires methodology capable of site-specific structural characterization with spatial resolution. Here, we used confocal Raman spectroscopy in conjunction with an alkyne-modified amino acid (4-ethynyl-l-phenylalanine, FCC) to probe aging in individual TDP-43CTD droplets at seven aromatic sites. While nascent droplets are composed of disordered proteins, β-sheet conformers develop in aged droplets and amyloid aggregates. All three states are spectrally distinct via the alkyne stretching band, with sensitivity that varies depending on the aromatic site probed. C-terminal sites (Y374FCC, W385FCC, and F397FCC) are highly sensitive amyloid probes, revealing multiple polymorphs at the single-residue level that are not resolvable by global secondary structure or morphological characterization alone. Strikingly, while W334FCC abolishes β-sheet formation in droplets, de novo aggregation still occurs, demonstrating that droplet aging is not required for amyloid formation. Given its broad applicability to other proteins and compatibility with cellular imaging, this work establishes a generalizable approach for investigating conformational changes underlying LLPS and amyloid formation in cellulo.}, }
@article {pmid42228326, year = {2026}, author = {Dey, A and Das, R and Uppal, S}, title = {FUS modulates R-loops by functionally interacting with RNase H1.}, journal = {Human cell}, volume = {39}, number = {6}, pages = {}, pmid = {42228326}, issn = {1749-0774}, mesh = {*RNA-Binding Protein FUS/physiology/metabolism/genetics ; Humans ; *Ribonuclease H/metabolism ; *R-Loop Structures/genetics/physiology ; HeLa Cells ; Transcription, Genetic/genetics ; RNA/metabolism/genetics ; DNA Damage/genetics ; RNA Polymerase II/metabolism ; }, abstract = {R-loops are three-stranded nucleic acid structures consisting of an RNA:DNA hybrid and a displaced single-stranded DNA, typically formed during transcription. Emerging evidence indicates that R-loops are not merely transcriptional byproducts, but serve as functional regulatory structures that influence chromatin organization, transcriptional pausing, and RNA processing. However, dysregulated accumulation of R-loops can induce DNA damage and genomic instability, necessitating precise mechanisms for their regulation. This study aims to elucidate the role of the RNA-binding protein FUS (Fused in Sarcoma), a protein mutated in Amyotrophic Lateral Sclerosis (ALS) and cancer, in modulating R-loop dynamics. Knockdown of FUS in HeLa cells resulted in a significant increase in global R-loop levels, as assessed by immunofluorescence and dot blot assays. Proximity ligation assay (PLA) demonstrated that FUS is in close proximity to R-loops and nascent RNA. Further, FUS was found to interact with RNase H1, a key endonuclease involved in R-loop resolution, in an R-loop dependent manner, as demonstrated by PLA and co-immunoprecipitation assay. Importantly, in vitro assays show that FUS enhances RNase H1-mediated degradation of RNA:DNA hybrids. Moreover, FUS depletion reduces RNase H1 proximity to elongating RNA polymerase II, suggesting altered engagement of RNase H1 with the transcription machinery. These findings highlight a crucial role for FUS-RNase H1 axis in regulating R-loop levels, providing insights into the potential mechanisms underlying R-loop-associated pathologies in neurodegenerative diseases linked to FUS.}, }
@article {pmid42229207, year = {2026}, author = {Pavey, N and Tu, S and Foster, S and Geevasinga, N and Calma, A and Tsuji, Y and Kiernan, MC and Vucic, S and Menon, P}, title = {Cortical changes in amyotrophic lateral sclerosis: comparing biomarkers of glymphatic flow and cortical excitability.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {190}, number = {}, pages = {2111949}, doi = {10.1016/j.clinph.2026.2111949}, pmid = {42229207}, issn = {1872-8952}, abstract = {OBJECTIVE: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves a multistep process, with a central role for cortical hyperexcitability and misfolded protein accumulation. The glymphatic system mediates clearance of misfolded proteins, yet its role in modulating cortical excitability is unknown. This study aims to determine whether glymphatic dysfunction is associated with cortical hyperexcitability, thereby linking impaired protein clearance to excitotoxic neurodegeneration in ALS.<br><br>METHODS: Glymphatic function was assessed using diffusion tensor imaging analysis along perivascular spaces (DTI-ALPS) and correlated with measures of corticomotoneuronal function assessed by transcranial magnetic stimulation (TMS). The DTI-ALPS index and cortical excitability testing were performed in 35 ALS patients and compared to 25 age-matched controls. The DTI-ALPS index was correlated with TMS and clinical measures.<br><br>RESULTS: A significant reduction in the DTI-ALPS index was observed in ALS (p&#xa0;=&#xa0;0.016), along with cortical hyperexcitability evident as shortened cortical silent period (CSP) duration (p&#xa0;=&#xa0;0.001) and reduced short interval intracortical inhibition (p&#xa0;<&#xa0;0.001). The DTI-ALPS index significantly correlated with CSP duration (R&#xa0;=&#xa0;0.48, p&#xa0;=&#xa0;0.027). The DTI-ALPS index was significantly reduced in ALS participants with mild functional impairment. The possibility that reduced DTI-ALPS index represents an epiphenomenon of tract degeneration cannot be completely excluded.<br><br>CONCLUSION: This study identified a potential association between impaired glymphatic clearance and disrupted GABAB-mediated cortical inhibition, suggesting that glymphatic dysfunction may play a role in the neurodegenerative cascade in ALS.<br><br>SIGNIFICANCE: Glymphatic dysfunction may be associated with impaired cortical inhibition, thereby contributing to cortical hyperexcitability in ALS and providing further mechanistic insight.}, }
@article {pmid42229507, year = {2026}, author = {Swanson, E and Dohle, E and Bashford, L and Horsfall, HL and Jovanovic, L and Muirhead, W and Brannigan, JFM}, title = {Recalibration of implantable brain-computer interfaces to enable long-term independent use - a systematic review.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/ae7694}, pmid = {42229507}, issn = {1741-2552}, abstract = {Implantable brain-computer interfaces (iBCIs) decode neural signals to generate command signals for effector devices to restore lost functions, such as movement or speech. However, maintaining device performance over time requires recalibration of decoding algorithms due to inherent instability in neural signals. Objective: To systematically review recalibration procedures in iBCIs for patients with motor impairments, focusing on the clinical implications of recalibration requirements and strategies which can enable long-term, independent use. Approach: A systematic search was conducted across EMBASE, MEDLINE, and CINAHL databases to identify studies involving recalibration of iBCIs. Data on recalibration frequency, duration, staff requirements, and location were extracted and analysed. Main Results: Recalibration practices varied widely amongst studies and were typically performed according to predetermined study protocols, rather than practical need following deteriorating device performance. Common practices include manual recalibration requiring a specialist research team, semi-automatic recalibration which could be performed by a non-specialist caregiver, and automatic recalibration methods whereby patients did not require assistance. Devices utilising electrocorticography (ECoG) recording arrays generally required less frequent recalibration compared to those using microelectrode arrays (MEAs). Extended independent use was more frequently reported with ECoG-based iBCIs. Significance: Reducing recalibration frequency or complexity can improve patient autonomy, which is crucial for enhancing long-term independent iBCI use in home and clinical settings. ECoG iBCIs typically have a low recalibration burden due to inherent signal stability. Conversely, MEA iBCIs typically involve a higher recalibration burden, though recent studies have reduced this by incorporating spectral data and continuously updating models. Despite this progress, recalibration procedures are often not fully defined in iBCI studies, and where they are, they usually relate to the study protocol rather than the clinically meaningful recalibration requirement due to worsening device performance. Future studies should continue to develop user-friendly recalibration procedures and outline the clinically relevant recalibration requirements where possible.}, }
@article {pmid42229706, year = {2026}, author = {Alqahtani, SM and Afzal, M and Afzal, O and Alabbas, A and Phalak, P and Goyal, K}, title = {Platelet-derived extracellular vesicles as neurodegenerative disease biomarkers.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {}, number = {}, pages = {121130}, doi = {10.1016/j.cca.2026.121130}, pmid = {42229706}, issn = {1873-3492}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are increasingly prevalent worldwide and have not yet been adequately diagnosed, especially because they require minimally invasive, non-invasive techniques. Although established blood-based biomarkers, such as plasma p-tau217, neurofilament light chain (NfL), and GFAP, have shown clinical utility, limitations in sensitivity and scalability remain. Platelets, anucleate cytoplasmic fragments originating from megakaryocytes, are the primary producers of extracellular vesicles in the peripheral blood. These vesicles contain disease-specific cargo, including amyloid-β, α-synuclein, tau, disease-associated glycoproteins, and microRNAs (miRNAs) derived from platelets. Recent findings suggest that the cargo of platelet-derived extracellular vesicles (pEVs) may be associated with neurodegenerative changes linked to disease severity. However, validation through a prospective multicenter study is necessary. A systematic narrative review was performed by searching the PubMed, Scopus, and Web of Science databases with the keywords "platelet-derived extracellular vesicles," "platelet microvesicles," "neurodegeneration," and "biomarkers" (inception through April 2026). This review discusses the biogenesis of pEV, their composition in relation to blood markers, and their pathomechanistic roles, such as platelet-mediated blood-brain barrier disruption, neuroinflammation, and misfolded protein seeding. The diagnostic evidence of pEV-associated cargo in neurodegenerative diseases is critically evaluated and contextualized with current blood markers. Key preanalytical considerations, including the selection of anticoagulants, isolation procedures, storage conditions, and the number of freeze-thaw cycles, as well as analytical considerations, such as flow cytometric calibration, single-vesicle resolution, and multiplexed platforms, are examined for their applicability in clinical laboratory settings. The emphasis is on reporting according to the MISEV and the harmonization between laboratories. The limitations of this study are the small heterogeneous cohorts, lack of preanalytical handling standardization, ex vivo platelet activation artifact, and lack of external validation.}, }
@article {pmid42230361, year = {2026}, author = {Barba, L and Steinacker, P and Halbgebauer, S and Oeckl, P and Landwehrmeyer, B and Weishaupt, J and Verde, F and Ticozzi, N and Silani, V and Levin, J and Schönecker, S and Kornhuber, J and Prudlo, J and Schroeter, ML and Fassbender, K and Fliessbach, K and Diehl-Schmid, J and Jahn, H and Lauer, M and Dorst, J and Rosenbohm, A and Abu-Rumeileh, S and Anderl-Straub, S and Söntgerth, M and Böhm, F and Wiltfang, J and Otto, M}, title = {Serum neurofilaments for motoneuron and dementia diseases: a German multicenter cohort study.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, pmid = {42230361}, issn = {1432-1459}, support = {JCS24/02//Martin Luther Christian University/ ; CS22/06//Martin-Luther-University Halle-Wittenberg/ ; RF-2021-12374238)//Ministero della Salute/ ; TelDem//S&#xe4;chsische Aufbaubank/ ; 100757914//EFRE InfraProNet/ ; }, abstract = {BACKGROUND: Serum neurofilament light and heavy chains (sNfL and sNfH) have been assessed as neuronal markers for amyotrophic lateral sclerosis (ALS) and dementias. Whereas sNfL has robust literature, systematic studies on sNfH are lacking. Here, we aimed to assess the diagnostic value of sNfH in comparison to sNfL in a broad range of neurodegenerative disorders.<br><br>METHODS: We measured with immunoassays sNfH and sNfL in patients recruited in the multicenter German Frontotemporal Lobar Degeneration (FTLD) Consortium (n&#x2009;=&#x2009;340) and in a single-center German cohort (n&#x2009;=&#x2009;290). We assessed the diagnostic accuracy of serum biomarkers for ALS and dementia subtypes and their relationship with cognitive impairment.<br><br>RESULTS: sNfH and sNfL were significantly increased in ALS (n&#x2009;=&#x2009;90) vs. controls (n&#x2009;=&#x2009;109) and ALS mimics (n&#x2009;=&#x2009;56, p&#x2009;<&#x2009;0.001), with sNfL showing higher discriminative accuracy (AUC&#x2009;=&#x2009;0.94-0.95) than sNfH (AUC&#x2009;=&#x2009;0.87-0.88). sNfH/sNfL ratio did not improve the diagnostic performance. Both markers were elevated in patients with dementia (n&#x2009;=&#x2009;289) vs. controls (p&#x2009;<&#x2009;0.001). sNfL was higher in behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and Creutzfeldt-Jakob disease (CJD) than in Alzheimer's disease (AD), whereas sNfH was similar in AD, PPA and bvFTD. sNfL, but not sNfH, was correlated with cognitive impairment at baseline&#xa0;and cognitive decline at follow-up&#xa0;in AD and bvFTD.<br><br>CONCLUSIONS: sNfH and sNfL are elevated in motoneuron and dementia disorders. sNfH showed good discriminative accuracy for ALS, which was slightly lower than that of sNfL. sNfL, but not sNfH, showed prognostic value for assessing&#xa0;cognitive decline&#xa0;in dementia.}, }
@article {pmid42230882, year = {2026}, author = {Morishita, H and Umezawa, K and Kojima, M}, title = {Alkyl shikimates promote proliferation of human dermal fibroblasts and exhibit structure-activity relationships.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-55244-y}, pmid = {42230882}, issn = {2045-2322}, abstract = {Alkyl shikimates (SAEs) bearing linear and branched alkyl groups (R) ranging from CH3 to C5H11 were synthesized and assayed for proliferative activity toward human dermal fibroblasts; proliferation increase (PRA), measured using a CCK-8 assay kit, was used as the primary endpoint. Several SAEs exhibited significant PRA, depending on the concentration added to the culture medium and alkyl group structure. However, shikimic acid (SA) added to the culture medium did not induce fibroblast proliferation. SAEs with CH3, C2H5, and C3H7 alkyl groups (SAE-1, SAE-2, and SAE-3a,b) induced a 30-50% increase in cell proliferation at a concentration of 5.5 mM, while SAEs with a C4H9 groups (SAE-4a,b,c) showed low PRA and those with a C5H11 groups (SAE-5a,b,c) exhibited strong cytotoxicity (CYT: decrease in cell viability) at this concentration. The proliferation rates of SAEs at 5.5 mM correlated significantly with their calculated log P (ClogP) values, which reflect hydrophobicity and cell membrane permeability (quadratic regression; coefficient of determination, r[2] = 0.977-0.953. Based on these results, we proposed a mechanism in which membrane-permeable SAEs could form complexes with carboxylesterase (CES) present in dermal fibroblasts and be subsequently hydrolyzed into SA and alcohols (ALs) intracellularly, with the resulting SA potentially inducing PRA. In contrast, SA added extracellularly cannot enter cells due to its high hydrophilicity and therefore cannot induce PRA. In order to evaluate the stability of the proposed complexes, we estimated binding energies between CES and SAEs by quantum mechanical methods; however, the results showed no significant differences in binding energy attributable to alkyl chain length or steric effects of the SAE alkyl groups. The most plausible explanation for the differences in PRA among SAEs is that intracellularly regenerated SA promotes fibroblast proliferation, whereas the regenerated ALs may cause CYT. Alkyl group-dependent differences in AL toxicity may account for the concentration-dependent variation in SAE-induced PRA. In fact, when the CYT of linear alkyl alcohols (ALs-1, 2, 3a, 4a, and 5a) was measured by CCK-8 at a concentration of 100 mM, the results showed that differences in AL alkyl chain length significantly influenced cell viability, which was consistent with their ClogP values (CYT order; R = C5H11 > C4H9 > C3H7 > C2H5 ≥ CH3).}, }
@article {pmid42232224, year = {2026}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1818660}, pmid = {42232224}, issn = {1663-4365}, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.<br><br>METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs. 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.<br><br>RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (< 1 year) to 0.25 (> 6 years). Risk reduction was greatest in older participants (75-79 years).<br><br>DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.}, }
@article {pmid42232333, year = {2026}, author = {Chalitsios, CV and Turner, MR}, title = {Considering prediagnostic environmental modifiers of progression in amyotrophic lateral sclerosis.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001702}, pmid = {42232333}, issn = {2632-6140}, }
@article {pmid42002732, year = {2026}, author = {Atwa, H and Shehata, MH and Kumar, AP and Alansari, R and Al-Ansari, A and Deifalla, A}, title = {Readiness for self-directed learning among first-year medical and nursing students at the Arabian Gulf University in Bahrain.}, journal = {BMC medical education}, volume = {26}, number = {1}, pages = {}, pmid = {42002732}, issn = {1472-6920}, abstract = {BACKGROUND: Self-directed learning (SDL) is a fundamental skill in health professions education, enabling students to take ownership of their learning and adapt to evolving healthcare challenges. Understanding SDL readiness among students is crucial for optimizing curriculum design and enhancing lifelong learning competencies. This study aimed to explore SDL readiness among first-year medical and nursing students at the College of Medicine and Health Sciences, Arabian Gulf University (CMHS-AGU) in Bahrain.<br><br>METHODS: A cross-sectional study was conducted among first-year medical and nursing students at the CMHS-AGU. Data were collected using an electronic questionnaire that included demographic information and Fisher et al.&#x2019;s validated 40-item Self-Directed Learning Readiness Scale (SDLRS). The scale measured students&#x2019; readiness across self-management, desire for learning, and self-control. Descriptive statistics, independent t-tests, one-way ANOVA, and correlation analyses were conducted using IBM SPSS v.25. Effect sizes were reported as Cohen&#x2019;s d for two-group comparisons and eta-squared (&#x3b7;&#xb2;) for multi-group comparisons. A p-value&#x2009;<&#x2009;0.05 was considered statistically significant.<br><br>RESULTS: A total of 410 students participated (Medicine: 202, Nursing: 208), yielding a response rate of 83.7%. The mean total SDLRS score was 151.96 (SD&#x2009;=&#x2009;20.75), indicating overall high SDL readiness, though with notable subgroup variability. Nursing students had significantly higher SDLRS scores (159.78&#x2009;&#xb1;&#x2009;16.02) than medical students (143.90&#x2009;&#xb1;&#x2009;21.97) (p&#x2009;<&#x2009;0.001; Cohen&#x2019;s d&#x2009;=&#x2009;0.83, large effect). Female students demonstrated greater SDL readiness than males (155.26&#x2009;&#xb1;&#x2009;20.78 vs. 143.58&#x2009;&#xb1;&#x2009;18.21, p&#x2009;<&#x2009;0.001; Cohen&#x2019;s d&#x2009;=&#x2009;0.58, medium effect). Country of origin was also a significant differentiator (p&#x2009;<&#x2009;0.001; &#x3b7;&#xb2; = 0.132), with Bahraini students scoring highest and Omani students lowest. Higher SDLRS scores were further associated with graduation from American or International Baccalaureate curricula (p&#x2009;<&#x2009;0.001; &#x3b7;&#xb2; = 0.066), lack of reliance on private tutoring (p&#x2009;=&#x2009;0.004), regular engagement in extracurricular activities (p&#x2009;=&#x2009;0.001), and the frequent use of educational technology, including artificial intelligence (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: First-year medical and nursing students generally demonstrated SDL readiness above the high threshold; however, this aggregate finding warrants cautious interpretation, and significant differences were observed based on academic program, gender, nationality, and prior educational experiences. Nursing students and female participants exhibited higher readiness, potentially reflecting early variations in learning orientation and professional socialization. The findings underscore the need for targeted interventions, particularly for medical students transitioning from highly structured curricula, to foster essential SDL competencies. Future research should utilize mixed-methods and learning analytics to examine the longitudinal development of these critical lifelong learning skills.}, }
@article {pmid42153537, year = {2026}, author = {Shi, J and Wu, Y and Liu, X and Xia, W and Wu, J and Lou, J and Zhang, X and Zhang, J and Yang, N and Chi, W and Xiang, L and Zhang, Y and Shu, Y and Miao, R and Zhao, J and Zhu, X and Qi, J and Xiao, J and Zhou, K}, title = {MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-30}, doi = {10.1080/15548627.2026.2677180}, pmid = {42153537}, issn = {1554-8635}, abstract = {Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the MT-RNR1/12S rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, in vivo overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.Abbreviations: AA = arachidonic acid, AAV = adeno-associated virus, ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta, ALs = autolysosomes, BECN1 = beclin 1, CASP1 = caspase 1, CQ = chloroquine, CTSB = cathepsin B, CTSD = cathepsin D, CTSL = cathepsin L, Co-IP = co-immunoprecipitation, DEGs = differentially expressed genes, ELISA = enzyme-linked immunosorbent assay, F-CHP = 5-FAM-conjugated collagen hybridizing peptide staining, GSDMD = gasdermin D, GO = gene Ontology, GPT/ALT = glutamic pyruvic transaminase, soluble, GOT1/AST = glutamic-oxaloacetic transaminase 1, soluble, HE = hematoxylin-eosin, HUVECs = human umbilical vein endothelial cells, IP/MS = immunoprecipitation coupled with mass spectrometry, IL1B/IL-1β = interleukin 1 beta, IL18 = interleukin 18, IP = intraperitoneal injection, IV = intravenous injection, LDBF = laser Doppler blood flow, LMP = lysosomal membrane permeability, MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3, MAPK = mitogen-activated protein kinase, NAGLU = alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-κB = nuclear factor kappa B, NLRP1 = NLR family pyrin domain containing 1, NLRP3 = NLR family pyrin domain containing 3, PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1, PLA2G4A/cPLA2 = phospholipase A2, group IVA (cytosolic, calcium-dependent), PYCARD/ASC = PYD and CARD domain containing, PIK3C3/VPS34 = phosphatidylinositol 3-kinase catalytic subunit type 3, PMA = phorbol 12-myristate 13-acetate, ROS = reactive oxygen speciesSQSTM1/p62 = sequestosome 1, SPR = surface plasmon resonance, scRNA-seq = single-cell RNA sequencing, UMAP = uniform manifold approximation and projection, WB = western blotting.}, }
@article {pmid42183611, year = {2026}, author = {Ji, F and Dai, M and Wang, Z and Dai, E and Kang, R and Klionsky, DJ and Tang, D and Huang, Y and Sun, Y and Liu, T}, title = {Mammalian lysophagy: mechanisms and pathophysiological implications.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/15548627.2026.2679642}, pmid = {42183611}, issn = {1554-8635}, abstract = {Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.Abbreviations: ALR, autophagic lysosome reformation; ALS, amyotrophic lateral sclerosis; ATG8, mammalian Atg8-family protein; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; LAMPs, lysosome associated membrane proteins; LIR, LC3-interacting region; LLOMe, L-leucyl-L-leucine methyl ester; LMP, lysosomal membrane permeabilization; PITT, phosphoinositide-initiated membrane tethering and lipid transport; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns4P, phosphatidylinositol-4-phosphate; ROS, reactive oxygen species; V-ATPase, vacuolar-type H[+] -ATPase.}, }
@article {pmid42222887, year = {2026}, author = {Michels, S and Chen, C and Ruf, WP and Garcia Garcia, MM and Arnold, FJ and Wu, Z and Bennett, CL and Shams, D and Thompson, LM and Walker, AC and Dickson, DW and Petrucelli, L and Dorst, J and Prudencio, M and Li, W and La Spada, AR}, title = {Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {11}, pages = {}, pmid = {42222887}, issn = {1558-8238}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; *Cell-Free Nucleic Acids/genetics/blood/cerebrospinal fluid ; Female ; *Epigenesis, Genetic ; *DNA Methylation ; Male ; Biomarkers/blood/cerebrospinal fluid ; C9orf72 Protein/genetics ; Disease Progression ; Middle Aged ; Aged ; Neurofilament Proteins/cerebrospinal fluid ; Adult ; }, abstract = {The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 nondisease control individuals. Following targeted enzymatic methyl-sequencing (EM-seq) of approximately 4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of approximately 70% of patients with ALS with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.}, }
@article {pmid42222897, year = {2026}, author = {Inoue, H and Horimoto, Y and Tsuda, Y and Madokoro, Y and Kawashima, S and Akagi, A and Iwasaki, Y and Matsukawa, N}, title = {Visible Tongue Fasciculations With Electromyographic Denervation in Autopsy-Proven Progressive Supranuclear Palsy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70308}, pmid = {42222897}, issn = {1097-4598}, }
@article {pmid42222958, year = {2026}, author = {Zeigler-Hill, V}, title = {Desperate to connect: Men's dependence on romantic relationship in a competitive mating landscape.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e130}, doi = {10.1017/S0140525X25102483}, pmid = {42222958}, issn = {1469-1825}, mesh = {Humans ; Male ; *Competitive Behavior ; *Sexual Partners/psychology ; *Interpersonal Relations ; Emotions ; }, abstract = {This commentary builds on Wahring et al.'s model of male emotional dependency by integrating mating market dynamics. It argues that men's reliance on romantic partners, combined with competitive pressures and limited emotional networks, creates a volatile psychological landscape. Romantic failure, in this context, can deeply threaten self-worth - fueling distress, behavioral issues, and, in extreme cases, ideological radicalization.}, }
@article {pmid42223005, year = {2026}, author = {Kafetsios, K and Strand, PS}, title = {The cultural plasticity of intimacy behavior: A socioecological attachment perspective.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e105}, doi = {10.1017/S0140525X25102707}, pmid = {42223005}, issn = {1469-1825}, mesh = {Humans ; *Object Attachment ; *Interpersonal Relations ; Female ; *Culture ; *Sexual Behavior/psychology ; Male ; *Social Behavior ; }, abstract = {Gender imbalances in intimacy behavior reflect culturally contingent expressions of attachment organization rather than fixed gender differences. Building on Wahring et al.'s model, we apply the Biobehavioral Cultural Model of Attachment to show how affiliative behaviors vary with socioecological conditions, early reinforcement patterns, and cultural norms, offering a dynamic, context-sensitive account of intimacy across diverse settings.}, }
@article {pmid42223083, year = {2026}, author = {Zhang, Q and Valério, M and Grünewald, L and Borges-Araújo, L and Grünewald, F and Wang, S and Marrink, SJ and Gong, Y and Souza, PCT}, title = {Coarse-Grained Simulations Reveal Salt- and Length-Dependent Condensation of G4C2 RNA Repeats.}, journal = {The journal of physical chemistry letters}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jpclett.6c00916}, pmid = {42223083}, issn = {1948-7185}, abstract = {RNA-RNA interactions drive the formation of biomolecular condensates via liquid-liquid phase separation (LLPS), but their underlying molecular mechanisms remain poorly understood. Here, we employ Martini 3 coarse-grained molecular simulations to investigate phase transitions of G4C2 RNA repeats─sequences implicated in neurodegenerative disorders such as ALS and FTD─across varying salt concentrations. The model captures salt-dependent transitions from dispersed to condensed-like states and suggests that dominant interaction patterns, including Watson-Crick-like and G-G contacts, shift with ionic strength. Notably, longer RNA sequences maintain phase-separated states at salt concentrations that dissolve shorter ones, in line with experimental observations. Our findings demonstrate the ability of the Martini coarse-grained model to reproduce key biophysical features of RNA LLPS, including sequence-length dependence and interaction specificity. This work provides molecular-level insight into RNA-driven phase separation and reveals how sequence composition and ionic strength govern the emergence and stability of RNA-rich assemblies.}, }
@article {pmid42223334, year = {2026}, author = {He, C and Liu, Z and Yuan, Y and Tang, L and Wang, M and Li, Y and Zhao, Q and Weng, L and Du, J and Wu, H and Hu, F and Xu, R and Guo, J and Shen, L and Tang, B and Wang, J}, title = {Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {6}, pages = {e70653}, doi = {10.1111/ene.70653}, pmid = {42223334}, issn = {1468-1331}, support = {2021YFA0805202//the National Key R&amp;D Program of China/ ; STI2030&#x2011;MajorProjects2021ZD0201803//National Science and Technology Innovation 2030 Major Program/ ; 82371445//the National Natural Science Foundation of China/ ; 82171431//the National Natural Science Foundation of China/ ; 20242BAB26135//the Jiangxi Provincial Natural Science Foundation/ ; 20243BCE51002//the Ganpo Outstanding Talents Support Program-Cultivation Project for Academic and Technical Leaders in Key Disciplines/ ; gpyc20240194//the Ganpo Talents Program-Innovation Leading Talent Project (Medical and Health Care Category)/ ; 202510014//the Jiangxi Provincial Health Technology Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality/diagnosis ; Haplotypes ; Female ; Male ; Asian People/genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; *Nerve Tissue Proteins/genetics ; Severity of Illness Index ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Aged ; Adult ; East Asian People ; }, abstract = {BACKGROUND: UNC13A is a genetic modifier of amyotrophic lateral sclerosis (ALS) in European populations, but its role in Chinese patients remains incompletely characterized. We investigated the spectrum of UNC13A variation and its impact on disease risk and progression in a Chinese ALS cohort.<br><br>METHODS: We performed an integrated genetic analysis of 1,533 Chinese ALS patients and 1,405 controls, including rare variant burden testing, genome-wide survival analysis, haplotype mapping, and conditional analyses. An integrated clinical-genetic prognostic score was developed and validated.<br><br>RESULTS: Rare deleterious UNC13A variants were not associated with ALS risk. We identified two independent haplotype blocks with distinct clinical impacts. Block 1 (tagged by rs75421007) was associated with reduced baseline muscle strength (p&#x2009;=&#x2009;0.030), while Block 2 (tagged by rs78549703), a brain-specific splicing QTL, was the primary driver of survival heterogeneity. The European variant rs12608932 showed a survival association in single-marker analysis (p&#x2009;=&#x2009;0.024), but conditional analyses revealed its effect was not independent of Block 2. An integrated prognostic score combining clinical factors and Block 2 haplotype stratified patients into low-, intermediate-, and high-risk groups (median survival: 52.6, 37.1, and 32.0&#x2009;months; p&#x2009;<&#x2009;0.001), with decision curve analysis confirming clinical utility.<br><br>CONCLUSIONS: This study delineates UNC13A genetic architecture in Chinese ALS, identifying two independent haplotype blocks that differentially influence disease severity and survival. The Block 2 haplotype, which includes a brain sQTL, is a major determinant of survival heterogeneity and may inform patient stratification in future studies.}, }
@article {pmid42224592, year = {2026}, author = {Galloway, DA and Patterson, HL and Hoye, ML and Shen, T and Shabsovich, M and Schoch, KM and Ly, CV and Miller, TM}, title = {miR-146a is a pleiotropic regulator of motor neuron degeneration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {23}, pages = {e2526314123}, doi = {10.1073/pnas.2526314123}, pmid = {42224592}, issn = {1091-6490}, support = {R01NS078398//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; F31NS092340//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Here, we have profiled motor neuron microRNAs (miRNAs) during motor neuron degeneration in vivo to gain a better understanding of ALS pathophysiology. We demonstrate that one miRNA, miR-146a, is downregulated in diseased motor neurons despite upregulation in bulk tissue. Genetic deletion of miR-146a significantly extended survival in SOD1[G93A] mice with heterozygous animals demonstrating the largest benefit. A corresponding reduction in spinal cord gliosis but not motor neuron loss was observed. Finally, we observed that a proportion of miR-146a knockout animals develop spontaneous paralysis, motor neuron loss and chronic neuroinflammation with advanced age. Together these findings demonstrate that a single miRNA influences multiple aspects of motor neuron disease and highlights the complex role for neuroinflammation in ALS pathogenesis.}, }
@article {pmid42225765, year = {2026}, author = {Costello, E and Kiyui, K and Brennan, C and Obain, NN and Leonard, S and Heverin, M and Barbey, F and Dyer, J and Rueda-Delgado, L and Diggin, S and Tunbridge, E and Marston, H and Lai, RYK and Hargreaves, R and Shinobu, L and Nguyen, V and Hake, AM and Dawson, G and Latzman, R and Buick, A and Murphy, B and Hardiman, O and Pender, N}, title = {Longitudinal cognitive assessment using the Cumulus NeuLogiq platform in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-53099-x}, pmid = {42225765}, issn = {2045-2322}, abstract = {People living with ALS (plwALS) and/or FTD (plwFTD) often experience cognitive and behavioural changes. However, detection can be confounded due to factors like fatigue and testing anxiety. Cumulus neuroscience developed NeuLogiq[(R)], a multi-modal neurocognitive platform that can be used in clinic or at home, providing an ecologically valid measure of cognition. This study examined the feasibility and usability of NeuLogiq in plwALS, plwFTD, and controls, and compared performance on gold standard neuropsychological assessments with corresponding NeuLogiq digital assessments. Over 8 months, plwALS (n = 11), plwFTD (n = 7), and matched healthy controls (n = 10) completed longitudinal full neuropsychological assessment, as well as three 25-minute NeuLogiq Platform sessions every 2 weeks in their homes. Participants adhered well to the study schedule, conducting over 32/54 sessions on average. All groups rated usability in the 'good' or 'excellent' range and had > 80% complete data. Baseline group differences were detectable on both NeuLogiq digital assessments and benchmark neuropsychological assessments of similar cognitive domains. Longitudinal mixed effects models found that the ALS group showed decline on NeuLogiq measures of emotion recognition and speech fluency. These findings suggest that the NeuLogiq platform is feasible and usable for plwALS and plwFTD, and can identify cognitive deficits to a similar extent as benchmark assessments over time.}, }
@article {pmid42225893, year = {2026}, author = {Pervaiz, I and Blazier, AS and Nyarko-Danquah, I and Wesseling, H and Ramos, A and Woodworth, L and Taksir, TV and Ryan, SK and Wirak, G and Zhao, Z and Hammond, TR and Morel, C and Bangari, DS and Ofengeim, D and Rapino, F and Hagan, N}, title = {Targeting MAPK-dependent pathways to modulate reactive astrocyte pathology in neurodegeneration.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-10323-8}, pmid = {42225893}, issn = {2399-3642}, abstract = {Reactive astrocytes play a crucial role in the pathogenesis of neurodegenerative diseases; however, the mechanisms underlying glial cell interactions remain poorly understood. Here, we show that human primary astrocytes and iPSC-derived astrocytes in a tri-culture system adopt a reactive state with a distinct molecular phenotype overlapping with transcriptomic signatures observed in ALS astrocytes. Integrated proteomic and phosphoproteomic analyses revealed dysregulated cytoskeletal remodeling and kinase signaling in reactive astrocytes. Surface marker screening identified ICAM-1 as a novel in-vitro marker, validated in ALS spinal cord. Functionally, reactive astrocytes induced neurotoxicity and altered neuronal activity. To elucidate mechanisms regulating neurotoxicity, a phenotypic small molecule screen identified MAP kinase as a functional regulator, with subsequent single-nucleus RNA sequencing uncovering dysregulated signaling pathways modulated by MAPK inhibition in the tri-culture system. Together, these complementary approaches define the molecular landscape of reactive astrocytes, providing a systems-level framework for exploring disease mechanisms and therapeutic strategies in neurodegeneration.}, }
@article {pmid42226981, year = {2025}, author = {Romina, A and Mohaddeseh, L and Mansour, B}, title = {Fabrication and Evaluation of PVA-NYS-THY Nanofiber Scaffolds as Antifungal Agents Against Fluconazoleresistant Candida glabrata.}, journal = {Archives of Razi Institute}, volume = {80}, number = {5}, pages = {1229-1238}, pmid = {42226981}, issn = {2008-9872}, abstract = {INTRODUCTION: The emergence of fluconazole-resistant Candida glabrata presents a significant challenge in antifungal therapy, necessitating the development of alternative treatment strategies. C. glabrata, an opportunistic yeast, is increasing resistance to common antifungals like fluconazole, often due to efflux pump overexpression, leading to compromised treatment efficacy, higher mortality, prolonged hospital stays, and increased healthcare costs. This study focused on fabricating and evaluating polyvinyl alcohol-nystatin-thymol (PVA-NYS-THY) nanofibrous scaffolds as a novel antifungal approach against fluconazole-resistant C. glabrata.<br><br>MATERIALS &amp; METHODS: Clinical isolates were identified and assessed for resistance using culture methods, molecular assays, and antifungal susceptibility testing. PVA-NYS-THY nanofibers, produced via electrospinning, exhibited uniform fibers with an average diameter of ~100 nm as confirmed by scanning electron microscopy (SEM). Fourier transform infrared spectroscopy confirmed the successful incorporation of functional groups. Real-time polymerase chain reaction (PCR) was employed to evaluate the nanofibers' effect on the expression of secreted aspartyl proteinases (SAP) and agglutinin-like sequence (ALS) gene. Scaffold release kinetics were characterized, and antifungal efficacy was assessed using minimum inhibitory concentration (MIC) assays.<br><br>RESULTS: PVA-NYS-THY scaffolds showed favorable release profiles and significantly downregulated ALS and SAP gene expression. MIC values for PVA-NYS-THY, PVA-NYS, and PVA-THY were 7.81, 15.62, and 62.5 &#xb5;g/mL, respectively, demonstrating superior antifungal activity of the PVA-NYS-THY formulation.<br><br>CONCLUSION: These findings suggest PVA-NYS-THY nanofibrous scaffolds offer a promising therapeutic strategy for combating fluconazole-resistant C. glabrata, providing a novel solution to overcome current limitations in antifungal treatment.}, }
@article {pmid42215790, year = {2026}, author = {Li, S and Xu, S and Li, F and Zhao, Q and Zhang, P and Guan, Q and Sun, X and Bi, J and Xiao, H and Tang, Y and Peng, C and Chen, Q and Wang, Y and Yang, M}, title = {The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A ESCRT-mediated lysosomal repair.}, journal = {The EMBO journal}, volume = {}, number = {}, pages = {}, pmid = {42215790}, issn = {1460-2075}, support = {32070743//MOST | National Natural Science Foundation of China (NSFC)/ ; 32560156//MOST | National Natural Science Foundation of China (NSFC)/ ; 202401BF070001-015//Yunnan Provincial Science and Technology Department ()/ ; 202401AS070131//Yunnan Provincial Science and Technology Department ()/ ; C619300A142//Yunnan Provincial Science and Technology Department ()/ ; C1762201000139//Yunnan University (YNU)/ ; KC-242410334//Yunnan University (YNU)/ ; }, abstract = {Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.}, }
@article {pmid42215819, year = {2026}, author = {Ream, A and Woodcock, A and Zlatkovic, S and Pedersen, RM and Bonilla, A and Middleton, H and Hernandez, PR and Schultz, PW}, title = {Implementing multiple implicit association tests in Qualtrics: A guide and demonstration using balanced identity design theory.}, journal = {Behavior research methods}, volume = {58}, number = {7}, pages = {}, pmid = {42215819}, issn = {1554-3528}, mesh = {Humans ; *Association ; Software ; Surveys and Questionnaires ; Attitude ; }, abstract = {Interest in implicit processes, such as attitudes and identities, has grown in behavioral sciences since Greenwald and colleagues (1998) developed and introduced the Implicit Association Test (IAT). The IAT was developed to measure these processes, which has become more accessible with the popularity of Qualtrics as a data collection tool, especially through methods and code provided by Carpenter et al. (2019). They demonstrated how to construct a single IAT for use on the Qualtrics platform, providing research resources for creating IATs to examine concept-pair associations. However, there is no guidance on constructing multiple IATs on survey software platforms for research that requires two or more IATs in a single study. This paper extends Carpenter et al.'s (2019) work by outlining the process of developing, implementing, and utilizing multiple IATs within a single Qualtrics survey. We provide a tutorial using examples from our research using the Balanced Identity Design (BID) framework, including step-by-step written and visual instructions and templates, instructions for planning and building multiple IATs and dynamically presenting them in a single Qualtrics survey and code for processing IAT data. We also demonstrate the utility of the multiple IAT approach by reporting a short study utilizing BID theory wherein we measure implicit racial/ethnic identity, STEM identity, and race/ethnicity-STEM associations in a single study via three IATs.}, }
@article {pmid42215859, year = {2026}, author = {La Cognata, V and Gentile, G and Morello, G and Guarnaccia, M and Cavallaro, S}, title = {RNA-centric approaches in amyotrophic lateral sclerosis: prospects for future therapeutics.}, journal = {Expert opinion on therapeutic targets}, volume = {}, number = {}, pages = {}, doi = {10.1080/14728222.2026.2682782}, pmid = {42215859}, issn = {1744-7631}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by profound clinical and molecular heterogeneity, which has substantially hindered the development of effective therapies. Significant advances in ALS research have been driven by the study of RNA biology, together with the implementation of advanced transcriptomic technologies and artificial intelligence - based algorithms, which are assuming a transformative role in reshaping the field.<br><br>AREAS COVERED: We discuss how genome-wide expression profiling enables the identification of molecular signatures for drug discovery and repurposing, facilitates the stratification of patients into biologically distinct subtypes for more refined clinical trials, and guides the development of novel nucleic acid-based therapies. Furthermore, we explore the potential of transcriptomics to identify molecular vulnerabilities during pre-symptomatic stages, paving the way for early intervention.<br><br>EXPERT OPINION: The convergence of transcriptomics and artificial intelligence is poised to fundamentally redefine ALS, transforming it from a single clinical entity into a spectrum of molecularly defined disorders, each potentially amenable to targeted therapeutic intervention. While challenges in translating high-dimensional data into clinical practice remain, the integration of transcriptomics with advanced computational tools promises to accelerate the transition toward a new era of personalized medicine in ALS.}, }
@article {pmid42216417, year = {2026}, author = {Curman, P and Alam, U and Ludwig, RJ}, title = {Response to Meisenheimer et al's "Behind the data: Pitfalls and bias in database research".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e135-e136}, doi = {10.1016/j.jaad.2025.09.108}, pmid = {42216417}, issn = {1097-6787}, }
@article {pmid42217760, year = {2026}, author = {Jiang, Y and Hu, S and Yang, B and Zhang, L and Wang, Y and Yang, G and Zhang, H}, title = {Fluid-based biomarkers of amyotrophic lateral sclerosis: recent advances and future prospects.}, journal = {Brain research}, volume = {}, number = {}, pages = {150395}, doi = {10.1016/j.brainres.2026.150395}, pmid = {42217760}, issn = {1872-6240}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with no definitive cure. The absence of specific diagnostic biomarkers leads to diagnostic delays, hindering early intervention and management. This review provides a critical appraisal of fluid-based biomarkers for ALS across multiple sources-cerebrospinal fluid (CSF), blood, urine, saliva, and tears-with emphasis on their diagnostic and prognostic potential, limitations, and readiness for clinical translation. While neurofilaments (NfL, pNfH) are well-established as sensitive indicators of neuroaxonal injury and are increasingly used as prognostic and pharmacodynamic markers in clinical trials, they lack disease specificity. Biomarkers reflecting ALS-specific pathology, such as TDP-43 species and C9orf72 dipeptide repeat proteins (DPRs), show promise but remain in early validation stages with limited multicenter data. Emerging markers from non-invasive sources (urine p75ECD, salivary chromogranin A, tear metabolomics) offer potential for repeated sampling but require rigorous external validation before clinical adoption. To address current gaps, we introduce a standardized evidence grading framework (Tier 1-3) and a comprehensive reporting template for biomarker studies, including explicit performance metrics (AUC, sensitivity, specificity, confidence intervals) and validation status. We also propose minimum reporting standards for study design, pre-analytical variables, and statistical rigor, modeled on REMARK guidelines. A roadmap for biomarker validation and a cross-fluid comparison matrix are provided to guide future research. Despite considerable progress, significant challenges remain, including biological heterogeneity, pre-analytical variability, and insufficient external validation. Future efforts should prioritize multicenter prospective studies, assay harmonization, ethical frameworks for early diagnosis, and integration of emerging technologies such as artificial intelligence and digital twins. Fluid-based biomarkers, while not yet replacing clinical evaluation, are essential tools for accelerating drug development, enabling patient stratification, and moving toward personalized medicine in ALS.}, }
@article {pmid42218400, year = {2026}, author = {Abbasi, H and Shafaatdoost, M and Mohajerani, A and Asadollahi, M and Rashidi, M and Malekahmadi, M and Sarraf, P}, title = {Association between body composition and disease progression in adults with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-04971-w}, pmid = {42218400}, issn = {1471-2377}, support = {IR. TUMS.NI.REC.1401.059//Tehran University of Medical Sciences and Health Services/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle wasting, and respiratory failure, with a median survival of 30 months. Due to the strong link between dysphagia, weight loss, and disease progression, this study investigates the relationship between body composition and clinical outcomes in ALS adults. This cross-sectional study involved 93 ALS adults (29 females, 64 males) from Imam Khomeini Hospital in Tehran, selected based on EI Escorial criteria. Researchers assessed body composition, functional abilities, and disease progression using ALSFRS-R, MRC scores, and DPR, analyzing associations through linear regression models with RStudio in conjunction with R software. In this study, significant differences were found between the third and first tertiles for various measures. Significant associations were observed between body composition and ALSFRS-R for MAC (β: 3.0; P = 0.006), with underweight and moderately active adults exhibiting notable differences. The MRC score was positively associated with FFM (β: 5.8; P = 0.002), SLM (β: 5.6; P = 0.002), SMM (β: 3.8; P = 0.001), MAC (β: 3.2; P = 0.002), ICW (β: 2.7; P = 0.002), and ECW (β: 1.5; P = 0.003), while underweight and low-to-moderate physical activity adults indicated inverse associations. For DPR, significant relationships were noted for weight (β: 4.5; 95% CI: 0.02, 9.3; P = 0.002) and FFM (β: 11; P < 0.001), influenced by gender and physical activity. The findings highlight the role of gender, weight, and activity in ALS management, suggesting that maintaining a healthy weight along and muscle mass along with regular activity is associated with better outcomes. This can inform personalized treatment strategies for better patient care.}, }
@article {pmid42218846, year = {2026}, author = {Bridge, F and Thevathasan, W and Schultz, D and Zhang, W and Wright, E and Yeh, WZ}, title = {Neurosymptomatic HIV CSF viral escape with parkinsonism and amyotrophic lateral sclerosis-like syndrome: a case report.}, journal = {Journal of neuroimmunology}, volume = {418}, number = {}, pages = {578992}, doi = {10.1016/j.jneuroim.2026.578992}, pmid = {42218846}, issn = {1872-8421}, abstract = {Human immunodeficiency virus (HIV) infection can lead to various neurologic complications affecting central and peripheral nervous systems. Rarely, patients on combined anti-retroviral therapy (CART) with peripheral virologic suppression may develop compartmentalised central nervous system infection with cerebrospinal fluid (CSF) viral escape. We report the case of a 42-year-old man with chronic HIV infection and a previous diagnosis of Parkinson's disease referred for neurologic evaluation with diffuse hyperreflexia including brisk jaw jerk. He was adherent to combined anti-retroviral therapy (CART). During follow-up, he developed mild upper and lower limb weakness and gait instability. Electromyography was consistent with a motor neuropathy or neuronopathy. Neuraxial MRI showed non-specific supratentorial white matter lesions. Plasma HIV viral load was suppressed (<20 copies/mL) whereas CSF viral load was 35 copies/mL, consistent with CSF viral escape. CSF neopterin level was elevated indicating neuroinflammation. HIV-associated neurological overlap syndrome, with parkinsonism and an amyotrophic lateral sclerosis-like syndrome, in the context of neurosymptomatic CSF escape was diagnosed. The patient's HIV CART regime was adjusted to improve CNS penetration. Neurosymptomatic HIV CSF escape is a rare and likely under-recognised complication which can occur despite compliance with CART. When suspected, CSF viral load should be tested. CART optimisation to improve CNS penetration may be potentially beneficial in neurosymptomatic CSF viral escape and to reduce HIV-associated neurotoxicity, but these require further study to confirm.}, }
@article {pmid42219148, year = {2026}, author = {Martin, R and Beauchamp-Chalifour, P and Rayes, J and Matovinovic, K and Schneider, PS}, title = {Incidence and Strategies for Prevention of Adjustable Loop Suspensory Fixation Maldeployment in Multiligament Knee Reconstruction.}, journal = {Journal of ISAKOS : joint disorders &amp; orthopaedic sports medicine}, volume = {}, number = {}, pages = {101151}, doi = {10.1016/j.jisako.2026.101151}, pmid = {42219148}, issn = {2059-7762}, abstract = {INTRODUCTION/OBJECTIVES: Adjustable loop suspensory (ALS) fixation offers the ability to re-tension grafts in complex multiligament knee reconstruction. A frequent complication of adjustable loop fixation is implant maldeployment. This study's primary objective was to determine the incidence of implant maldeployment associated with ALS fixation in a cohort of patients that underwent multiligament knee reconstruction and to identify the most at risk tunnel(s). Our secondary objective was to determine the clinical impact of implant maldeployment.<br><br>METHODS: Demographic, radiological, and clinical data were collected from adult patients who underwent multiligament knee reconstruction using ALS fixation, between January 1, 2018, and January 1, 2020. The primary outcome measure was the incidence of implant maldeployment, as defined by radiologic soft-tissue interposition of >5 mm or radiologic intraosseous button flip. Secondary outcomes were the rate of reoperation, postoperative Lysholm and Tegner scores and postoperative knee range of motion. Statistical analyses were conducted using univariate logistic regression, and Odds Ratio (OR) with 95% confidence interval (CI) were reported.<br><br>RESULTS: A total of 241 ALS buttons were included in 56 patients, predominantly male patients (N=39, 70%), with a median age of 32 [26.0-42.0] years. The incidence of ALS implant maldeployment was 5% (N=11/241). Soft-tissue interposition maldeployment only occurred for the femoral medial collateral ligament (MCL) and the femoral posterior cruciate ligament posteromedial bundle fixation (PCL PM). Reoperation occurred in five out of nine (56%) patients with maldeployment, and six out of 34 (18%) in patients with well deployed implants (OR 6.8, 95% CI 1.1 to 49, p=0.022). Maldeployment did not appear to impact postoperative knee patient reported outcomes or range of motion (p&#x2265;0.05). The median follow-up duration was 9.1 [7.4-13.6] months.<br><br>CONCLUSION: This cohort demonstrates a 5% incidence of maldeployment when using ALS fixation. Despite maldeployment, ALS fixation demonstrated similarly favorable clinical outcomes, but higher rate of reoperation. In multiligament reconstructions, surgeons should be particularly attentive with femoral ALS button deployment for PCL and MCL grafts.<br><br>LEVEL OF EVIDENCE: IV.}, }
@article {pmid42219616, year = {2026}, author = {Busi, R and Goggin, D and Eyres, N and Runge, F and Porri, A and Flower, K}, title = {A Trp574-Leu substitution confers resistance to three classes of acetolactate synthase inhibitors in Australian brome grass (Bromus diandrus).}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.70979}, pmid = {42219616}, issn = {1526-4998}, support = {UWA2007-002RTX//Grains Research and Development Corporation/ ; }, abstract = {BACKGROUND: Brome grass (Bromus diandrus) is a prevalent weed in southern Australian cropping regions which causes significant economic damage in crops and pastures. Before harvest 2023, two populations (named 6-24 and 7-24) suspected of resistance to imidazolinone herbicides were collected from separate fields. Preliminary screening indicated that these populations were resistant to several different acetolactate synthase (ALS)-inhibiting herbicides. Therefore, further characterisation of the level and mechanism of resistance was carried out.<br><br>RESULTS: There was high survival of the resistant populations at the maximum tested rates of sulfometuron (600&#x2009;g&#x2009;ha[-1]) and imazamox&#x2009;+&#x2009;imazapyr (74&#x2009;+&#x2009;34&#x2009;g&#x2009;ha[-1], 2&#xd7; the label rate for use in imidazolinone-tolerant crops). All examined individuals (15 from each population) carried the same point mutation causing a tryptophan-to-leucine substitution at position 574 in the ALS protein. Application of the cytochrome P450 inhibitor malathion prior to herbicide treatment did not affect survival rates.<br><br>CONCLUSIONS: This is the first study reporting a Trp574-Leu mutation as the basis for cross-resistance to ALS-inhibiting herbicides (sulfonylureas, imidazolinones and triazolopyrimidines) in Australian populations of B. diandrus. Control of these populations will require strategic use of pre-emergence herbicides and herbicide-tolerant crops in combination with harvest weed seed control. &#xa9; 2026 The Author(s). Pest Management Science published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.}, }
@article {pmid42219776, year = {2026}, author = {Patera, E and Avilova, O and Choudhury, B and Burns, D}, title = {Empowering anatomists at all career stages: The vital role of reflective practice for professional growth.}, journal = {Anatomical sciences education}, volume = {}, number = {}, pages = {}, doi = {10.1002/ase.70271}, pmid = {42219776}, issn = {1935-9780}, abstract = {Supporting the growth of anatomy educators is both an investment in individuals and in the future of anatomy education. Anatomy educators come from diverse academic and professional backgrounds and hold varied teaching portfolios. Consequently, their professional needs differ depending on their training, qualifications, and roles. Empowering anatomy educators requires a long-term commitment that combines personal development, institutional initiatives, and a culture of reflection. A cornerstone of this process is reflective practice, which enables anatomy educators to strengthen their teaching, refine their professional identity, and adapt to evolving educational needs. In this viewpoint commentary, we recommend three practical strategies for getting started with critical reflection: (a) writing a teaching philosophy statement (TPS), (b) adopting the Teaching Squares approach, and (c) developing a teaching portfolio, each providing structured opportunities for educators to critically examine and enhance their practice. Established reflective models such as Gibbs' Reflective Cycle, Rolfe et al.'s Reflective Model, and Brookfield's Four Lenses of Reflection can help guide anatomy educators in structuring their critical reflection. Finally, we emphasize that engaging in critical self-reflection is not a tick-box exercise but a deliberate and ongoing practice essential for the professional growth of anatomy educators, as well as the cultivation of a reflective academic culture.}, }
@article {pmid42221419, year = {2019}, author = {Kocia, L and Love, P}, title = {The non-disjoint ontic states of the Grassmann ontological model, transformation contextuality, and the single qubit stabilizer subtheory.}, journal = {Journal of physics. A, Mathematical and theoretical}, volume = {52}, number = {9}, pages = {}, pmid = {42221419}, issn = {1751-8113}, abstract = {We show that it is possible to construct a preparation non-contextual ontological model that does not exhibit 'transformation contextuality' for single qubits in the stabilizer subtheory. In particular, we consider the 'blowtorch' map and show that it does not exhibit transformation contextuality under the Grassmann Wigner-Weyl-Moyal (WWM) qubit formalism. Furthermore, the transformation in this formalism can be fully expressed at order ℏ 0 , where it satisfies all of Kolmogorov's axioms of classical probability theory, and so does not qualify as a candidate quantum phenomenon. In particular, we find that the Grassmann WWM formalism at order ℏ 0 corresponds to an ontological model governed by an additional set of constraints arising from the relations defining the Grassmann algebra. Due to this additional set of constraints, the allowed probability distributions in this model do not form a single convex set when expressed in terms of disjoint ontic states and so cannot be mapped to models whose states form a single convex set over disjoint ontic states. However, expressing the Grassmann WWM ontological model in terms of non-disjoint ontic states corresponding to the monomials of the Grassmann algebra results in a single convex set. We further show that a recent result by Lillystone et al that proves a broad class of preparation and measurement non-contextual ontological models must exhibit transformation contextuality lacks the generality to include the ontological model considered here; Lillystone et al's result is appropriately limited to ontological models whose states produce a single convex set when expressed in terms of disjoint ontic states. Therefore, we prove that for the qubit stabilizer subtheory to be captured by a preparation, transformation and measurement non-contextual ontological theory, it must be expressed in terms of non-disjoint ontic states, unlike the case for the odd-dimensional single-qudit stabilizer subtheory.}, }
@article {pmid42221822, year = {2026}, author = {Sreeram, A and Baron, DM and Brusati, A and Stallworth, K and Humphrey, J and Landers, JE}, title = {Global transcriptional changes across multiple isogenic C9orf72 patient iPSC-derived neurons.}, journal = {iScience}, volume = {29}, number = {6}, pages = {116054}, pmid = {42221822}, issn = {2589-0042}, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD); yet, mechanisms underlying selective neuronal vulnerability remain unclear. A major challenge in identifying consistent transcriptomic changes across C9orf72 patient-derived neuron lines has been heterogeneous differentiations, lack of isogenic controls and low sequencing depth. To overcome these challenges, we generated homogeneous cortical neuron (iCNs) cultures from multiple isogenic C9orf72 patient iPSC pairs and performed RNA deep sequencing. We identified robust and reproducible gene expression and splicing alterations in pathways related to cytoskeletal organization, extracellular matrix adhesion and synaptic signaling. Notably, we observed exon 30 skipping in the cytoskeletal regulator filamin B (FLNB), resulting in loss of its hinge domain. This was accompanied by altered FLNB localization, disrupted actin crosslinking, and mechanotransduction signaling. These findings reveal convergent transcriptomic and functional disruptions across multiple isogenic C9orf72 patient-derived iCNs offering insights into ALS/FTD pathogenesis.}, }
@article {pmid42214007, year = {2026}, author = {Bracaval, K and De Vocht, J and Ombelet, F and Den Bulcke, LV and Peeters, AM and Deleu, B and Vrijsen, B and Kalkanis, A and Buyse, B and Testelmans, D and Van Den Bossche, M and Van Damme, P}, title = {Sleep disturbances and respiratory dysfunction in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2671162}, pmid = {42214007}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate how respiratory dysfunction and site of onset influences changes in sleep architecture in people with ALS (pwALS).<br><br>METHODS: We conducted a retrospective observational study, analyzing demographic data, lung function tests, and polysomnography (PSG) measures. Descriptive statistics, correlation analyses, and survival analyses were performed.<br><br>RESULTS: Our cohort had 240 pwALS, 63% male, median age at onset 59.3 (IQR 16.5) years. Median time from onset to PSG was 27.5 (IQR 25) months. Most pwALS had spinal onset (79%). Spirometry at time of PSG showed a reduced Forced Vital Capacity (FVC) (58; (IQR 26) %). We saw a significant FVC decline (3.9; (IQR 4) % per month) in the months before PSG. The sleep quality assessment in pwALS revealed a reduced total sleep time (339; (IQR 144.7) minutes), diminished sleep efficiency (62.8; (IQR 26.5)%) and increased wake after sleep onset (172; (IQR 130.2) minutes) when compared to normal values of healthy age-matched adults. The spinal onset group had a higher number of arousals. In the multivariate linear regression model adjusted for age and sex, FVC is a significant predictor for sleep efficiency (&#x3b2;&#x2009;=&#x2009;3.359, p&#x2009;=&#x2009;0.0059). Spinal onset, a slower rate of FVC decline in the months preceding PSG and a preserved FVC (&#x2265; 70%) at the time of PSG were associated with improved survival.<br><br>CONCLUSION: We observed substantial sleep disturbances in our cohort overall with substantially increased arousals in the spinal group. FVC is a significant predictor for sleep efficiency and the decline in FVC is linked to survival.}, }
@article {pmid42214042, year = {2026}, author = {de Boer, EMJ and Willemse, SW and Veldink, JH and Goedee, HS and Vrancken, AFJE and van Rheenen, W and Westeneng, HJ and van den Berg, LH and van Es, MA}, title = {Diagnostic Revision From Primary Lateral Sclerosis to Amyotrophic Lateral Sclerosis: A Cohort Study.}, journal = {Neurology}, volume = {106}, number = {12}, pages = {e218055}, doi = {10.1212/WNL.0000000000218055}, pmid = {42214042}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; *Motor Neuron Disease/diagnosis/physiopathology/epidemiology ; Male ; Middle Aged ; Aged ; Disease Progression ; Cohort Studies ; Retrospective Studies ; Registries ; Netherlands ; Electromyography ; }, abstract = {BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is defined as a pure upper motor neuron syndrome and is a diagnosis of exclusion, amyotrophic lateral sclerosis (ALS) being the most likely alternative diagnostic consideration. A minimum disease duration of 2 years is required for the diagnosis of PLS, after which patients are classified as probable PLS (P-PLS) and subsequently as definite PLS (D-PLS) after 4 years. Our aim is to apply the current diagnostic criteria to a population-based cohort and investigate which clinical characteristics are associated with a diagnostic revision to ALS.<br><br>METHODS: This cohort study included patients meeting the current diagnostic criteria for PLS retrospectively from the Dutch Motor Neuron Disease Registry. Diagnostic revision to ALS was based on clinical assessment, EMG findings according to the revised El Escorial Criteria, or if patients had died from disease progression within 4 years of disease onset. Clinical characteristics were compared for patients who underwent diagnostic revision with ALS vs true PLS. Subdistribution hazard ratios (SHRs) for characteristics associated with diagnostic revision were determined using Fine-Gray regression.<br><br>RESULTS: We included 478 patients (median age of onset 59.3 years, interquartile range 50.8-67.0, 47.9% female), of whom 311 (65.1%) met criteria for P-PLS and 167 (34.9%) for D-PLS at diagnosis. Eighty-eight patients (18%) underwent diagnostic revision to ALS, 76 cases (86%) before 4 years of disease duration. Patients whose diagnosis was revised to ALS had higher median age at onset (63.4 vs 58.0 years, p = 5.20 &#xd7; 10[-4]), more often had bulbar onset (38.6% vs 19.7%, p = 6.19 &#xd7; 10[-4]), and faster progression (median ALS Functional Rating Scale-revised slope 0.43 vs 0.18, p = 6.05 &#xd7; 10[-11]). The risk of diagnostic revision increased if progression rate was faster (SHR 3.08 95% CI 1.69-5.60, p = 2.35 &#xd7; 10[-4]) and if diagnosis was P-PLS compared with D-PLS (SHR 3.08, 95% CI 1.65-5.74, p = 3.96 &#xd7; 10[-4]).<br><br>DISCUSSION: In our cohort, most diagnostic revisions from PLS to ALS were in patients with a disease duration of less than 4 years. Besides disease duration, a faster progression rate was associated with diagnostic revision from PLS to ALS. Adding progression rate to the current diagnostic criteria could increase accuracy and help identify patients at higher risk of developing ALS.}, }
@article {pmid42214472, year = {2026}, author = {Garrett, TL and Wintermute, L and Armitage, M and Ward, S and Gerber, K and Elbasiouny, SM}, title = {Optimized multiplex immunofluorescent protocols for simultaneous in situ identification of α-motoneuron subtypes.}, journal = {Journal of neuroscience methods}, volume = {}, number = {}, pages = {110815}, doi = {10.1016/j.jneumeth.2026.110815}, pmid = {42214472}, issn = {1872-678X}, abstract = {BACKGROUND: Accurate identification of α-motoneuron (α-MN) subtypes - slow (S), fast fatigue-resistant (FR), fast fatigue-intermediate (FI), and fast fatigable (FF) - is essential for studying motor circuit organization and selective vulnerability in neurodegenerative disease. While electrophysiological approaches can distinguish these subtypes, existing immunohistochemical (IHC) methods lack the ability to simultaneously identify all four α-MN classes in situ, particularly the FI subtype, limiting their utility for large-scale or tissue-based analyses.<br><br>NEW METHOD: Here, we present novel multiplex immunofluorescent strategies that enables simultaneous in situ identification of S, FR, FI, and FF &#x3b1;-MN subtypes, including intermediate populations, within single sections of mouse lumbar spinal cord. This approach integrates a combinatorial marker framework with optimized co-labeling conditions to resolve subtype-specific molecular signatures, including FI MNs, which have not been previously distinguishable using standard IHC methods.<br><br>RESULTS: We establish a systematic validation pipeline demonstrating robust and reproducible subtype classification across multiple protocols, sexes, mouse strains, and disease conditions, including the G93A-SOD mouse model of amyotrophic lateral sclerosis. Labeled populations recapitulate known size distributions and exhibit consistent subtype-specific patterns across lumbar segments, supporting both the accuracy and reproducibility of the method.<br><br>CONCLUSIONS: By enabling comprehensive in situ classification of all major &#x3b1;-MN subtypes, this approach represents a substantive refinement of multiplex IF, overcoming key limitations of existing IF methods and enabling analyses of &#x3b1;-MN subtype organization and selective vulnerability that were previously not feasible with standard histological techniques. This framework is broadly applicable to studies of motor system organization, aging, and neurodegenerative disease.}, }
@article {pmid42214970, year = {2026}, author = {Franzoia, B and de Diego-Balaguer, R}, title = {The beat in speech: A window into the attentional mechanisms supporting the detection of non-adjacent dependencies.}, journal = {Cognition}, volume = {274}, number = {}, pages = {106596}, doi = {10.1016/j.cognition.2026.106596}, pmid = {42214970}, issn = {1873-7838}, abstract = {Converging evidence suggests that musical training can elicit positive transfer effects across multiple domains of language processing, including grammar. In humans, exposure to musical rhythm induces beat and meter perception, which has been shown to enhance attentional allocation and temporal prediction. Theories hypothesize that the predictive gains intrinsic to music rhythmicity may exert cascading effects on syntactic processing by modulating sensitivity to speech prosody. From this perspective, learning should also be boosted insofar as prosody tends to align with grammatical structure. In the present study, we introduce a novel behavioural paradigm to investigate the link between rhythmicity and grammar learning by testing whether the rhythmic beat facilitates the detection of grammar-like structures in artificial languages (ALs), implemented as non-adjacent dependencies (NADs) between variable syllables forming a speech stream (e.g., PU reliably predicts KI in PUlaruKI). A total of 147 participants were exposed to four ALs that varied in rhythmic, grammatical structure, and the alignment between the two: (i) a beat-inducing rhythm with no NADs; (ii) a beat-hindering rhythm with NADs; (iii) a beat-inducing rhythm with embedded NADs temporally misaligned, and (iv) NADs aligned with beat time-points. Results of the implicit and, after exposure, explicit learning measures demonstrate enhanced learning when NADs are embedded within beat-inducing rhythmic structures. Together, these findings suggest that rhythm enhances predictive and attentional mechanisms implicated in grammar learning, underscoring their role in its acquisition.}, }
@article {pmid42215498, year = {2026}, author = {Viuff, JH}, title = {Immortal time bias from conditioning on future events in Parkinson's disease survival analysis.}, journal = {NPJ Parkinson's disease}, volume = {12}, number = {1}, pages = {}, pmid = {42215498}, issn = {2373-8057}, abstract = {This comment highlights potential immortal time bias in Brakedal et al.’s study of Parkinson’s disease (PD) survival. Because PD status and exclusion criteria rely on future prescription patterns, individuals classified as having PD are, by design, unable to die during early follow-up. This likely inflates survival estimates, particularly among the oldest patients. Aligning eligibility criteria with the start of follow-up and avoiding conditioning on future events would reduce this bias in future research.}, }
@article {pmid42213237, year = {2026}, author = {Leboeuf, M and Nijssen, J and Comley, LH and Aguila Benitez, JC and Mei, I and Gómez Alcalde, S and Muñoz de Bustillo-Alfaro, RA and Radoi, V and Nichterwitz, S and Schweingruber, C and Acevedo Arozena, A and Hedlund, E and Cullheim, S}, title = {Reevaluating the role of beta2-microglobulin: new insights on selective vulnerability in ALS pathology.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {42213237}, issn = {1432-0533}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *beta 2-Microglobulin/metabolism/genetics ; Animals ; Humans ; *Motor Neurons/pathology/metabolism ; Mice ; Female ; Spinal Cord/pathology/metabolism ; Male ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; HLA Antigens/metabolism/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons are particularly vulnerable in ALS remains unclear, as does why certain MN groups remain resistant throughout the disease course. We investigated the role of the human leukocyte antigens (HLAs) and beta2-microglobulin (β2m) in MN susceptibility to ALS, given their reported involvement in both prolonging and shortening disease progression. Loss of HLAs in ALS has also been shown to increase MNs vulnerability to toxicity exerted by activated astrocytes. RNA sequencing of control tissues demonstrated that disease-resistant oculomotor neurons (OMNs) and Onuf's MNs exhibited β2m and HLA mRNA levels comparable to those of vulnerable spinal MNs, suggesting that baseline differences in these transcripts do not explain the differential vulnerabilities of these MN groups. However, HLA protein levels showed an inverse correlation with spinal MN size, with the large MNs, those lost early in ALS, displaying the lowest HLA expression. HLA protein levels were also reduced in spinal MNs from end-stage ALS patient tissues, while remaining relatively unchanged in OMNs. In contrast, spinal MNs uniquely exhibited significant upregulation of β2m and HLA-C transcripts during disease, likely reflecting a protective compensatory response. Together, these findings suggest that β2m and HLAs may contribute to spinal MN vulnerability in ALS. To assess their functional role, β2m knockout mice were crossbred with SOD1G93A ALS mice. Loss of β2m did not alter life span of the ALS mice, but led to partial preservation of lumbrical muscle innervation that was insufficient to maintain motor function. Analysis of GFAP immunoreactivity revealed marked neuroinflammation activation in the spinal cords of β2m knockout mice. As these mice retain normal MN numbers and life-span, this indicates that loss of functional MHC-I, even in the presence of astrocyte activation, is insufficient to cause MN disease. Furthermore, β2m knockout significantly increased GFAP activation in SOD1G93A mice, but did not further exacerbate disease progression, suggesting that loss of functional MHC-I does not necessarily render MNs more vulnerable to astrocyte toxicity. Overall, these findings indicate that β2m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease modifiers in ALS.}, }
@article {pmid42204151, year = {2026}, author = {Jia, Q and Zhu, L and Li, D and Nan, Z and Hou, J and Zhao, Y and Zhu, G and Ou, K and Guo, M and Dui, H and Liu, X and Yan, XX and Yang, S and Huang, L and Fan, D and Li, S and Li, XJ and Yin, P}, title = {Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-73724-7}, pmid = {42204151}, issn = {2041-1723}, support = {32270564//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.}, }
@article {pmid42204279, year = {2026}, author = {Fowler, M and Carr, JM and Gold, J and Walker, A and Rogers, ML}, title = {Evaluation of triumeq treatment on a TDP-43 mouse model of amyotrophic Lateral sclerosis.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-55433-9}, pmid = {42204279}, issn = {2045-2322}, support = {DIS-202303-00932//FightMND/ ; DIS-202303-00932//FightMND/ ; IG1950//Motor Neurone Disease Research Australia/ ; IG1950//Motor Neurone Disease Research Australia/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the accumulation of TAR DNA Binding Protein (43 kDa; TDP-43) within the cytoplasm of neurons. Endogenous retroviruses (ERVs) have been implicated in ALS pathology and the application of antiretroviral therapy, specifically Triumeq, has been proposed for treatment of ALS. However, evidence to support the actions of Triumeq in ALS is lacking. This study investigates the effects of the antiretroviral treatment Triumeq on ALS disease that occurs through TDP-43 pathology by utilising the doxycycline (Dox)-suppressible rNLS8 TDP-43 expression mouse model. In this model, TDP-43 accumulation in the cytoplasm is induced after removal of Dox. Disease was assessed through measures of body weight, neurological score, motor function, urinary p75[ECD] and inflammatory marker expression. Mice were treated with Triumeq and TDP-43 pathology and inflammatory marker expression examined. Triumeq treatment significantly improved motor function early on in the disease course but did not impact other disease progression markers or disease endpoint. In this TDP-43 ALS mouse model, there was a positive association of TDP-43 mRNA levels with transcription factor ATF4, and inflammatory markers CXCL10 and IRF-1, and Triumeq treatment negated this association. Triumeq treatment transiently and modestly improved motor function and influenced TDP-43 associated inflammatory gene expression in an ALS mouse model. These findings support the potential use of Triumeq in treating TDP-43-associated ALS and supports further investigation to better understand if the beneficial actions of Triumeq are via disruption of TDP-43-driven inflammation in ALS.}, }
@article {pmid42204548, year = {2026}, author = {Jin, X and Fu, Y and Qiu, T and Li, J and Zhang, H and Chen, Y and Chen, K and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L and Braden, BB}, title = {Putative glymphatic dysfunction links extracellular fluid dysregulation to white matter degeneration and clinical impairment in amyotrophic lateral sclerosis.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04948-z}, pmid = {42204548}, issn = {1741-7015}, support = {No. 2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders/ ; 2024ZZTS0954//Fundamental Research Funds for the Central Universities of Central South University/ ; U22A20377//National Natural Science Foundation of China/ ; No.2024PT5109//Scientific Research Program of FuRong Laboratory/ ; CB-C2022//Sant&#xe9;/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and prominent extra-motor involvement. Impaired clearance of neurotoxic proteins has led to increasing interest in the brain glymphatic system; however, its in vivo associations with brain microstructure and clinical heterogeneity remain incompletely understood.<br><br>METHODS: One hundred forty-six patients with ALS and 149 demographically matched healthy controls (HCs) underwent multimodal MRI and comprehensive clinical assessments. Putative glymphatic function was quantified using diffusion tensor imaging along perivascular space (DTI-ALPS). Extracellular free water fraction (FWF) and free-water-corrected fractional anisotropy (fwcFA) were derived to characterize extracellular fluid and white matter microstructure. Group differences were assessed using vertex-wise and voxel-wise analyses with correction for multiple comparisons. Associations among imaging metrics and clinical measures were evaluated using correlation and serial mediation analyses.<br><br>RESULTS: Compared with HCs, patients with ALS exhibited significantly reduced DTI-ALPS index, widespread increases in cortical FWF, bidirectional alterations in white matter FWF, and extensive reductions in fwcFA across major white matter tracts. Reduced DTI-ALPS was associated with changes in extracellular free water and white matter microstructural integrity, whereas FWF and fwcFA measures were associated with functional, cognitive, and emotional outcomes. Mediation analyses identified significant indirect associations between DTI-ALPS and both functional and cognitive measures through a pathway involving cortical FWF, white matter FWF, and fwcFA, although direct associations were not observed.<br><br>CONCLUSIONS: These findings provide in vivo evidence that putative glymphatic dysfunction co-occurs with extracellular fluid alterations, white matter microstructural changes, and clinical impairment in ALS. Multi-compartment diffusion imaging may offer complementary markers for characterizing brain microstructure and its clinical relevance in ALS.}, }
@article {pmid42204729, year = {2026}, author = {Pasetto, L and Callegaro, S and Corbelli, A and Fiordaliso, F and Ferrara, D and Brunelli, L and Sestito, G and Pastorelli, R and Bianchi, E and Cretich, M and Chiari, M and Potrich, C and Moglia, C and Corbo, M and Sorarù, G and Lunetta, C and Calvo, A and Chiò, A and Mora, G and Pennuto, M and Quattrone, A and Rinaldi, F and D'Agostino, VG and Basso, M and Bonetto, V}, title = {Correction: Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {21}, number = {1}, pages = {}, doi = {10.1186/s13024-026-00955-z}, pmid = {42204729}, issn = {1750-1326}, }
@article {pmid42205021, year = {2026}, author = {Sun, QH and Xuan, X and Du, YG and Zhai, YC and Ma, T and Duan, F and Xia, CQ and Huang, XS and Huang, YH and Wang, HF}, title = {APOE ε4 Allele is Associated with Cognitive Impairment in Chinese Sporadic ALS: A Retrospective Cohort Study.}, journal = {Biomedical and environmental sciences : BES}, volume = {39}, number = {5}, pages = {564-571}, doi = {10.3967/bes2026.038}, pmid = {42205021}, issn = {2214-0190}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Alleles ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Apolipoprotein E4/genetics/blood ; China ; *Cognitive Dysfunction/genetics/etiology ; Genotype ; Retrospective Studies ; East Asian People/genetics ; }, abstract = {OBJECTIVE: To evaluate the effects of apolipoprotein E (APOE) genotype and serum APOE levels on cognitive and motor phenotypes in Chinese patients with sporadic amyotrophic lateral sclerosis (ALS).<br><br>METHODS: APOE genotypes were determined in 289 patients with sporadic ALS, and serum APOE levels were measured in a subset of 222 patients. Cognitive function was assessed using the Edinburgh Cognitive and Behavioural ALS Screen. We examined the association of APOE genotype and serum levels with age at onset, site of onset, disease progression rate (DPR), time to generalization of symptoms (TTG), and cognitive performance.<br><br>RESULTS: No significant differences were observed in sex, age at onset, site of onset, DPR, or TTG among patients with different APOE genotypes. Similarly, serum APOE levels did not correlate with these clinical variables. However, the APOE-&#x3b5;4 allele was associated with lower ALS-specific cognitive scores, particularly in the domain of verbal fluency.<br><br>CONCLUSION: Our study provides preliminary evidence linking the APOE-&#x3b5;4 allele to cognitive impairment, particularly in language fluency, among Chinese patients with ALS. These findings support the hypothesis that APOE genotype contributes to ALS etiology and suggest its role in shaping distinct cognitive phenotypes in the disease.}, }
@article {pmid42206537, year = {2026}, author = {Pulecio, J and Parra, S and Quiroz, W and Bravo, MA}, title = {Chemometric-Assisted Determination of Benzo[a]pyrene (BaP) and Benzo[a]anthracene (BaA) in Water Samples Using Fluorescence and Commercial Membranes: A White Analytical Chemistry Approach.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {41}, number = {6}, pages = {e70523}, doi = {10.1002/bio.70523}, pmid = {42206537}, issn = {1522-7243}, support = {Fondecyt Regular 1240296//Agencia Nacional de Investigaci&#xf3;n y Desarrollo, ANID/ ; ANID-PFCHA/Doctorado nacional/2024-21242116//Agencia Nacional de Investigaci&#xf3;n y Desarrollo, ANID/ ; }, mesh = {*Benzo(a)pyrene/analysis ; *Benz(a)Anthracenes/analysis ; *Water Pollutants, Chemical/analysis ; Spectrometry, Fluorescence ; *Membranes, Artificial ; Fluorescence ; }, abstract = {This study evaluates different solid membranes to develop an analytical method for the immobilization of two priority PAHs, benzo[a]pyrene (BaP) and benzo[a]anthracene (BaA), followed by the measurement of excitation-emission fluorescence matrices (directly measured over the membrane) coupled to second-order multivariate calibration. Commercially available membranes, such as nylon and C18, proved to be suitable supports for these purposes, especially for aqueous samples. The multivariate curve resolution-alternating least squares (MCR-ALS) algorithm showed adequate flexibility to fit the data and achieve the second-order advantage, even in the presence of unmodeled interferences. Even though both membranes showed different selectivity, the developed method allows quantification of PAH at ng L[-1] levels with a prediction error below 10%. The proposed methodology was successfully applied to spiked real water samples, demonstrating its suitability for detecting PAHs at trace levels. Finally, the proposed method was evaluated and compared with reported analytical approaches based on white analytical chemistry principles, showing remarkable analytical performance for monitoring PAHs in natural water samples.}, }
@article {pmid42206648, year = {2026}, author = {Pupillo, E and Bianchi, E and Diamanti, L and Bergamaschi, R and Pisoni, E and Riva, N and Lunetta, C and Filosto, M and Padovani, A and Tremolizzo, L and De Lodovici, ML and Leone, MA and , }, title = {Air pollutants and amyotrophic lateral sclerosis in a population-based registry: investigating disease susceptibility, progression and survival.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2677537}, pmid = {42206648}, issn = {2167-9223}, abstract = {Objective: to investigate the association between long-term exposure to fine particulate matter (PM2.5) and nitrogen oxides (NOx) with ALS risk, progression, and survival. Methods: We conducted a population-based study in Lombardy, Italy. A case-control analysis included 161 incident ALS cases (2011-2014) and 161 age-, sex-, and province-matched controls. Average residential exposures to PM2.5 and NOx over the 20 years before diagnosis were estimated using European Monitoring and Evaluation Programme data and analysed with conditional logistic regression. A retrospective cohort of 135 ALS cases was used to assess associations with disease progression (ΔFS) and mortality using logistic and Cox regression models, adjusting for demographic and lifestyle factors. Results: Higher PM2.5 exposure in the 20 years preceding diagnosis was associated with increased ALS risk (adjusted OR per 5 µg/m[3] increase 1.19; 95% CI 1.01-1.40), with consistent findings across sensitivity analyses. NOx was not associated with ALS incidence. In contrast, NOx exposure in the 5 years before diagnosis was marginally associated with increased mortality (adjusted HR 1.12; 95% CI 1.00-1.26), whereas PM2.5 was not. Neither pollutant was significantly associated with disease progression rate. Conclusions: Long-term PM2.5 exposure was associated with higher ALS risk, while NOx showed a modest association with mortality. These findings support a role of air pollution in ALS susceptibility and highlight the need for integrated environmental prevention strategies to mitigate the burden of neurodegenerative diseases.}, }
@article {pmid42207242, year = {2026}, author = {Alarcan, H and Veyrat-Durebex, C and Pradat, PF and Cassereau, J and Destee, A and Couratier, P and Camu, W and Neau, JP and Fleury-Lesaunier, MC and Emond, P and Dufour, D and Al Ojaimi, Y and Lefèvre, A and Vourc'h, P and Corcia, P and Andres, CR and Blasco, H}, title = {Anchoring ALS Prognosis: Neurofilament Light Chain Outperforms Inflammatory, Metabolic, and CNS Barrier Biomarkers in the METABALS Cohort.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42207242}, issn = {1559-1182}, mesh = {Humans ; *Neurofilament Proteins/blood/metabolism/cerebrospinal fluid ; Biomarkers/metabolism/blood ; *Amyotrophic Lateral Sclerosis/metabolism/blood/diagnosis/pathology ; Female ; Male ; Prognosis ; Middle Aged ; Cohort Studies ; *Inflammation/metabolism/blood ; *Blood-Brain Barrier/metabolism ; *Blood-Spinal Cord Barrier/metabolism ; *Metabolomics/methods ; Aged ; Kynurenine/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder with marked biological heterogeneity. Despite extensive research, reliable prognostic biomarkers remain limited, with neurofilament light chain (NfL) being the only marker increasingly implemented in clinical practice. The objective of this study is to assess and compare the prognostic value of NfL, circulating markers of central nervous system (CNS) barrier dysfunction, inflammatory mediators, kynurenine pathway metabolites, and global metabolomic profiles in patients with ALS. Seventy-two patients with ALS from the prospective multicenter METABALS cohort were included. Serum, cerebrospinal fluid (CSF), and urine samples were collected at diagnosis. NfL concentrations, markers of blood-brain and blood-spinal cord barrier permeability (albumin quotient, S100B, neuron-specific enolase [NSE]), 48 inflammatory mediators, kynurenine pathway metabolites, and untargeted metabolomic profiles were measured. Associations with clinical features, disease progression, and survival were investigated using univariate analyses and multivariate models. Serum and CSF NfL concentrations were strongly associated with ALS Functional Rating Scale-Revised scores, respiratory function, diagnostic delay, and survival. Higher serum NfL concentrations at diagnosis predicted shorter survival (ROC AUC = 0.86). In all multivariate and multi-block models, serum NfL was the only biomarker independently associated with survival. Markers of CNS barrier integrity, inflammatory mediators, and metabolomic signatures showed limited prognostic value but provided insights into metabolic remodeling and barrier dysfunction. In this integrated multi-omics study, serum NfL clearly outperformed inflammatory, metabolic, and CNS barrier markers as a prognostic biomarker in ALS, supporting its central role in clinical stratification while complementary biological markers highlighted several relevant pathophysiological mechanisms.}, }
@article {pmid42207631, year = {2026}, author = {Valenti, D and Joshi, V and Pankivskyi, S and Cai, HH and Hamon, L and Desforges, B and Molliex, A and Duez, J and Bursztyka, J and Davignon, L and Maucuer, A and Bollot, G and Pastré, D}, title = {RNA-binding protein diversity and NLS arginines regulate FUS mixing in mRNA-rich compartments.}, journal = {Cell reports}, volume = {45}, number = {6}, pages = {117430}, doi = {10.1016/j.celrep.2026.117430}, pmid = {42207631}, issn = {2211-1247}, abstract = {Despite being prone to condensation, many RNA-binding proteins (RBPs) do not form large condensates in cells. This issue is still widely researched, particularly because aggregation of RBPs, such as FUS, is the hallmark of some neurodegenerative diseases. Elevated RNA levels and protein chaperone activity have already emerged as key factors preventing aberrant phase separation. Here, we explored the role of RBP diversity in mRNA-rich condensates. While FUS and its partners form distinct compartments when probed one by one, increasing RBP diversity buffers FUS spatial segregation. In addition, we found that frequently mutated arginine residues in the nuclear localization signal (NLS) at the C-terminal end promote FUS mixing with multiple RBPs. Therefore, we anticipate that pathological NLS mutations in FUS not only alter its active nuclear import but also regulate FUS interactions with its partners in mRNA-rich compartments with putative consequences for the onset and progression of FUS-related neurodegenerative diseases.}, }
@article {pmid42207731, year = {2026}, author = {Queiroz, EM and Couto, CM and Ferreira, AR and de Souza, LC and Caramelli, P}, title = {Clinical presentation and diagnostic challenges of frontotemporal dementia in Brazil: A 15-year cohort study.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-23}, doi = {10.1159/000552730}, pmid = {42207731}, issn = {1423-0208}, abstract = {INTRODUCTION: Frontotemporal dementia (FTD) comprises heterogeneous neurodegenerative syndromes with limited data from low- and middle-income countries, where diagnostic delay and misdiagnosis are common.<br><br>METHODS: A retrospective cohort study was conducted of 190 patients with FTD meeting criteria for behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), or FTD-amyotrophic lateral sclerosis (FTD-ALS) who were evaluated at a publicly-funded Brazilian tertiary referral center (2009-2024). Clinical features, diagnostic trajectories, neuroimaging, genetic testing, and survival outcomes were analyzed. Standardized mortality ratios (SMRs) were calculated using IBGE 2017 life tables as a reference.<br><br>RESULTS: The cohort comprised 95 bvFTD (50.0%; 73 probable and 22 possible), 79 PPA (41.6%), and 16 FTD-ALS (8.4%) patients. Accurate initial diagnosis was achieved in only 15.8% of bvFTD patients and 17.7% of PPA patients, with Alzheimer's disease being the most common misdiagnosis (36.8% and 34.2%, respectively). Survival differed significantly between subtypes (p < 0.001), with FTD-ALS having the shortest median survival (79.0 months) compared with PPA (119.0 months) and bvFTD (144.0 months). Compared with PPA, FTD-ALS was associated with increased mortality risk (HR: 4.01; 95% CI: 1.94-8.31; p < .001). FTD patients had approximately twice the expected mortality for age- and sex-matched individuals in the general population (SMR: 1.97; 95% CI: 1.59-2.38), with the highest excess mortality in FTD-ALS patients (SMR: 4.08).<br><br>DISCUSSION: This Brazilian hospital-based cohort reveals alarming diagnostic delays despite typical clinical phenotypes and high mortality across all FTD subtypes relative to the general population. These findings highlight the need for improved FTD awareness and specialized training among healthcare providers in Brazil and similar Latin American countries, underscoring the value of hospital-based cohort studies in characterizing FTD in low- and middle-income countries.}, }
@article {pmid42210215, year = {2026}, author = {Paley, CA and Henderson, M and Freeman, S and Acosta, CR and Ziegler, L and Chapman, EJ}, title = {Adapting a brief mindful breathing intervention for self-management of distress in advanced cancer patients: the RESOLVE-i study.}, journal = {BMC palliative care}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12904-026-02148-3}, pmid = {42210215}, issn = {1472-684X}, support = {L412/YCR_/Yorkshire Cancer Research/United Kingdom ; L412/YCR_/Yorkshire Cancer Research/United Kingdom ; L412/YCR_/Yorkshire Cancer Research/United Kingdom ; L412/YCR_/Yorkshire Cancer Research/United Kingdom ; L412/YCR_/Yorkshire Cancer Research/United Kingdom ; L412/YCR_/Yorkshire Cancer Research/United Kingdom ; }, abstract = {BACKGROUND: Psychological distress is common among patients with advanced cancer and can be a barrier to effective symptom management. Despite national guidance, psychological support in UK palliative care remains limited. Existing interventions are frequently delivered by untrained staff lacking confidence. Adapting evidence-based interventions offers an efficient strategy to improve care. This study describes the adaptation of a brief mindful breathing intervention, originally developed in Malaysia, for self-management of distress by patients with advanced cancer in the UK.<br><br>METHODS: Using Moore et al.'s ADAPT framework, we followed four stages: Step 1: A systematic review (PROSPERO: CRD42022311729) established a rationale for adapting a brief mindful breathing intervention for distress in advanced cancer. Step 2: Semi-structured interviews with healthcare professionals (HCPs) explored acceptability, perceived utility, and integration into routine care. Step 3: A series of interviews with patients and carers informed the cultural and contextual iterative adaptation of the mindful breathing intervention and the development of accessible self-management resources. Step 4: A feasibility study was designed to assess acceptability, implementation, and to generate pilot data.<br><br>RESULTS: The systematic review supported the effectiveness of mindful breathing, though evidence found was context-specific to Malaysian clinical settings. HCPs endorsed integration into routine care but noted time constraints and concerns about information accessibility. Feedback from patients and carers informed several adaptations for self-management, including simplified language, inclusive imagery, removal of prescriptive instructions (e.g., breathing through the nose), and development of low-literacy resources. A video animation, infographic, and HCP training package were created to support implementation.<br><br>CONCLUSIONS: This stakeholder-informed adaptation resulted in a self-management mindful breathing intervention tailored for patients with advanced cancer in the UK. The intervention is now ready for feasibility testing and represents a scalable, resource-efficient strategy to enhance psychological support in palliative care, in line with NHS goals for community-based self-management.}, }
@article {pmid42210413, year = {2026}, author = {Tripathi, P and Guo, H and Yamoah, A and Mathur, R and Doukas, P and Dreser, A and Jesse, CM and Aronica, E and Hermann, A and Steinbusch, H and Brook, GA and Weis, J and Goswami, A}, title = {VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02298-8}, pmid = {42210413}, issn = {2051-5960}, abstract = {During the progression of amyotrophic lateral sclerosis (ALS), only specific motor neurons (MNs) preferentially deteriorate, while others are spared until the disease reaches its end stage. Resilient MNs possess several protective factors, yet the precise molecular mechanism(s) underlying selective neuronal vulnerability remains poorly understood. Vesicle-associated membrane protein (VAMP)-binding protein B (VAPB) is an endoplasmic reticulum (ER) protein involved in protein quality control (PQC) mechanisms, including unfolded protein response (UPR) as well as autophagy. A dominantly inherited P56S mutation in the VAPB gene has been linked to ALS8, atypical ALS, and late-onset spinal muscular atrophy (SMA). The P56S VAPB mutation causes ER-associated inclusions, disorganization, and ER stress, contributing to MN degeneration through toxic gain and loss of function. Over-expression of VAPB protein confers neuroprotection in a mouse model of ALS, and increased levels of neuronal VAPB inversely correlate with the absence of pathological aggregates. We hypothesize that VAPB is crucial for motor neuron survival by promoting autophagic degradation of ALS-associated aggregates, while lack of VAPB confers neuronal vulnerability. We analyzed the brain and spinal cord from sporadic (s) and familial (f) ALS patients, comparing patterns of VAPB immunoreactivity using immunohistochemistry, complemented by Western and dot blot analysis. Pathophysiological insights from these studies were further explored using cell culture models, including MNs derived from induced pluripotent stem cells (iPSCs). Consistent with our hypothesis we observed that MNs/neurons resistant to ALS exhibited elevated levels of VAPB and were devoid of pathogenic aggregates. Similarly, ALS-resistant oculomotor neurons showed increased VAPB immunoreactivity compared to normal controls. VAPB was often found to be sequestered within toxic aggregates alongside autophagy-related proteins in the lumbar spinal cord MNs. Notably, a compensatory increase in VAPB immunoreactivity was observed at the C-bouton synapse, suggesting a potential alternative mechanism of neuroprotection. Supporting these findings, in vitro experiments indicated that VAPB overexpression promoted autophagy and assisted in clearing ALS-associated RNA-binding protein aggregates. In summary, VAPB promotes selective neuronal survival by facilitating the autophagic clearance of toxic aggregates. Abnormal VAPB accumulations likely disrupt these neuroprotective processes.}, }
@article {pmid42211895, year = {2026}, author = {Yang, X and Yang, J and Li, R and Dong, H and Liu, Y}, title = {Peripheral immune cells and glycation indices as potential diagnostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {251}, number = {}, pages = {10987}, pmid = {42211895}, issn = {1535-3699}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/immunology ; *Biomarkers/blood ; Female ; Male ; Glycosylation ; Retrospective Studies ; Middle Aged ; Glycated Hemoglobin/analysis ; ROC Curve ; Monocytes ; Aged ; Leukocytes ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) mainly relies on clinical symptoms and the exclusion of other diseases, with a lack of specific biomarkers, leading to delayed diagnosis and a high rate of misdiagnosis. This study aims to explore the utility of peripheral immune cells and glycosylation indices as potential diagnostic biomarkers for ALS to enhance the accuracy and efficiency of early ALS diagnosis. This retrospective study included 54 ALS patients diagnosed in our hospital from June 2023 to October 2024, along with 54 healthy controls. Blood samples and laboratory data, including levels of peripheral immune cells and glycosylation indices, were collected from both groups. Through logistic regression, random forest models, receiver operating characteristic (ROC) curve analysis, and SHAP interpretability analysis, the predictive abilities and clinical significance of each candidate indicator were screened and evaluated. Notable disparities were detected in age, leukocyte count, monocyte levels, glycated haemoglobin A1c (HbA1c), and haemoglobin glycation index (HGI) between the control and ALS groups (all P < 0.05). Logistic regression analysis revealed that age (OR = 1.114) and monocyte (OR = 3.174) were risk factors for ALS, while leukocyte (OR = 0.533) and HbA1c (OR = 0.069) were protective factors. The random forest algorithm, ranked by decreasing importance, showed that leukocyte, HGI, monocyte, and HbA1c level all influenced ALS. Using these indicators to predict ALS resulted in a false-positive rate of 18% and a false-negative rate of 6%. ROC curve analysis indicated that the combined use of leukocyte, monocyte, HbA1c level, and HGI provided the highest diagnostic value for ALS (AUC = 0.774), which was higher than that of any individual indicator (all P < 0.05). SHAP analysis visualization demonstrated that increased monocyte and decreased leukocyte, HGI, and HbA1c level were all associated with an increased risk of ALS onset, ranked in descending order of feature importance as monocyte, leukocyte, HGI, and HbA1c. Peripheral blood white blood cells, monocytes, HbA1c, and HGI can serve as potential diagnostic biomarkers for ALS. Combined detection can improve the diagnostic accuracy of ALS, facilitating early diagnosis and intervention, and ultimately improving patient prognosis. Further validation in cohorts including disease controls is required to confirm specificity.}, }
@article {pmid42212627, year = {2026}, author = {Raymond, J and Larson, T and Mohidul, S and Martin-Greene, D and Love, K and Mehta, V and Wymer, J and Howard, I and Horton, DK and Mehta, P}, title = {Diagnostic differences between military veterans and non-veterans: data from the United States National ALS Registry.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2677528}, pmid = {42212627}, issn = {2167-9223}, abstract = {Background and Aim: Veterans in the U.S. have been reported to have a higher risk of developing amyotrophic lateral sclerosis (ALS) than the general population. However, it is unclear whether veterans experience differences in symptom recognition, diagnostic timing or access to care. This study examined differences reported in clinical characteristics and diagnostic trajectories between male veteran (MV) and non-veteran male (NVM) ALS patients enrolled in the U.S. National ALS Registry. Methods: We conducted a propensity score-matched analysis using self-administered military and clinical surveys from 2014 to 2024. Among 2,891 male ALS patients, MV were matched 1:1 with NVM on smoking history, birth year, head injury history, and region of residence at diagnosis. Outcomes included reported symptoms, time from symptom onset to diagnosis, and time to selected interventions. Results: Overall, 802 MV were matched to 802 NVM. Veterans were older at and reported longer intervals from symptom onset to ALS diagnosis (20.8 vs 16.7 months, p = 0.0004). MV were more likely to report difficulty swallowing and falls. Veterans were also more likely to use noninvasive breathing equipment (p = 0.0322). Findings from time-to-event analyses showed MV received wheelchairs or scooters statically earlier than NMV (log-rank p = 0.0028). Conclusions: Among participants in the Registry, MV reported differences in diagnostic timing, symptoms, and the use of supportive interventions compared to NVM. These findings may reflect differences in healthcare access, care pathways, and disease recognition over intrinsic differences in ALS biology. Because Registry participation is voluntary and data are self-reported, the result may not be generalizable to the broader ALS population.}, }
@article {pmid42212756, year = {2026}, author = {Zhou, L and Li, M and Dai, Q and Liu, X and Li, C and Jiao, H and Pan, H and Xu, R}, title = {5-Hydroxytryptamine Distribution Alteration in Both Neuron and Synapse of Tg(SOD1*G93A)1gur Mice: A Potential Intervention Candidate Strategy for Amyotrophic Lateral Sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {32}, number = {6}, pages = {e70946}, doi = {10.1002/cns.70946}, pmid = {42212756}, issn = {1755-5949}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20142BBG70062//Jiangxi Provincial Department of Science and Technology/ ; 20171BAB215022//Jiangxi Provincial Department of Science and Technology/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20212BAB216026//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202110016//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; 2024SSY06081//Jiangxi Province Key Laboratory of Neurology/ ; 2024A0159//Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; 20243BBI91030//Key Research and Development Project of Jiangxi Provincial Department of Science and Technology/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Serotonin/metabolism ; *Synapses/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Mice, Transgenic ; Mice ; *Neurons/metabolism/pathology ; Brain Stem/metabolism/pathology ; Receptor, Serotonin, 5-HT2A/metabolism ; Superoxide Dismutase-1/genetics ; Tryptophan Hydroxylase/metabolism ; Male ; Receptor, Serotonin, 5-HT1A/metabolism ; Disease Models, Animal ; Female ; Superoxide Dismutase/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; the precise pathogenesis of sporadic ALS (sALS) has not yet been elucidated up to now. Previous studies revealed that the abnormal alterations of some non-motor neurons (non-MN) were a potential pathogenesis of sALS. Therefore, this study aims to search the potential evidences of non-MN in the pathogenesis of ALS via exploring potential relationships between 5-hydroxytryptamine (5-HT) neurons and the development of ALS.<br><br>METHODS: We employed fluorescent immunohistochemistry to investigate the altered distribution patterns of 5-HT and tryptophan hydroxylase 2 in the spinal cord and brainstem of Tg(SOD1*G93A)1Gur (TG) and wild-type (WT) mice. Additionally, we used western blot to analyze the expression levels of 5-hydroxytryptamine receptor 1A (5-HTR1A) and 5-HTR2A.<br><br>RESULTS: Our findings revealed that 5-HT synapses were primarily distributed in the funiculus lateralis, anterior horn, posterior horn, central lateral column, and the area around the central canal of cervical, thoracic, and lumbar segments, and raphe nucleus as well as lateral paragigantocellular nucleus, and gradually reduced following age increase in WT mice. However, 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem gradually increased following the progression of disease and presented a significantly negative correlation between the increased distribution of 5-HT synapses and neurons and the reduction of neural cell number (positively correlated with the increase in neural cell death) at the onset and/or progression stage of TG mice. 5-HTR1A significantly increased, while 5-HTR2A significantly decreased at the onset stage of TG mice.<br><br>CONCLUSION: Our study speculated that the distribution changes of 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem play a potential protective role in the pathogenesis of sALS through a compensatory 5-HT increase.}, }
@article {pmid42212889, year = {2026}, author = {Sommers-Spijkerman, M and Müller, F and Kruitwagen-Van Reenen, E and Visser-Meily, JMA and Uitslag, R and Beelen, A}, title = {Understanding psychological adjustment in patients with amyotrophic lateral sclerosis and their caregivers: a scoping review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/21678421.2026.2671166}, pmid = {42212889}, issn = {2167-9223}, abstract = {OBJECTIVE: Psychological adjustment is a major focus in the care of people with amyotrophic lateral sclerosis (ALS) and their caregivers, given its critical role in maintaining quality of life (QoL). This scoping review aimed to gain a better understanding of ALS patients' and caregivers' psychological adjustment, to inform future care and research.<br><br>METHODS: PubMed, Web of Science, PsycINFO, Embase and CINAHL were searched for peer-reviewed studies reporting associations of psychological factors with patient/caregiver QoL. Psychological factors were categorized by type (cognitive, emotional or behavioral responses), and by strength (weak, moderate, strong) and direction (positive, negative) of their association with patient/caregiver QoL.<br><br>RESULTS: Twenty-nine studies were included, identifying twelve cognitive responses (hope, positive thinking/reframing, psychological flexibility, resilience, coping/pain self-efficacy, helplessness, hopelessness, pain catastrophizing, rumination, self-perceived burden, self-stigma), two emotional responses (emotional support, venting) and three behavioral responses (independence, positive action, substance use) associated with patient QoL. Five cognitive responses (resilience, mindfulness, hopelessness, passive reaction coping, psychological inflexibility) and one behavioral response (positive action) were found associated with caregiver QoL.<br><br>CONCLUSIONS: A range of cognitive, emotional and behavioral responses, most notably cognitive responses, were found to shape patient and/or caregiver psychological adjustment, hence may serve as potential targets in ALS clinical practice. Nonetheless, empirical evidence is limited by heterogeneity in outcomes and measures and a lack of longitudinal, multivariable, and caregiver-oriented research. More systematic, standardized and longitudinal data collection is needed to clarify how psychological adjustment processes evolve throughout the disease trajectory and to identify modifiable targets for psychological supportive care.}, }
@article {pmid42212970, year = {2026}, author = {Kallambettu, V and Maureen, F and Chapin, J and Hutcheson, K and Plowman, E}, title = {DIGEST Grades Remain Stable With Inclusion of Moderately Thickened Liquids in the Videofluoroscopic Examination in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-6}, doi = {10.1044/2026_JSLHR-25-00478}, pmid = {42212970}, issn = {1558-9102}, abstract = {PURPOSE: The Dynamic Imaging Grade of Swallowing Toxicity (Version 2; DIGESTV2) is a videofluoroscopy (VF) scale that measures pharyngeal swallowing severity based on functional measures of swallowing safety and efficiency. Original validation is based on a standard VF testing protocol including thin liquid, puree, and solid consistencies. Given that thickened liquid bolus trials are common in VF clinical testing protocols, we sought to determine the agreement in DIGESTV2 grades with and without the inclusion of moderately thick liquid bolus trials on DIGESTV2 outcomes in people with amyotrophic lateral sclerosis (pALS).<br><br>METHOD: This study represents a secondary analysis of VF examinations from a prospective longitudinal study conducted in 109 pALS. VF evaluations contained 10 barium trials spanning three International Dysphagia Diet Standardisation Initiative (IDDSI) levels (0-7). Duplicate, independent, and blinded ratings were completed. DIGESTV2 Efficiency and Safety grading was then completed under two conditions-with and without the inclusion of moderately thick liquid bolus trials into DIGESTV2 grading-to produce two sets of DIGESTV2 ratings for each VF study. Descriptives, percent agreement, and a weighted Cohen's kappa were performed on DIGESTV2 grades.<br><br>RESULTS: A total of 373 VF examinations were included in this analysis. DIGESTV2 grade percent agreement with and without IDDSI Level 3 was excellent for Safety (98.1%), Efficiency (93.8%), and Total (94.1%) grades. Kappa values for Safety, Efficiency, and Total grades were .96, .89, and .91, respectively, indicating excellent agreement across bolus trial inclusion methods.<br><br>CONCLUSIONS: Standard inclusion of moderately thick liquid bolus trials did not significantly impact DIGESTV2 grading in this data set. These results add to the preliminary but growing evidence suggesting stability of DIGEST grading with alternate bolus protocols in another patient population.<br><br>SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32348451.}, }
@article {pmid41987206, year = {2026}, author = {Zheng, M and Li, M and Liu, S and Guan, R and Liu, X}, title = {RNA-binding proteins: a comprehensive review of multifaceted regulatory mechanisms in neuroinflammation and implications in the pathogenesis of neurological disorders.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41987206}, issn = {1742-2094}, support = {82230063//National Natural Science Foundation of China/ ; }, abstract = {Neuroinflammation stands as a cornerstone pathological hallmark across a spectrum of neurological disorders, drawing intensified scientific scrutiny owing to its profoundly intricate and multi-layered regulatory networks. At the heart of this complexity, RNA-binding proteins (RBPs) emerge as masterful post-transcriptional orchestrators, exerting precise control over a vast array of neuroinflammatory cascades. Mounting evidence underscores that RBPs transcend their classical roles in RNA sensing and innate immune recognition, actively shaping pivotal biological pathways—ranging from inflammatory signal transduction and programmed cell death to metabolic reprogramming, epigenetic remodeling and dynamic crosstalk with non-coding RNAs. Furthermore, the functional versatility of RBPs is amplified by nuanced alterations in their nucleocytoplasmic trafficking, stress granule formation, post-translational modifications, and RNA-binding specificities, all of which intricately fine-tune their regulatory impact within the neuroinflammatory milieu. Strikingly, the cell type-specific actions of RBPs in neurons, microglia, and astrocytes unveil a sophisticated tapestry of molecular specialization, offering transformative insights into their context-dependent functions. Abnormal function of RNA-binding proteins is closely related to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, RNA-binding proteins are involved in various pathological processes, including central nervous system infections, stroke, high-altitude cerebral hypoxia, and traumatic brain injury. This review systematically organizes the multifaceted regulatory mechanisms of RNA-binding proteins in neuroinflammation. It deeply explores their key roles in the occurrence and development of nervous system diseases. The review aims to construct a comprehensive theoretical framework and provide a scientific basis for developing new diagnostic methods and targeted therapeutic strategies.}, }
@article {pmid42203724, year = {2026}, author = {Zeigler-Hill, V}, title = {Seeking significance from significant others: Rethinking romantic love.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e22}, doi = {10.1017/S0140525X25102203}, pmid = {42203724}, issn = {1469-1825}, mesh = {*Love ; Humans ; Narcissism ; Self Concept ; Object Attachment ; *Interpersonal Relations ; Models, Psychological ; }, abstract = {Kruglanski et al.'s model redefines love as a pathway to personal significance, offering a compelling new lens through which to understand romantic relationships. This commentary explores the model's implications for areas of the literature, including mate value, attachment styles, self-esteem, and narcissism. It also outlines promising directions for future research, emphasizing love's role in fulfilling the need to feel significant.}, }
@article {pmid42203737, year = {2026}, author = {Fowers, BJ}, title = {Are merit and appreciation instrumental aims?.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e10}, doi = {10.1017/S0140525X25102264}, pmid = {42203737}, issn = {1469-1825}, mesh = {Humans ; *Love ; }, abstract = {This commentary responds to Kruglanski et al.'s paper, which theorizes that love is one means that can result in significance. The commentary's first focus is whether love is well conceptualized as an instrumental activity (a means-end relation) and concludes that a constitutive-ends conceptualization is necessary (love helps to constitute significance). Secondly, the evidence base for their hypotheses appears thin.}, }
@article {pmid42203744, year = {2026}, author = {Boudesseul, J and Cova, F and Lantian, A}, title = {Beyond the equation: An evolutionary reassessment of the love formula.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e4}, doi = {10.1017/S0140525X25102276}, pmid = {42203744}, issn = {1469-1825}, mesh = {Humans ; *Love ; *Biological Evolution ; *Sexual Behavior/psychology ; }, abstract = {Kruglanski et al.'s love formula - partner merit, appreciation, and the quest for meaning - offers a novel perspective but overlooks key evolutionary insights. It oversimplifies mating preferences, neglects contextual flexibility, and downplays reproductive signals crucial to partner selection. While innovative, the model fails to account for the complexity of human romantic behavior shaped by ecological, social, and developmental factors.}, }
@article {pmid42203747, year = {2026}, author = {Esch, T}, title = {What's love got to do with it? The formula for love needs psychological and motivational neurobiological components.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e7}, doi = {10.1017/S0140525X25102227}, pmid = {42203747}, issn = {1469-1825}, mesh = {*Love ; Humans ; *Motivation/physiology ; *Brain/physiology ; }, abstract = {Kruglanski et al.'s love model rightly highlights motivation and meaning as core to love, aligning with current research. However, this commentary expands the view, emphasizing love's biological basis in brain systems and evolving different types of motivation. Love fulfills both individual and species-level needs, promoting health, connection, and generativity. True love transcends ego, growing into unconditional, spiritually rich connectedness over time.}, }
@article {pmid42203750, year = {2026}, author = {Van Dessel, P and Boddez, Y}, title = {Extending the motivational model of love: A Goal-Directed Predictive Processing perspective.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e19}, doi = {10.1017/S0140525X25102161}, pmid = {42203750}, issn = {1469-1825}, mesh = {*Love ; Humans ; *Goals ; *Motivation ; *Models, Psychological ; }, abstract = {We extend Kruglanski et al.'s model by embedding it within a Goal-Directed Predictive Processing framework. This perspective conceptualizes romantic love as arising from self-referential inferences tied to personal goals and reveals that love may include merit, appreciation, and significance, but is not defined or limited by them. It also explains love experiences that exceed the scope of the authors' model.}, }
@article {pmid42203757, year = {2026}, author = {Lucchi Basili, L and Sacco, PL}, title = {Significance is not enough: The biopsychological foundations of romantic love.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e2}, doi = {10.1017/S0140525X25102318}, pmid = {42203757}, issn = {1469-1825}, mesh = {Humans ; *Love ; Female ; Male ; Emotions/physiology ; }, abstract = {Kruglanski et al.'s significance-based model overlooks fundamental biopsychological mechanisms driving romantic love. The Tie-Up Theory reveals how women's subconscious biological compatibility assessments through physical, chemical, and behavioral signals operate independently of conscious significance calculations. Their gender-neutral framework ignores how men's receptive emotional orientation differs from women's active emotional competence. By reducing love to significance enhancement, the model cannot explain irrational attractions, persistent relationships despite low "merit," or gendered dissolution patterns determined by reward cycle breakdowns.}, }
@article {pmid42188687, year = {2026}, author = {Fajkić, A and Belančić, A and Pilipović, K and Rački, V and Mežnarić, S and Janković, T and Gkrinia, EMM and Vitezić, D and Mršić-Pelčić, J}, title = {Nanotube-Assisted Motor Neuron and Neuromuscular Junction Stabilization in Spinal Muscular Atrophy: A Hypothesis for Adjunctive Therapy.}, journal = {Neurology international}, volume = {18}, number = {5}, pages = {}, pmid = {42188687}, issn = {2035-8385}, abstract = {Spinal muscular atrophy (SMA) therapies that restore SMN expression improve survival and motor function but often fail to fully stabilize distal motor units or sustain endurance. We propose a hypothesis-driven adjunctive approach, intended to complement SMN-restoring therapies, in which localized nanotube-enabled interfaces acting at or near the distal motor unit and neuromuscular junction enhance neuromuscular transmission reliability in surviving, remodeled motor units. The model predicts a temporal cascade: improved junctional reliability and reduced activity-dependent failure, followed by consistent motor unit output across repeated activation, and ultimately, enhanced endurance and functional reserve. Phenotype-specific responsiveness identifies patients most likely to benefit, specifically those with preserved-but-limited residual motor unit substrate accompanied by measurable neuromuscular junction instability. Drawing on shared mechanisms from ALS, spinal cord injury, and other neuromuscular disorders, we discuss mechanistic, translational, safety, regulatory, and ethical considerations. This framework links objective physiological constructs to functional outcomes, offering a mechanistically grounded path for adjunctive therapy development in SMA and related conditions.}, }
@article {pmid42189100, year = {2026}, author = {Lockhart, ENS}, title = {Cybernetic Feedback: an Apt Realignment of Batterham et al.'s Three-Body Problem of Suicide (2025).}, journal = {Journal of evaluation in clinical practice}, volume = {32}, number = {4}, pages = {e70487}, doi = {10.1111/jep.70487}, pmid = {42189100}, issn = {1365-2753}, }
@article {pmid42190746, year = {2026}, author = {Zheng, P and Chen, L}, title = {Comments on Wu et al's "The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.126}, pmid = {42190746}, issn = {1097-6787}, }
@article {pmid42190754, year = {2026}, author = {Wu, X and Wang, X and Zhang, Z}, title = {Response to Chen et al., "Comments on Wu et al's "The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.05.061}, pmid = {42190754}, issn = {1097-6787}, }
@article {pmid42190894, year = {2026}, author = {Oriquat, G and Abdulqader, AF and Farid, H and Ashurov, Z and Sottarov, A and Ghafl, NY and Bainsal, N and Singh, R}, title = {From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation.}, journal = {Brain research bulletin}, volume = {241}, number = {}, pages = {111963}, doi = {10.1016/j.brainresbull.2026.111963}, pmid = {42190894}, issn = {1873-2747}, abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of the innate immune system designed to combat pathogens, is now implicated as a critical driver of sterile inflammation in the brain. This review synthesizes compelling evidence that in the aging and diseased central nervous system, endogenous cytosolic DNA, sourced from genomic instability, mitochondrial dysfunction, and activated retrotransposons, hijacks this pathway. Chronic cGAS-STING activation transforms microglia into inflammatory amplifiers, instigates neurotoxic astrocyte programs, and directly compromises neuronal health, creating a self-perpetuating cycle of neuroinflammation. We dissect the cell-type specific consequences within the neurovascular unit and establish the pathway's role in the pathogenesis of ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. Crucially, we evaluate the therapeutic potential of targeting this axis, discussing small-molecule inhibitors, oligonucleotide therapies, and upstream interventions to quell the source of immunogenic DNA. We also explicitly examine contradictory preclinical data, including the retracted PINK1-Parkin-STING report and context-dependent neurovascular findings, to provide a balanced appraisal of STING biology in the CNS. By reconciling its dual protective and pathogenic roles, this review posits cGAS-STING as a pivotal mechanism-based therapeutic node for halting the progression of neurodegenerative disorders.}, }
@article {pmid42191539, year = {2026}, author = {Pérez-Bonilla, M and Díaz-Borrego, P and Mora-Ortiz, M and Mayordomo-Riera, FJ and Girela-López, E}, title = {Discovering Hidden Vocal Subtypes: An Unsupervised Acoustic-Biomechanical Exploration of Voice Profiles.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.05.002}, pmid = {42191539}, issn = {1873-4588}, abstract = {OBJECTIVE: This study aims to explore latent acoustic-biomechanical patterns of voice production using an unsupervised multivariate approach, and to identify data-driven vocal profiles across individuals with amyotrophic lateral sclerosis (ALS) and nonneurological dysphonia.<br><br>METHODS: A cross-sectional sample of 100 individuals, including patients with ALS&#xa0;and individuals with nonneurological dysphonia, was analyzed. Sustained vowel phonation was recorded and characterized using 26 variables, including standard acoustic measures (fundamental frequency -fo-, jitter, shimmer, and harmonics-to-noise ratio (HNR)) and 22 biomechanical parameters. Principal component analysis&#xa0;was applied to investigate relationships among variables and reduce dimensionality. Unsupervised clustering was performed at both the variable level to identify functional groupings and the participant level to derive data-driven voice profiles. Cluster validity was assessed using internal indices. Post hoc statistical comparisons and chi-square tests were used descriptively to characterize between-cluster differences and their relationship with clinical categories.<br><br>RESULTS: The first five principal components explained 70.7% of the total variance, revealing structured relationships between acoustic and biomechanical features. Participant level clustering consistently supported a two-profile solution. Fifteen voice parameters differed significantly between profiles after false discovery rate correction, with the largest effects observed for shimmer, HNR, and the biomechanical parameter Pr11, reflecting differences in vocal stability and noise-related characteristics. The identified profiles were not significantly associated with clinical diagnostic categories.<br><br>CONCLUSIONS: An unsupervised multimodal analysis of sustained phonation revealed two coherent vocal profiles that transcend traditional diagnostic labels. These data-driven voice phenotypes may capture functional patterns of voice production and support future efforts toward more refined and personalized characterization of voice disorders.}, }
@article {pmid42191846, year = {2026}, author = {Zhang, J and Tian, M and Niu, T and Li, R and Liu, Q and Liu, M and Zhou, X and Dong, H and Liu, Y}, title = {The role of adiponectin and cytokines in Amyotrophic lateral sclerosis: assessment of disease progression and survival status.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-54291-9}, pmid = {42191846}, issn = {2045-2322}, support = {H2023206055//Key Project of Natural Science Foundation of Hebei Province/ ; 20240391//Scientific Research Foundation of Health Commission of Hebei Province/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder. ALS typically progresses rapidly, leading to respiratory failure within 3 to 5 years of symptom onset. Identifying risk factors that influence disease progression and survival is critical for enhancing management strategies. The present study therefore investigated the roles of inflammatory factors and adipokines (especially adiponectin) in the progression and prognosis of ALS. The study included 80 ALS patients, with a follow-up period of 1.5 years. Survival analysis was performed using a Cox regression, with hazard ratios (HR) and 95% confidence intervals (CI) presented via forest plots. Our results indicated that ALS patients in the fast-progressing group exhibited lower levels of adiponectin (p < 0.001) and IL-10 (p < 0.001). The Cox regression and forest plot results suggest the potential of adiponectin (HR = 0.905, 95%CI: 0.866-0.946, p < 0.001), IL-10 (HR = 0.968, 95%CI: 0.951-0.986, p < 0.001), δFS (HR = 1.234, 95%CI: 1.065-1.430, p = 0.005) and ALSFRS-R (HR = 0.820, 95%CI: 0.765-0.878, p < 0.001) as potential risk factors. In addition, these risk factors are significantly associated with poor survival prognosis in high-risk populations (all p < 0.001). This study identifies adiponectin, IL-10, ALSFRS-R, and δFS as key risk factors influencing ALS progression and prognosis.}, }
@article {pmid42191932, year = {2026}, author = {Heckmann, JM and Floudiotis, N and Makanjuola, A and Ogunniyi, A and Mochan, A and Mongwe, RR and Sokhi, DS and Nel, M}, title = {Motor neuron disease in Africa: a critical appraisal of the literature.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42191932}, issn = {1759-4766}, abstract = {Motor neuron disease (MND) refers to a group of neurodegenerative diseases that cause motor neuron degeneration and death. The most common subtype, amyotrophic lateral sclerosis (ALS), is characterized by both upper and lower motor neuron impairment, which can manifest clinically in the bulbar region or asymmetrically in a limb. Typically, the disease progresses over several months, and death from respiratory failure occurs within 2-5 years of onset. As we highlight in this Review, data on MND in Africa are sparse, although common observations in this region - and in other populations with relatively low life expectancy - include apparent earlier disease onset and lower disease incidence compared with the rest of the world. In view of the HIV epidemic in Africa, we critically examine the evidence for an association between ALS and HIV infection. We briefly discuss conditions that might be regarded as ALS mimics and summarize the limited data on MND genetics in this region. Other issues pertinent to people living with MND in Africa include the absence of cognitive and behavioural data and the limited access to multidisciplinary clinics, therapies and palliative care. We share our perspective on how the ALS Africa Network is coordinating a shift in the African MND landscape to improve patient care.}, }
@article {pmid42192558, year = {2026}, author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B}, title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.}, journal = {Animal models and experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/ame2.70226}, pmid = {42192558}, issn = {2576-2095}, support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.}, }
@article {pmid42192595, year = {2026}, author = {Liu, Y and Wu, W}, title = {Clinical Value and Research Prospects of 1024 Matrix Optimization in 64-Slice Cerebral CTA for Perforating Artery Visualisation.}, journal = {Journal of medical radiation sciences}, volume = {}, number = {}, pages = {}, doi = {10.1002/jmrs.70101}, pmid = {42192595}, issn = {2051-3909}, abstract = {This letter comments on Nagumo et al.'s study evaluating 1024-matrix reconstruction for intracranial perforating artery visualisation in 64-slice cerebral CTA, affirming its cost-effective value for standard CT scanners (https://doi.org/10.1002/jmrs.70055). We endorse the key finding that 1024-matrix improves small artery detection via higher sampling density, while highlighting the need for cross-vendor validation, workflow impact quantification, and clinical outcome assessment. This simple post-processing strategy is highly scalable, and further multicentre studies are warranted to confirm its universal utility.}, }
@article {pmid42193936, year = {2026}, author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK}, title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.}, journal = {Cells}, volume = {15}, number = {10}, pages = {}, doi = {10.3390/cells15100928}, pmid = {42193936}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.}, }
@article {pmid42194069, year = {2026}, author = {Malá, P and Váňová, N and Malý, O and Vyšata, O}, title = {Oxidative-Nitrosative Stress and Routine Biochemical Parameters in Amyotrophic Lateral Sclerosis: Associations with Clinical Status and Disease Duration-A Pilot Study.}, journal = {Biomolecules}, volume = {16}, number = {5}, pages = {}, doi = {10.3390/biom16050721}, pmid = {42194069}, issn = {2218-273X}, support = {Cooperatio Program, research area NEUR//Charles University/ ; Grant No. DRO-UHHK 00179906//Ministry of Health of the Czech Republic/ ; }, mesh = {Humans ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; *Nitrosative Stress ; *Oxidative Stress ; Female ; Biomarkers/blood ; Middle Aged ; Male ; Tyrosine/analogs &amp; derivatives/blood ; Aged ; 8-Hydroxy-2'-Deoxyguanosine/blood ; Glutathione/blood ; Malondialdehyde/blood ; }, abstract = {BACKGROUND: This pilot study examined whether oxidative-nitrosative stress is associated with clinical status in amyotrophic lateral sclerosis (ALS). We analyzed associations between plasma markers of oxidative-nitrosative imbalance and ALSFRS-R, disease duration, survival, and routine biochemical parameters.<br><br>METHODS: Twenty-nine ALS patients fulfilling the Gold Coast diagnostic criteria were enrolled. Plasma levels of 3-nitrotyrosine (3-NT), 8-oxo-2'-deoxyguanosine (8-oxodG), malondialdehyde (MDA), glutathione (GSH), non-protein thiols (NP-SH), and non-protein disulfides (NP-SS-NP), as well as creatinine, urea, uric acid and BMI, were measured. Associations with ALSFRS-R and disease duration were evaluated using non-parametric correlation analyses and second-order polynomial regression (adjusted R[2]), while survival was explored using Kaplan-Meier analysis and multivariable Cox regression. Given the modest sample, we considered statistical power and applied Benjamini-Hochberg false discovery rate (FDR) correction within marker families.<br><br>RESULTS: At the uncorrected significance level, 3-NT showed a positive correlation with ALSFRS-R and a negative correlation with disease duration, and NP-SH correlated negatively with disease duration; however, these associations did not remain significant after FDR correction (FDR-adjusted p &#x2265; 0.099). Other oxidative-nitrosative markers and biochemical parameters showed no robust relationships with clinical measures. In Cox models, 3-NT was not significantly associated with survival (HR 3.44 per 1 nM, 95% CI 0.25-47.97, p = 0.358), whereas older age predicted higher mortality (HR 1.05 per year, 95% CI 1.00-1.10, p = 0.036).<br><br>CONCLUSIONS: 3-NT and NP-SH exhibited the strongest trends among the investigated markers, but their clinical associations in this small cross-sectional cohort remain exploratory and require confirmation in larger longitudinal studies.}, }
@article {pmid42194544, year = {2026}, author = {Nord-Bronzyk, A and Ng, B and Lan, T and Schaefer, GO and Takahashi, S}, title = {Guiding Policymakers Toward Better AI Ethics Integration in Healthcare Regulation-Lessons from Singapore.}, journal = {Journal of clinical medicine}, volume = {15}, number = {10}, pages = {}, doi = {10.3390/jcm15103576}, pmid = {42194544}, issn = {2077-0383}, support = {MOH-000951-00//Ministry of health singapore/ ; }, abstract = {In terms of rollout, comprehensiveness, and strategy, Singapore's regulatory landscape governing the ethical use of Artificial Intelligence (AI) in healthcare has generally kept pace with other global leaders in AI advancement. However, establishing a robust and holistic regulatory framework that evolves along with emerging technologies is not easy-especially in healthcare, where the stakes are high and resources may be limited. We conducted a structured scoping analysis of key AI regulatory and professional documents in Singapore, selected using predefined inclusion criteria. Documents were systematically mapped against Savulescu et al.'s nine categories of ethical risk, followed by cross-document comparison to identify integration gaps and inconsistencies, and benchmarking against international AI governance frameworks. These recommendations are generalizable beyond Singapore for developers, implementers, healthcare professionals and patients and include dealing with bias in AI, enhancing human productivity without deskilling, facilitating more informed decision-making, and cultivating greater knowledge exchange between clinicians and patients, to name a few.}, }
@article {pmid42195033, year = {2026}, author = {Richard, E and Al-Hajj Vourc'h, S and Marouillat, S and Beltran, S and Blasco, H and Corcia, P and Vourc'h, P}, title = {From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {17}, number = {5}, pages = {}, doi = {10.3390/genes17050576}, pmid = {42195033}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Penetrance ; *Mutation ; Superoxide Dismutase-1/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Genetic Counseling ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS.}, }
@article {pmid42196191, year = {2026}, author = {Giordano, A and Mandrioli, J and Cerri, F and Lunetta, C and Saebfar, H and Catania, M and Battipaglia, C and Leone, L and Trojsi, F and Vizziello, M and Gerardi, F and Farè, M and Zulueta, A and Piras, R and Giacchino, M and Gianferrari, G and Dalla Bella, E and Domi, T and Bonanomi, D and Ganci, G and Lombardi, R and Lauria, G and Riva, N}, title = {Longitudinal CSF and Serum Biomarker Dynamics in Tofersen-Treated SOD1-ALS: A Real-World Multicentre Cohort Study.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, doi = {10.3390/ijms27104208}, pmid = {42196191}, issn = {1422-0067}, support = {IDEALS//AriSLA/ ; RF-2021-12373036//Ministero della salute Ricerca Finalizzata bando 2021/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; Giovanni Marazzina Project//Giovanni Marazzina Foundation/ ; }, mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/blood/cerebrospinal fluid/genetics ; Longitudinal Studies ; tau Proteins/blood/cerebrospinal fluid ; Ubiquitin Thiolesterase/blood/cerebrospinal fluid ; Male ; Glial Fibrillary Acidic Protein/blood/cerebrospinal fluid ; Middle Aged ; Neurofilament Proteins/blood/cerebrospinal fluid ; Retrospective Studies ; Aged ; }, abstract = {Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL-1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL-1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL-1 also showed increases during follow-up. ALS Functional Rating Scale-Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL-1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.}, }
@article {pmid42196458, year = {2026}, author = {Prodromos, CC and Del Villar, R and Striegel, A and Pena, G and Dixit, R}, title = {The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, doi = {10.3390/ijms27104483}, pmid = {42196458}, issn = {1422-0067}, mesh = {Humans ; *Exosomes/metabolism/transplantation ; *Amyotrophic Lateral Sclerosis/therapy/metabolism ; *Parkinson Disease/therapy/metabolism ; Female ; Male ; *Lewy Body Disease/therapy/metabolism ; Aged ; *Mesenchymal Stem Cells/metabolism ; Middle Aged ; *Secretome/metabolism ; Case-Control Studies ; Administration, Intranasal ; }, abstract = {Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson's disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up.}, }
@article {pmid42197088, year = {2026}, author = {Herrmann, C and Satari, S and Weber, A and Ruschitzka, T and Jagodzinski, L and Elmas, Z and Becker, F and Richter, L and Wiesenfarth, M and Michels, S and Weishaupt, JH and Schuster, J and Dorst, J}, title = {Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis-A Dose-Finding Case Series.}, journal = {Nutrients}, volume = {18}, number = {10}, pages = {}, doi = {10.3390/nu18101628}, pmid = {42197088}, issn = {2072-6643}, support = {N/A//Nutricia (Germany)/ ; N/A//KetoneAid/ ; N/A//KetoForce/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/blood ; *Diet, Ketogenic/methods/adverse effects ; Female ; Male ; Middle Aged ; Feasibility Studies ; Aged ; Adult ; 3-Hydroxybutyric Acid/blood/administration &amp; dosage ; Ketone Bodies/administration &amp; dosage/blood ; Treatment Outcome ; }, abstract = {Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce[®] (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4[®] (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal[®] 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2-2.7 mmol/L vs. 0.8-1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative.}, }
@article {pmid42197516, year = {2026}, author = {Tavares, GC and Carneiro, SP and Barbanti, ACC and Rosário, AECD and Matos, HC and Maia, CRMDS and Costa, HL and Egger, RC and Nogueira, LFF and Rosa, JCC and Pereira, FL and Pilarski, F and Gallani, SU and Soto, E and Leal, CAG and Figueiredo, HCP}, title = {Multilocus Sequence Typing Reveals New Insights into the Population Structure and Genetic Diversity of Lactococcus spp. from Brazilian Fish.}, journal = {Microorganisms}, volume = {14}, number = {5}, pages = {}, doi = {10.3390/microorganisms14051131}, pmid = {42197516}, issn = {2076-2607}, support = {88881.200614/2018-01//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; APQ-01227-22, APQ-04309-22 and PPM-00779-18//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; 01.02.016301.03071/2022-11//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado do Amazonas/ ; }, abstract = {Lactococcosis has emerged as an economically and ecologically significant disease in aquatic animals worldwide. This study employed multilocus sequence typing (MLST) to investigate the genetic diversity of Lactococcus spp. strains from Brazilian fish species and evaluate their phylogenetic relationships with global isolates to elucidate potential epidemiological connections involving multiple host species and distinct geographic regions. A total of 55 isolates from different laboratories had their DNA extracted, followed by the amplification and sequencing of the internal fragments of seven housekeeping genes (als, atpA, tuf, gapC, gyrB, rpoC and galP). Sequence types (STs) and clonal complexes (CCs) were defined. An unrooted neighbor-joining phylogenetic tree was generated using allele profiles from this study and those previously reported from other aquatic animal species. The isolates comprised 29 STs (11 previously reported, 18 novel ones), which were grouped into species-specific CCs: CC5 (L. formosensis); CC4, CC17, CC62 (L. garvieae); CC24, CC29, CC97 (L. petauri). Considerable genetic divergence was observed, with L. formosensis and L. garvieae forming heterogeneous populations, while L. petauri was more homogeneous. These findings describe the MLST structure of the sampled isolates and should be interpreted as hypothesis-generating rather than population-level estimates of genotype prevalence. Phylogenetics confirmed groupings within the CCs and revealed additional phylogenetic clustering patterns. In conclusion, the Brazilian Lactococcus spp. strains analyzed in this study constitute a genetically diverse population based on their STs. MLST and phylogenetic analysis demonstrated genetic relatedness between the L. garvieae and L. formosensis isolates from this study and those from other aquatic animal species. In contrast, all the STs identified for L. petauri in this study were unrelated to the MLST lineages responsible for outbreaks in Brazilian Nile tilapia (Oreochromis niloticus) and North American rainbow trout (Oncorhynchus mykiss). This suggests that piscine L. petauri populations in the Americas evolved from distinct ancestral origins.}, }
@article {pmid42198024, year = {2026}, author = {Aminfar, K and Scafide, K and Wojtusiak, J and Lattanzi, D}, title = {Evaluation Framework for Bruise Detection: Systematic ALS/White-Light Training and Skin-Tone Balancing with Deep Learning.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {10}, pages = {}, doi = {10.3390/s26103215}, pmid = {42198024}, issn = {1424-8220}, support = {1625039//National Science Foundation/ ; 2018631//National Science Foundation/ ; 15PNIJ-21-GG-04145-SLFO//National Institute of Justice/ ; }, mesh = {Humans ; *Deep Learning ; *Contusions/diagnosis/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Forensic Imaging ; *Skin Pigmentation/physiology ; Algorithms ; Lighting ; }, abstract = {Accurate and consistent forensic bruise assessment is critical in ensuring positive clinical and legal outcomes for victims of violence. In this study, a framework for automated bruise detection is presented that, for the first time, integrates narrowband alternate-light-source (ALS) forensic imaging and ambient white light imaging. This evaluation framework is designed to address long-standing issues with respect to equitable performance across skin tones and lighting scenarios via a combination of novel model diagnostic strategies. In particular, skin-tone balancing during training and testing, threshold-sensitivity analysis, and embedding-similarity partitioning are employed to quantify the model robustness and deployment trade-offs that arise in forensic image analysis. Models were implemented with ImageNet-pretrained backbones and trained on a unique, multi-annotator full-consensus dataset comprising both white-light and ALS (415 nm and 450 nm) images. The protocol emphasizes three axes of operational relevance: (1) illumination composition in training (W/ALS ratio); (2) subgroup fairness via targeted balancing; and (3) model operating-point selection (confidence and IoU thresholds) informed by confidence-stability metrics and bootstrapped uncertainty estimates. Systematic W/ALS ratio sweeps indicate peak accuracy under ALS-dominant training and declining performance as the proportion of white-light images increases within the training set. Skin-tone balancing reduced failure rates for darker skin tones but increased overprediction in some demographic subgroups. Embedding-similarity and seen/unseen injury analyses demonstrate inflated generalization under image-level partitioning. Ultimately, the findings suggest that future researchers and developers should employ injury-level data partitioning and ensure a weighted balance of ALS images during training.}, }
@article {pmid42199117, year = {2026}, author = {Zhou, Q and Gong, T and Liu, J and Ma, J and Zheng, M and Zhong, Z and Deng, H and Lin, H and Feng, N and Lei, X and Zhang, C}, title = {An integrated single-nucleus ribonucleic acid sequencing and spatial transcriptomic atlas reveals stage-specific neuronal and glial trajectories in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00859}, pmid = {42199117}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a progressive multifocal neurodegenerative condition involving motor neurons and other cell types. To analyze spatiotemporal cellular dynamics in amyotrophic lateral sclerosis, we performed single-nucleus ribonucleic acid sequencing and spatial transcriptomics analysis of cervical spinal cords from wild-type control mice and SOD1-G93A transgenic mice in the pre-symptomatic (d50), early symptomatic (d90), and late-stage (d130) phases of disease. Single-nucleus ribonucleic acid sequencing identified 17 cell clusters and showed that progressive neuronal loss occurred over time, paralleled by glial expansion. Spatial transcriptomics mapped these clusters anatomically onto oligodendrocytes in white matter, neurons in horns, and diffuse astrocytes/microglia. Subcluster analysis demonstrated neuronal heterogeneity, with early mitochondrial stress in ventral motor neurons evolving into synaptic dysfunction, transient maturation peaks in interneurons, and amplified age-related decline in amyotrophic lateral sclerosis. Astrocyte and oligodendrocyte subclusters, which were originally misclustered due to spot-level contamination, were reinterpreted to highlight A1-reactive states and progenitor expansions, validated by immunohistochemistry detection of serum/glucocorticoid regulated kinase 1. Temporal profiles tracked the transition from compensatory to inflammatory gliosis, while gene signatures were linked to human amyotrophic lateral sclerosis cohorts, including complement activation and mitochondrial dysfunction. This study provides a high-resolution spatiotemporal cellular map of amyotrophic lateral sclerosis pathogenesis through the integration of single-nucleus and spatial transcriptomics, uncovering early mitochondrial impairment in neurons, delineating the trajectory of neurotoxic glial states, and identifying compensatory progenitor responses, to highlight the highly intricate interaction between glial reactivity and neuronal susceptibility that drives the pathogenesis of ALS.}, }
@article {pmid42199142, year = {2026}, author = {Gerbino, V}, title = {Targeting the type-I interferon response in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-26-00133}, pmid = {42199142}, issn = {1673-5374}, }
@article {pmid42200208, year = {2026}, author = {Peerbhai, N and Ramsunder, N and Europa, T and Heckmann, J and Nel, M}, title = {Expanding African contributions to ClinVar through genetic counselor-led variant curation.}, journal = {Journal of genetic counseling}, volume = {35}, number = {3}, pages = {e70235}, doi = {10.1002/jgc4.70235}, pmid = {42200208}, issn = {1573-3599}, support = {226519/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Genetic Counseling ; *Genetic Variation ; *Databases, Genetic ; African People ; *Black People/genetics ; *Data Curation ; }, abstract = {Global variant databases such as ClinVar are vital in linking genetic variation to clinical significance and enabling shared interpretation across laboratories. However, African genetic variants remain underrepresented, comprising under 2% of global ClinVar submissions. This gap reflects inequities in access to genome sequencing, workforce capacity, and data-sharing systems, which limit visibility, contextual interpretation, and re-evaluation of African genetic variation. We describe our experiences of genetic counselor-led variant curation, ClinVar submissions, and ongoing monitoring of germline genetic variants identified in African neuromuscular and amyotrophic lateral sclerosis research cohorts. Between March 2023 and August 2025, the Clinical Omics and Informatics Unit (University of Cape Town) submitted 93 DNA sequence variants to ClinVar spanning 58 genes, including 27 first-time submissions to the database. ClinVar submissions require valid Monarch Disease Ontology (Mondo) identifiers; gaps or inaccuracies were identified (n = 3) and updated, or Mondo disease entities were created to ensure gene-disease pairs were correctly represented. Using African Genome Variation Database frequencies to guide variant classification provided sub-regional context, highlighting population differences and refining interpretations. Furthermore, we maintained a structured follow-up of variant records using ClinVar's "follow" feature. This enabled passive monitoring of new submissions or classification changes, which were evaluated to assess whether reinterpretation or resolution of variants of uncertain significance or those with conflicting assertions were warranted. This work highlights the critical role that African genetic counselors can play as contributors to variant curation in an underrepresented geography, given their expertise in human genetics and clinical reasoning. By embedding African-specific frequency data and locally trained expertise into variant curation pipelines, a sustainable, equity-driven model for genomic knowledge production in Africa is developed. African-led ClinVar contributions can strengthen interpretative accuracy, foster collaborative curation, and position genetic counselors as active agents in global genomic data sharing and interpretation.}, }
@article {pmid42200920, year = {2026}, author = {An, Y and Lan, H and Xiong, J and Jing, R and Gu, D and Zhang, H and Liu, X and Zhao, Q and Wang, F}, title = {From Axonal Growth to Neurodegeneration: The Dual Role of Neurofilament Dynamics in Health and Disease.}, journal = {NeuroSci}, volume = {7}, number = {3}, pages = {}, doi = {10.3390/neurosci7030058}, pmid = {42200920}, issn = {2673-4087}, support = {ZR2025MS434//Natural Science Foundation of Shandong Province/ ; }, abstract = {Neurofilaments (NFs) are the predominant type IV intermediate filaments in differentiated neurons, functioning not just as static scaffolds, but as active drivers of radial axonal growth and nerve conduction velocity. While their physical properties are well characterized, a critical gap remains in synthesizing how their dynamic assembly and developmental subunit switching directly dictate neurodegenerative outcomes. This review breaks down the molecular architecture and stepwise kinetic assembly of NFs, detailing their role in polarized transport and the formation of a protective viscoelastic gel network within axons. We specifically highlight the physiological expression switching of early subunits, such as alpha-internexin and peripherin, during neuronal maturation, a process often overlooked in traditional structural reviews. By examining how specific gene mutations and aberrant hyperphosphorylation trigger axonal transport jams and protein aggregation, we map the direct pathways leading to amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease. Finally, we emphasize that a precise mechanistic decoding of NF structural dynamics and their pathological disruption is essential for understanding the fundamental etiology of these neurodegenerative conditions.}, }
@article {pmid42201810, year = {2026}, author = {Gibbons, GM and Fuchsberger, T and Abdelgawad, M and Giandomenico, SL and Szebényi, K and Petrova, V and Wenger, LMD and Olschewski, DN and Chabros, J and Muresan, L and Feord, RC and Asif, M and Fawcett, JW and Mierau, SB and Paulsen, O and Lancaster, MA and Lakatos, A}, title = {A human corticospinal organoid-slice connectoid model informs enhancer strategies for post-injury axon regrowth.}, journal = {Cell reports}, volume = {45}, number = {6}, pages = {117399}, doi = {10.1016/j.celrep.2026.117399}, pmid = {42201810}, issn = {2211-1247}, abstract = {Axon elongation in the mammalian central nervous system (CNS) declines during development, limiting regenerative capacity after birth. Intrinsic regulators of this process are promising repair targets, as immature axons can regrow in tissues otherwise not conducive to regeneration. Yet the precise timing and mechanisms underlying the cessation of axon growth in the human CNS remain unresolved. Here, we developed a three-dimensional human corticospinal motor organoid-slice connectoid platform mimicking the developmental axon elongation program and its subsequent restriction through maturation. Cortical and spinal slices establish functional connections while remaining spatially segregated, enabling cortical cell-type-specific observations without direct confounding effects by spinal cells. Using single-cell transcriptomics, computational analyses, axon regrowth assays, and live imaging, we identified transcriptional alterations contributing to decreased axon growth in maturing human cortical projection neurons. We further demonstrate that this decline can be reversed using compounds and repurposable drugs targeting a maturation-associated transcriptional shift, promoting post-injury axon repair.}, }
@article {pmid42202251, year = {2026}, author = {Ronquillo, CE}, title = {Beyond Time Saved: Implementation, Equity, and the Utility Threshold for Nursing AI Scribes.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e101190}, doi = {10.2196/101190}, pmid = {42202251}, issn = {1438-8871}, mesh = {Humans ; *Artificial Intelligence ; *Documentation ; Long-Term Care ; }, abstract = {Schwabe et al's pre-post time-motion study of a domain-specific artificial intelligence (AI) speech assistant used by nurses in German long-term care provides one of the few real-world, full-shift evaluations of an AI scribe deployed to a nonphysician workforce, with paired objective observation and self-reported outcomes. This commentary points to the implications of these findings that extend well beyond the time savings headline. The study reports substantial reduction in self-reported documentation time and increased satisfaction with the documentation system, yet workplace satisfaction and the perception that AI scribes are "a good idea to implement" did not improve. Taken together, these findings show three undertheorized issues for AI scribe implementation in nursing and long-term care. First, postimplementation increases in time spent reviewing entries and retrieving information indicate that AI scribes redistribute cognitive effort from authoring to verification, with unknown consequences for satisfaction, mastery, and error detection. Second, the apparent paradox of rising documentation satisfaction alongside falling expectations of AI quality represents user calibration. Third, the substantial equity considerations of automatic speech recognition documentation reflect a broader trend of AI scribe studies that treat equity as a caveat, rather than treating equitable performance as empirically measurable and testable across variations in linguistic styles, dialects, and social linguistic dimensions. To advance the field, the next generation of nursing AI scribe research must treat documentation as a heterogeneous bundle of authoring, reviewing, retrieving, and verifying activities with distinct satisfaction and error profiles; specify and validate end-user-defined anchor utilities, rather than having a narrow focus on diffuse improvement; and treat equity testing and reporting of both automatic speech recognition systems and workforce adoption as standard reporting expectations, rather than caveats.}, }
@article {pmid42202610, year = {2026}, author = {Doğan, V and Sinanoğlu, GK}, title = {2D:4D ratio, affective lability, and impulsivity in men with cannabinoid and methamphetamine use disorders: A comparative analysis with healthy controls.}, journal = {Early human development}, volume = {221}, number = {}, pages = {106587}, doi = {10.1016/j.earlhumdev.2026.106587}, pmid = {42202610}, issn = {1872-6232}, abstract = {The second-to-fourth digit ratio (2D:4D) is considered a non-invasive marker of prenatal androgen exposure and has been proposed as a developmental indicator of behavioral vulnerability; however, findings in substance use disorders remain inconsistent. This study aimed to examine whether 2D:4D ratios are associated with substance use disorders and to compare their relative contribution with psychological factors, including affective lability, impulsivity, and anxiety. In this cross-sectional case-control study, male participants with cannabinoid use disorder (CUD; n = 47), methamphetamine use disorder (MUD; n = 48), and healthy controls (n = 53) were included. The mean age of participants was 32.7±8.95 years. All participants were assessed using the Structured Clinical Interview for DSM-5 (SCID-5), Affective Lability Scale-18 (ALS-18), Barratt Impulsiveness Scale-11 (BIS-11), and Generalized Anxiety Disorder-7 (GAD-7). The 2D:4D ratio was measured with a digital caliper by two trained psychiatrists, and 2D:4D ratios and right-left differences (Dr-I) were calculated. No significant group differences were observed in left or right 2D:4D ratios or Dr-I; however, a consistent trend toward lower 2D:4D values, particularly for right-hand 2D:4D, was observed in the CUD and MUD groups compared with controls. In contrast, affective lability, impulsivity, and anxiety scores were significantly elevated in both patient groups (p <0.05). In univariate logistic regression analyses, affective lability, impulsivity, anxiety, and lower right-hand 2D:4D were associated with substance use disorder; however, right-hand 2D:4D showed the weakest association among these predictors. In the multivariate model, lower right-hand 2D:4D, impulsivity, lower educational attainment, and smoking remained independently associated with substance use disorder. These findings suggest that while 2D:4D may reflect a distal developmental vulnerability, psychological factors, particularly impulsivity, have a more direct and clinically relevant role in substance use disorders. Incorporating the assessment of impulsivity into clinical evaluation and intervention strategies may improve risk identification and treatment planning.}, }
@article {pmid42202831, year = {2026}, author = {Gorenshtein, A and Omar, M and Barash, Y and Nadkarni, G and Klang, E}, title = {Large Language Models Integrated into Brain-Computer Interfaces for Communication and Control: A Systematic Review.}, journal = {Biomedical physics &amp; engineering express}, volume = {}, number = {}, pages = {}, doi = {10.1088/2057-1976/ae737b}, pmid = {42202831}, issn = {2057-1976}, abstract = {Large language models (LLMs) are starting to be coupled with brain-computer interfaces (BCIs) for assistive communication, but the resulting systems differ widely in where the model sits in the pipeline and in what they actually measure. We performed a systematic review, prepared according to PRISMA, of eleven studies that combine an LLM with a BCI for communication or control. The included work covers P300, SSVEP, cVEP, passive affective and auditory paradigms, and five integration patterns: autocomplete, post-edit correction, intent expansion, dynamic interface generation and affective support. For each study we extracted the hardware and decoding pipeline, the LLM and prompting strategy, latency reporting and outcomes; we used scenario-appropriate metrics rather than a single common metric. Risk of bias was judged with an adapted ROBINS-I framework that stratified studies into online, offline-simulation and system-proposal categories. In the copy-spelling scenario, two studies that measured keystroke savings directly reported values above 50%, with one study exceeding 60% in a multi-turn condition; on an intent-based ALS message-bank task, one online study reached 42 characters per minute with a semantic accuracy of 88%. None of the eleven studies enrolled motor-impaired patients, seven of eleven relied on remote OpenAI endpoints, and reporting of end-to-end latency and failure modes was sparse. We propose a five-category taxonomy of BCI/LLM integration, separate findings that are supported from those that are still speculative, and give a checklist of metrics that should be reported by future studies. The taxonomy and the reporting checklist are the main contributions; clinical benefit for the target population remains to be shown.}, }
@article {pmid42203709, year = {2026}, author = {Topal, MA and Park, HG and Impett, EA}, title = {Beyond significance: Toward a more dynamic, relational, and culturally inclusive framework on love.}, journal = {The Behavioral and brain sciences}, volume = {49}, number = {}, pages = {e18}, doi = {10.1017/S0140525X25102197}, pmid = {42203709}, issn = {1469-1825}, mesh = {*Love ; Humans ; *Culture ; *Interpersonal Relations ; }, abstract = {Kruglanski et al.'s "love as a quest" model casts romantic love as a path to personal significance. We argue this framing misrepresents love's core nature, overlooking relational, emotional, and cultural dimensions. Love is not merely a reflection of individual validation but is dynamic and co-constructed. We advocate for a more relationally grounded and culturally inclusive framework on love.}, }
@article {pmid42020662, year = {2026}, author = {Abati, E and Saccomanno, D and Alberti, C and Anastasia, A and Gagliardi, D and Ferri, E and Arosio, B and D Angelo, G and Cima, R and Bassi, MT and Oldoni, S and Comi, GP and Rizzo, F and Corti, SP}, title = {Investigating the role of serum NfL, FGF21, NCAM1 and GDF15 as disease biomarkers for Charcot-Marie-Tooth type 2A.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42020662}, issn = {2045-2322}, support = {GMR23T2153//Fondazione Telethon/ ; Ricerca Corrente 2024 MoH//Ministero della Salute/ ; GR-2018-12365358//Ministero della Salute/ ; }, mesh = {*Charcot-Marie-Tooth Disease/blood/diagnosis/genetics ; Humans ; Biomarkers/blood ; *Growth Differentiation Factor 15/blood ; Female ; *Fibroblast Growth Factors/blood ; Male ; Animals ; Middle Aged ; Adult ; *Neurofilament Proteins/blood ; Mice ; Mice, Transgenic ; Aged ; Case-Control Studies ; Neural Cell Adhesion Molecules/blood ; }, abstract = {Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal form of inherited peripheral neuropathy, caused by mutations in the mitofusin 2 (MFN2) gene that impair mitochondrial fusion and axonal transport, ultimately leading to progressive neurodegeneration. The identification of accessible molecular biomarkers may improve diagnostic accuracy, enable patient stratification, and support the development and monitoring of emerging therapies. We investigated serum levels of neurofilament light chain (NfL), neural cell adhesion molecule 1 (NCAM1), growth differentiation factor 15 (GDF15), and fibroblast growth factor 21 (FGF21) in CMT2A patients (n = 15), healthy controls (n = 10), and neurological disease controls (n = 16; amyotrophic lateral sclerosis [ALS], n = 10, spinal muscular atrophy type 3 [SMA3], n = 6), evaluating their utility as diagnostic and monitoring biomarkers. In parallel, serum NfL levels were assessed in transgenic Thy1-MFN2*R94Q mice, a validated preclinical model of CMT2A. Serum NfL levels were significantly elevated in CMT2A patients compared to healthy controls, a finding corroborated in transgenic mice. Notably, NfL levels in CMT2A patients were higher than in SMA3 but lower than in ALS patients, supporting the ability of this biomarker to discriminate between clinically overlapping neuromuscular conditions. Higher NfL levels were associated with younger age, earlier disease onset, and shorter disease duration, suggesting a role as a marker of early disease burden. However, no significant correlation was observed with clinical severity scores or electrophysiological measures. Serum FGF21 levels were also significantly elevated in CMT2A patients compared to controls, whereas NCAM1 and GDF15 levels did not differ significantly between groups. These findings support the role of serum NfL as a translational biomarker of axonal damage in CMT2A, capable of distinguishing affected individuals from both healthy and neurological disease controls. The concomitant elevation of FGF21 further underscores the contribution of mitochondrial dysfunction to CMT2A pathophysiology. Together, these results highlight the potential of serum biomarkers to refine diagnostic workflows and facilitate therapeutic development and future clinical trials for CMT2A.}, }
@article {pmid42182254, year = {2026}, author = {Fonda, BD and Murray, DT}, title = {Phosphorylation Mimicking Mutations Cause TDP-43 to Adopt Different Fibril Conformations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.14.725298}, pmid = {42182254}, issn = {2692-8205}, abstract = {UNLABELLED: The Tar-DNA Binding Protein-43 C-terminal region, TDP43LC, has been previously shown to form amyloid-like fibrils with distinct folds in ALS and FTD. In both diseases, proteinaceous inclusions contain TDP43 C-terminal protein fragments as well as phosphorylated TDP43. Here, we use solution NMR to show that soluble phosphomimetic TDP43LC, P-TDP43LC, is structurally similar to wild-type TDP43LC. Disperse P-TDP43LC, like wild-type protein, contains a central helical region flanked by long disordered regions. Despite this similarity, our turbidity measurements, imaging, and kinetic assays show that P-TDP43LC has different aggregation behavior than wild-type protein. Using solid state NMR measurements we find that that phosphomimetic mutations alter the wild-type fibril conformation. Electrostatic repulsion from negatively charged sidechains, despite having little effect on the soluble protein's structure, perturbs amyloid-like fibril formation and selects for a different conformation in vitro. These results shed light on the structural role of TDP43LC phosphorylation in fibril formation in disease.<br><br>SYNOPSIS: Phosphomimetic mutations at ALS and FTD neurodegeneration-associated sites in an amyloid forming protein perturbs the aggregated structure compared to wild-type protein.}, }
@article {pmid42182325, year = {2026}, author = {Chauhan, BS and Brennan, MA and Forstmeier, PC and Yifu, H and Godfrey, RK and Van Keuren-Jensen, K and Sattler, R and Ichida, J and Zarnescu, DC}, title = {C9orf72 -associated G4C2 hexanucleotide repeat expression in Drosophila mushroom bodies causes age dependent TDP-43 pathology and dementia relevant phenotypes mediated in part by the glypican Dlp/GPC6.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.08.723849}, pmid = {42182325}, issn = {2692-8205}, abstract = {Hexanucleotide repeat expansions (HREs) in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the age-, sex-, repeat-length-, and circuit-specific influence on the pathology of neurons remains incompletely understood. Here, we established a Drosophila model of C9orf72 -associated dementia by expressing G4C2 repeats in mushroom body neurons (MBNs), a brain region critical for memory, locomotion, and sleep. Expression of 44X G4C2 repeats ((G4C2) 44X) led to progressive axonal thinning, age-dependent accumulation of Repeat Associated Non-AUG (RAN) translated GR-GFP dipeptide repeat (DPR) puncta, premature nuclear-to-cytoplasmic mislocalization of endogenous TDP-43, increased caspase, reduced lifespan and a loss of presynaptic active zones. Behaviorally, (G4C2) 44X expression caused locomotor hyperactivity, altered spatial working memory, and fragmentation of sleep architecture in an age- and sex-dependent manner, recapitulating core features of FTD. Surprisingly, the shorter (G4C2) 12X repeat, traditionally considered a control, also produced detectable RAN translation and intermediate phenotypes in aging MBNs, suggesting that length- and tissue-associated factors modulate repeat toxicity. We further identified a repeat-length- and age-dependent reduction of the glypican Dally-like protein (Dlp) in (G4C2) 44X consistent with disrupted Wnt-related signaling linked to TDP-43 proteinopathies. Restoring Dlp expression in MBNs mitigated locomotor and working-memory alterations, and loss of presynaptic active zones. In contrast, axonal degeneration, TDP-43 mislocalization, and lifespan were not significantly improved by restoring Dlp, suggesting that multiple mechanisms contribute to G4C2-induced toxicity. Supporting our findings in Drosophila MBNs, a CRISPRi screen in TDP-43 knock-down iNeurons identified GPC6, a human ortholog of Dlp, as a significant contributor to TDP-43 dependent synaptic loss. Together, our findings reveal an aging-sensitive, circuit-specific model of C9orf72 -associated neurodegeneration and highlight roles for DPR accumulation and Dlp/GPC6 dependent synaptic loss in FTD pathomechanisms.}, }
@article {pmid42183197, year = {2026}, author = {Dashti, M and AlAbdulghafour, F and AlMutairi, O and Mohammad, A and Malik, MZ and AlRefaie, K and Nizam, R and Jacob, S and Chalabi, A and Al Khleifat, A and Al-Mulla, F}, title = {Classical HLA class II associations with ALS in Kuwait reveal a DR7-DQ2.2 risk haplotype.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1820694}, pmid = {42183197}, issn = {1664-3224}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; Kuwait ; Middle Aged ; Female ; *Haplotypes ; *Genetic Predisposition to Disease ; Aged ; Alleles ; Adult ; Genome-Wide Association Study ; *Histocompatibility Antigens Class II/genetics ; *HLA-DQ Antigens/genetics ; }, abstract = {BACKGROUND: Genome-wide association studies have implicated the human leukocyte antigen/major histocompatibility complex (HLA/MHC) region in amyotrophic lateral sclerosis (ALS) susceptibility, and immune dysregulation is increasingly recognised as a modifier of disease course. High-resolution HLA data for ALS remain confined to European and East Asian ancestries. We tested whether classical HLA class I and class II variation contributes to ALS susceptibility in a Kuwaiti cohort.<br><br>METHODS: We analysed 38 unrelated ALS cases (mean age, 57.4 years; 63.2% male) and 150 population-matched controls (mean age, 57.0 years) from Kuwait. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 alleles were typed at two-field resolution using HLA-HD from next-generation sequencing (NGS) data. Allele, haplotype, and amino-acid residue associations were tested in BIGDAWG with locus-specific Bonferroni correction, with additional across-locus sensitivity analysis. Significant class II residues were mapped onto AlphaFold 3 structural models and interpreted alongside published class II crystal structures.<br><br>RESULTS: No class I allele, haplotype, or residue remained significant after correction. In class II, DQA1*02:01 [odds ratio (OR) = 3.18, 95% confidence interval (CI) 1.67 to 5.95, p c = 0.0007], DRB1*07:01 (OR&#xa0;=&#xa0;3.00, 95% CI: 1.58-5.59, p c = 0.001), and DQB1*02:02 (OR&#xa0;=&#xa0;2.48, 95% CI: 1.28-4.69, p c = 0.03) were enriched in cases. The extended haplotype DQA1*02:01~DQB1*02:02~DRB1*07:01 (DR7-DQ2.2) conferred increased odds of ALS (OR&#xa0;=&#xa0;3.11, 95% CI: 1.53-6.19, p c = 0.002). Amino-acid residue analysis identified convergent risk positions in DQ&#x3b1;1 (positions 47, 52, and 54; OR&#xa0;=&#xa0;3.18, p c = 0.006) and DR&#x3b2;1 (positions 11, 13, 14, 25, and 30; OR&#xa0;=&#xa0;2.84, p c = 0.03) that map to the peptide-binding groove and correspond to the defining motifs of DQA1*02:01 and DRB1*07:01.<br><br>CONCLUSION: Using high-resolution NGS-based HLA typing in a Kuwaiti cohort, we identified a class II risk signal for ALS centred on the DR7-DQ2.2 haplotype with convergent residue-level support in the peptide-binding domains. These findings support a contribution of class II-restricted antigen presentation to ALS susceptibility and warrant functional validation and replication in larger, independent Middle Eastern cohorts.}, }
@article {pmid42183628, year = {2026}, author = {Wei, Z and Zhang, M and Tang, W and Singh, BK and Zhiwei, Z and Lei, Z and Goh Kim Wee, J and Tan Rui En, F and Jingxiu, H and Qiaoyang, S and Bin, X and Priyanka, G and Xuyang, AS and Li, Z and Han-Ming, S and King, TE}, title = {CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.}, journal = {Autophagy}, volume = {}, number = {}, pages = {}, doi = {10.1080/15548627.2026.2678427}, pmid = {42183628}, issn = {1554-8635}, abstract = {Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of CHCHD2, and also in human iPSC-derived CHCHD2[-/-] or CHCHD2[T61I] dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.}, }
@article {pmid42183665, year = {2026}, author = {Tavaglione, L and Madonia, N and Corrado, L and Comi, C and D'Alfonso, S and Mazzini, L and De Marchi, F}, title = {Expanding the phenotypic spectrum of SOD1‑related ALS: upper motor neuron predominance in a p.D91A case.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/17582024.2026.2676822}, pmid = {42183665}, issn = {1758-2032}, abstract = {Mutations in superoxide dismutase 1 SOD1 are the second most common genetic cause of ALS, usually associated with prevalent lower motor neuron phenotypes. We describe a 66-year-old woman with slowly progressive spastic paraparesis, initially diagnosed as primary lateral sclerosis, who carried a heterozygous p.D91A mutation. Clinical and neurophysiological findings indicated predominant upper motor neuron involvement, an unusual presentation for this mutation. This case broadens the SOD1 phenotypic spectrum and highlights the importance of early genetic testing in atypical motor syndromes, given the availability of targeted therapies where diagnostic delay may limit benefit.}, }
@article {pmid42183747, year = {2026}, author = {Ma, G and Shi, Y and Qiu, J and Ren, C and Shao, K and Shu, X}, title = {Cumulative Environmental Burden and Neurodegenerative Disease Mortality: A National Ecological Study in the United States.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag114}, pmid = {42183747}, issn = {1476-6256}, abstract = {Neurodegenerative diseases (NDDs) represent a growing cause of mortality and disability among aging populations worldwide. However, the relationship between cumulative, multi-domain environmental exposures and NDD mortality remains poorly characterized. This study aimed to examine the association between comprehensive environmental quality and NDD mortality in the United States. We used the Environmental Quality Index (EQI) from 2000 to 2005 to characterize cumulative environmental exposure. Associations between EQI quintiles and NDD mortality, including dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, were examined using Bayesian interval-censored mixed-effects models. During 2006-2020, among 3.66 million NDD deaths, poorer environmental quality (Q5 vs. Q1) was associated with mortality rate differences of 24.72 (95% CrI: 22.43, 27.06) per 100,000 at 5-year lag, 26.74 (95% CrI: 24.34, 29.21) at 10-year lag, and 22.74 (95% CrI: 20.49, 25.13) at 15-year lag. Within each lag period, a clear dose-response pattern was consistently observed across EQI quintiles. Furthermore, associations were most pronounced for the air quality, followed by sociodemographic disadvantage. In addition, demographic and geographic heterogeneity was observed across sex, race, census regions, urbanicity, climate zone and county economic type. These findings underscore the need for integrated, place-based environmental health policies targeting neurodegeneration prevention.}, }
@article {pmid42183749, year = {2026}, author = {Trad, G and Lenglet, T and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF}, title = {Beyond outcomes: patients' lived experience of exoskeleton-assisted gait training in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2674021}, pmid = {42183749}, issn = {2167-9223}, abstract = {OBJECTIVES: To explore patients' expectations and lived experience of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In the EXALS study (NCT06199284), 10 ambulatory ALS participants completed 18 sessions of Atalante exoskeleton-assisted gait training. After completion of the intervention phase, post-training semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative content analysis approach. Structured interview items were summarized descriptively.<br><br>RESULTS: Ten participants reported positive expectations and experiences. Initial expectations most often included contributing to research (5/10), maintaining walking ability (4/10), and improving gait quality/balance (3/10). Expectation fulfillment was high (very satisfied: 7/10). The rehabilitative aspect was most frequently ranked as most reflective of the experience (rank 1: 4/10), followed by motivational/recreational (rank 2: 4/10), psychological/emotional was most often ranked last (rank 5: 5/10). Participants described perceived benefits including improved upright posture, stability, reduced stiffness, smoother gait, and reduced fear of falling, though some effects were described as short-lived. Three-word summaries were predominantly positive (8/10), commonly "interesting" and "motivating," with occasional negatives (tiring/heavy/repetitive/disappointing; 2/10). Compared with conventional physiotherapy, sessions were perceived as more dynamic and walking-focused, with a structured, innovative, closely supervised set-up. Suggested improvements centered on increasing access/dose, expanding walking space and training content, and enhancing safety/user control. Most participants would continue training if available (8/10), most commonly preferring two sessions per week (4/8).<br><br>CONCLUSIONS: Exoskeleton-assisted gait training was experienced as acceptable and meaningful. Translating this into practice will require aligning future protocols with patient priorities, autonomy/safety, access and delivery logistics, and broader functional content alongside quantitative evaluation.}, }
@article {pmid42185781, year = {2026}, author = {Fujiwara, Y and Hashiguchi, A and Yamashiro, S and Seno, H and Ohya, Y and Yasutomi, D and Fujisaki, N and Kido, M and Suwazono, S and Tokashiki, T}, title = {Association between creatinine-to-cystatin C ratio and ALSFRS-R across clinical phenotypes.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-04983-6}, pmid = {42185781}, issn = {1471-2377}, abstract = {BACKGROUND: Reliable and accessible biomarkers for amyotrophic lateral sclerosis (ALS) are scarce. Creatinine (Cre) reflects muscle mass, whereas cystatin C (CysC) may reflect neurodegeneration without being directly influenced by muscle mass; however, both have limitations. We aimed to investigate whether the creatinine-to-cystatin C ratio (Cre/CysC) was cross-sectionally associated with functional status in patients with ALS.<br><br>METHODS: We retrospectively analyzed 30 patients diagnosed with ALS at the National Organization Hospital Okinawa Hospital between 2021 and 2024. Baseline ALS Functional Rating Scale-Revised (ALSFRS-R) scores and serum Cre and CysC levels were recorded. Associations with the ALSFRS-R were assessed using Spearman's correlation, with subgroup analyses by sex, site of onset, age at diagnosis, body mass index (BMI), and diagnostic delay. Multivariable analyses were performed to examine the independent association between Cre/CysC and ALSFRS-R while accounting for relevant clinical covariates.<br><br>RESULTS: Cre/CysC showed a stronger cross-sectional correlation with ALSFRS-R (rs=0.648, p&#x2009;=&#x2009;0.0001) than Cre alone (rs =0.427) or CysC (rs =-0.119). Exploratory subgroup analyses showed generally positive associations in several subgroups, although no statistically significant association was observed in the small bulbar-onset subgroup. In multivariable analysis adjusted for age at onset and diagnostic delay, Cre/CysC remained independently associated with ALSFRS-R (&#x3b2;&#x2009;=&#x2009;20.1, 95% CI 6.41-33.9, p&#x2009;=&#x2009;0.006). Given the small sample size and cross-sectional design, these findings should be interpreted as exploratory.<br><br>CONCLUSIONS: Cre/CysC showed a stronger cross-sectional association with functional status than either marker alone. Because it is derived from routine laboratory tests, Cre/CysC may represent a simple exploratory measure associated with functional status in ALS. However, the present findings do not establish prognostic utility or fully account for disease stage and biological heterogeneity. Prospective longitudinal studies incorporating disease progression measures and broader clinical and genetic characterization are warranted.}, }
@article {pmid42186042, year = {2026}, author = {Salgueiro, AM and Ferreira-Marques, M and Ribeiro, RFN and Lopes, SM and Pereira, D and Costa, DG and Santana, MM and de Almeida, LP and Cavadas, C}, title = {Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {42186042}, issn = {2047-9158}, support = {UIDB/04539/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDP/04539/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; LA/P/0058/2020(JPND/ 0001/2022//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; DOI: 10.54499/JPND/0001/2022; JPND/0002/2022//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; DOI: 10.54499/JPND/0002/2022//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; SFRH/BD/120023/2016; 2020.04850.BD//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; 2022.11293.BD//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; GeneT project-The Gene Therapy CoE at the Center of Portugal (Project ID: 101059981//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101059981); GCure - From Gene to Cure//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186929//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI:10.3030/101186929; GeneH - Excellence Hub for Advancing Innovation in Gene Therapy//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; }, mesh = {Humans ; *Diet, Ketogenic/methods ; *Neurodegenerative Diseases/diet therapy/metabolism ; Animals ; *Translational Research, Biomedical/methods ; Gastrointestinal Microbiome/physiology ; Oxidative Stress/physiology ; }, abstract = {The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.}, }
@article {pmid42186501, year = {2026}, author = {AlSabah, AA and Reda, H}, title = {SOD1 amyotrophic lateral sclerosis associated with Neurosarcoidosis: a case report and review of the literature.}, journal = {Oxford medical case reports}, volume = {2026}, number = {5}, pages = {omag078}, pmid = {42186501}, issn = {2053-8855}, abstract = {We describe a 37-year-old man with coexisting amyotrophic lateral sclerosis (ALS) caused by a mutation in superoxide dismutase 1 (SOD1) and probable neurosarcoid myeloradiculitis. The concurrence of the two rare conditions posed significant diagnostic and therapeutic challenges. We discuss the diagnostic timeline, therapeutic interventions, outcomes over half a decade of care, and a review of relevant literature.}, }
@article {pmid42186604, year = {2026}, author = {Albadri, Z and Häbel, H and Thorslund, K and Grönhagen, C and Seifert, O}, title = {Associations between bullous pemphigoid and comorbidities: A Swedish nationwide cohort study of 5,738 patients.}, journal = {Journal of multimorbidity and comorbidity}, volume = {16}, number = {}, pages = {26335565261455676}, pmid = {42186604}, issn = {2633-5565}, abstract = {BACKGROUND: Bullous pemphigoid (BP) has been linked to neurological and psychiatric disorders, but no nationwide population-based study has comprehensively examined the association of various comorbidities in BP patients in Sweden.<br><br>OBJECTIVES: To investigate the associations between BP and various comorbidities, comparing these conditions before and after BP diagnosis with a matched control group.<br><br>METHODS: A nationwide cohort study was conducted in Sweden from 2005 to 2016, including 5,738 BP cases and 17,167 age, sex and county of residence matched controls. Multivariable Cox proportional hazard regression models were used to calculate hazard ratios (HR). Univariable logistic regression assessed pre-diagnosis comorbidities, generating prevalence odds ratios (POR) with 95% confidence intervals (CI).<br><br>RESULTS: BP was associated with a significantly higher overall HR for comorbidity (HR: 2.20, 95% CI: 2.08-2.33). Before BP diagnosis, the overall comorbidity was significantly increased POR 2.72 (95% CI: 2.56-2.90). Pre-diagnosis association included dementia, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, unipolar/bipolar disorders, suicide, diabetes, stroke, systemic lupus erythematosus, systemic sclerosis, psoriasis, lichen planus, alopecia areata, and vitiligo. After diagnosis, the overall hazard ratio (HR) for comorbidities was highest within the first year (HR 2.88, 95% CI: 2.68-3.10) and remained elevated beyond one year (HR 1.57, 95% CI: 1.44-1.71). Post-diagnosis associations remained elevated for dementia, Parkinson's disease, epilepsy, schizophrenia, unipolar/bipolar, diabetes, psoriasis, lichen planus and autoimmune diseases such as systemic sclerosis and Sj&#xf6;gren's syndrome.<br><br>CONCLUSION: BP is strongly associated with neurodegenerative, psychiatric, autoimmune, and metabolic comorbidities before and after diagnosis, highlighting their clinical significance as predisposing and prognostic factors in BP patients.}, }
@article {pmid42186910, year = {2026}, author = {Tong, VS and Pontell, ME}, title = {Invited Commentary on: Islam et al.'s "Evaluating Appropriateness of Interfacility Transfers for Patients with Facial Trauma Including Acute Orbital Floor Fractures".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261452862}, doi = {10.1177/26893614261452862}, pmid = {42186910}, issn = {2689-3622}, }
@article {pmid42187212, year = {2026}, author = {Kibreab, F and Haraburda, A and Albaba, YAA and Yong, AC and Shah, K and Buthelezi, S and Chan, VF}, title = {A scoping review of theoretical and measurement approaches to women's empowerment in low-and middle-income countries' capacity-building interventions.}, journal = {Global health action}, volume = {19}, number = {1}, pages = {2676412}, doi = {10.1080/16549716.2026.2676412}, pmid = {42187212}, issn = {1654-9880}, mesh = {*Developing Countries ; *Empowerment ; Humans ; Female ; *Capacity Building/organization &amp; administration ; *Women's Rights ; Entrepreneurship ; Gender Equity ; *Power, Psychological ; }, abstract = {Women's empowerment is critical for achieving gender equality and sustainable development in low-and-middle-income countries (LMICs). Capacity-building interventions, such as vocational training, microfinance, and digital literacy programmes, are frequently employed to foster empowerment. However, wide variation exists in how empowerment is defined, theorised, and measured, limiting comparability across studies. This scoping review mapped the conceptual foundations, theoretical frameworks, and measurement approaches used in capacity-building interventions for women entrepreneurs in LMICs. The review followed Arksey and O'Malley's framework and was reported in line with PRISMA-ScR guidelines. Searches were conducted in PubMed, Scopus, Web of Science, and JSTOR, complemented by grey literature from major development agencies (2010-2024). Eligible studies focused on capacity-building interventions targeting women entrepreneurs in LMICs. Two reviewers independently screened and extracted data, which were synthesised thematically. Of 11,109 records identified, 25 met inclusion criteria. Most studies were cross-sectional, conducted in sub-Saharan Africa (48%) and South Asia (32%). While 76% defined empowerment, 60% did not employ any explicit theoretical or conceptual framework. Among those that did, frameworks, such as Kabeer's, Longwe's, and Malhotra et al.'s were used inconsistently. Economic empowerment was the most frequently assessed domain, often measured through income or business performance, while social, political, and psychological dimensions were seldom examined. Indicators were heterogeneous and largely self-reported. Conceptual ambiguity and inconsistent measurement hinder progress in women's empowerment research in LMICs. Future studies should adopt theoretically grounded, multidimensional, and context-sensitive frameworks to capture empowerment as a dynamic process beyond economic gains.}, }
@article {pmid42187452, year = {2026}, author = {Kolukisa Birgec, B and Toprak, B and Mullen, AB}, title = {Assessment of Respiratory Rate and Simulated Apnea Utilizing the PneumoWave Biosensor: In Vitro and In Vivo Validation.}, journal = {Biosensors}, volume = {16}, number = {5}, pages = {}, doi = {10.3390/bios16050256}, pmid = {42187452}, issn = {2079-6374}, support = {YLSY2018/YLSY2020//Mi&#x307;lli&#x307; E&#x11f;i&#x307;ti&#x307;m Bakanli&#x11f;i/ ; }, mesh = {Humans ; *Biosensing Techniques ; *Respiratory Rate/physiology ; *Apnea/diagnosis/physiopathology ; Monitoring, Physiologic ; Male ; Adult ; Female ; Manikins ; }, abstract = {Accurate monitoring of respiratory rates is critical for early detection of a range of clinical conditions. However, standard manual counting or inadequate clinical monitoring often fails to provide reliable measurements. This study evaluated and validated the PneumoWave biosensor for respiratory rate measurement across a broad physiological range and different body postures (45°, 90°, and 180°) in both in vitro and in vivo settings. In vitro validation was performed using a SimMan ALS manikin operated at respiratory settings of 6-30 breaths per minute, with 10 s periods of simulated apnea. In vivo validation involved 20 healthy volunteers performing metronome-guided breathing while wearing bilateral PneumoWave biosensors. In vitro results demonstrated an excellent correlation between biosensors and manikin respiratory settings and captured all apnea events (r = 0.99, ICC = 0.99). In vivo findings showed good agreement with direct observational count (r = 0.99, R[2] = 0.99, ICC = 0.99), with 97% of apnea events captured by both devices in all positions. Body postures had no significant impact on biosensor accuracy. These findings demonstrate that the PneumoWave biosensor provides accurate and reliable respiratory monitoring and supports its potential as a robust, non-invasive tool for continuous clinical and remote patient monitoring.}, }
@article {pmid42187823, year = {2026}, author = {Hayden, E and Kebe, A and Chen, S and Chumley, A and Xia, C and El-Zein, W and Zhong, Q and Ju, S}, title = {RNA-Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, doi = {10.3390/jof12050341}, pmid = {42187823}, issn = {2309-608X}, support = {1R15NS109804-01A1/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in an RNA-binding protein FUS are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA-binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Increasing evidence has emerged supporting a hypothesis that the impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through the genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity in yeast. The suppression by TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its suppression of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein-protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, the co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of increased p-body formation in the suppression of FUS toxicity by TAF15.}, }
@article {pmid42188341, year = {2026}, author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G}, title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.}, journal = {Journal of personalized medicine}, volume = {16}, number = {5}, pages = {}, doi = {10.3390/jpm16050246}, pmid = {42188341}, issn = {2075-4426}, abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.}, }
@article {pmid42174808, year = {2026}, author = {Bosoni, P and Vazifehdan, M and Aidos, H and Alves, I and Birolo, G and Faggioli, G and González-Martínez, S and Gromicho, M and Jovanović, A and Kostić, B and Longato, E and Manera, U and Tavazzi, E and Tavazzi, E and Bellazzi, R and Bergamaschi, R and Fernanda Cabrera, M and Chiò, A and de Carvalho, M and di Camillo, B and Fariselli, P and Ferro, N and Madeira, SC and Dagliati, A}, title = {Environmental Personal Exposure Clusters to Investigate Multiple Sclerosis and Amyotrophic Lateral Sclerosis Progression.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {173-177}, doi = {10.3233/SHTI260131}, pmid = {42174808}, issn = {1879-8365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology ; *Multiple Sclerosis/diagnosis/epidemiology ; *Environmental Exposure/analysis ; Disease Progression ; Male ; Female ; Middle Aged ; *Volatile Organic Compounds/analysis ; Prognosis ; Cluster Analysis ; Adult ; *Environmental Monitoring/methods ; }, abstract = {Reliable prognosis in Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) is hampered by data scarcity and variability. Beyond clinical variables, evidence suggests that environmental data can help capture disease trajectories. We investigated whether personal environmental measures can be organized into stable patterns that inform prognosis. In a multicenter cohort, 293 patients with MS or ALS were equipped with Atmotube air-quality sensors. We normalized volatile organic compound (VOC) time series and computed Dynamic Time Warping distances to capture temporal similarity. Hierarchical clustering yielded five daily exposure clusters, which were profiled using Atmotube variables (season, day type, humidity, temperature) and patient self-reports (work status, time outdoors), and evaluated by day-level differences between personal and fixed-station variables. These clusters can support interpolation of missing wearable intervals and generation of context-aware exposure estimates, thereby strengthening environmental inputs for prognostic modeling in MS and ALS.}, }
@article {pmid42174849, year = {2026}, author = {Ferraro, PM and Narteni, S and Lenatti, M and Oliveri, F and Gemelli, C and Cabona, C and Uccelli, A and Paglialonga, A and Mongelli, M and Schenone, A}, title = {A Consensus Clustering Approach to Amyotrophic Lateral Sclerosis Phenotyping.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {338-342}, doi = {10.3233/SHTI260173}, pmid = {42174849}, issn = {1879-8365}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification ; Humans ; Phenotype ; Cluster Analysis ; Consensus ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) phenotyping is a challenging task due to its heterogeneous nature and low prevalence. In this paper, we introduce a data-driven approach to support the characterization of ALS phenotypes based on clinical data from a battery of examinations. A consensus clustering method is proposed to identify stable clusters across multiple random data sub-samples, with the objective of discovering whether the retrieved patients' groups and related features align with clinical phenotypes and medical knowledge. Results suggest consistent profiles for bulbar onset ALS patients, driven by onset characteristics, whereas spinal onset ALS patients exhibit greater within-phenotype heterogeneity.}, }
@article {pmid42174910, year = {2026}, author = {Strube, T and Weltermann, L and Weber, J and Defosse, J}, title = {Guideline-Aligned Machine Learning for Predicting Ondansetron Administration at the End of Anaesthesia: Explainable Decision Support for PONV Prophylaxis.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {570-574}, doi = {10.3233/SHTI260235}, pmid = {42174910}, issn = {1879-8365}, mesh = {*Ondansetron/administration &amp; dosage ; *Machine Learning ; Humans ; *Postoperative Nausea and Vomiting/prevention &amp; control ; *Decision Support Systems, Clinical/standards ; *Practice Guidelines as Topic ; *Antiemetics/administration &amp; dosage ; }, abstract = {Artificial Intelligence (AI) and Clinical Practice Guidelines (CPGs) both aim to support clinical decision-making but may provide conflicting suggestions. This manuscript presents a Guideline-Aligned Machine Learning (GAML) model to predict ondansetron administration at the end of anaesthesia, based on Gan et al.'s Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting (PONV). n= 16,240 anaesthesia protocols were analysed for risk factors and administered PONV prophylaxes. Logistic regression, multinomial naïve Bayes, and CatBoost classifiers were trained on 80% of protocols with 12-fold cross-validation; optimal thresholds were set by the mean F1-maximising cut-off across folds. Models were evaluated on the remaining 20%, achieving high accuracy (90 ± 1%) and moderate precision and recall (60 ± 5%, 75 ± 4%) across all models. A SHAP decision plot was further computed on the test set to visualise predictor contributions and illustrate a potential interactive preoperative planning interface. Overall, GAML is a promising basis for explainable decision support in clinical care.}, }
@article {pmid42174979, year = {2026}, author = {Faujour, C and Bouee, S and Emery, C and Jannot, AS}, title = {Evaluating the Role of Order and Time Information for Classifying Sequences of Healthcare Events Derived from Claims Data.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {879-883}, doi = {10.3233/SHTI260305}, pmid = {42174979}, issn = {1879-8365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; *Insurance Claim Review/statistics &amp; numerical data ; }, abstract = {Sequences of healthcare events from claims data are increasingly used for predictive modeling. Despite the rise in popularity of neural networks, the benefit of modeling event order and timing remains underexplored. We simulated patient trajectories using parameters estimated from claims data including 22,000 amyotrophic lateral sclerosis (ALS) cases and 22,000 age and gender-matched controls. The simulation reproduced irregular event timing and condition-related activity that increased near an incident diagnosis. We compared three model families for population classification: frequency-based models, sequential models (long short-term memory and Transformer architectures) capturing event order, and sequential models incorporating temporal information. Performance was evaluated using the area under the ROC curve (AUC) at multiple time points before diagnosis. Sequential models outperformed frequency-based baselines by about +0.06 AUC on average, confirming the benefit of modeling event order. Adding time information provided no noticeable improvement, and results were stable across different time encoding and scaling methods. These findings suggest that, in claims-based classification tasks, event order captures most of the useful temporal signal, while explicit time encoding offers limited additional benefit under similar conditions.}, }
@article {pmid42175187, year = {2026}, author = {Yadav, R and Pragya, P and Agastinose Ronickom, JF}, title = {Identification of Reliable Biomarkers for ALS Through Machine Learning Approach.}, journal = {Studies in health technology and informatics}, volume = {336}, number = {}, pages = {1705-1709}, doi = {10.3233/SHTI260516}, pmid = {42175187}, issn = {1879-8365}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Machine Learning ; Biomarkers/analysis ; Gene Expression Profiling/methods ; Transcriptome ; Algorithms ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and limited diagnostic biomarkers. Identifying robust molecular biomarkers for ALS remains a major challenge due to disease heterogeneity and high-dimensional gene expression data. In this study, we developed a machine learning (ML) based pipeline integrating transcriptome data and feature selection to identify potential ALS biomarkers. RNA-Seq data of motor neuron disease patients and healthy controls were obtained from publicly available GEO datasets, followed by preprocessing was performed. We implemented two ensembled ML models such as eXtreme gradient boosting (XGBoost) and random forest (RF) algorithms under a five-fold stratified cross-validation framework to identify the differentially expressed genes. These models were evaluated using the performance metrics. We identified top 10 genes ranked by feature importance from the XGBoost and RF models. Notably, the DCN (Decorin) gene appears consistently in the top 10 features of both models, underscoring its stability and biological relevance. Both ML models exhibited excellent classification performance, with RF achieving 98.8% accuracy and XGBoost achieving 97.6% accuracy, alongside consistently high sensitivity, specificity, precision, and F1-score values. This work highlights the utility of transcriptomic data and ML in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.}, }
@article {pmid42177450, year = {2026}, author = {Ghasemi, F and Khoshnam Rad, N and Rashidinejad, B and Nasrollahzadeh, M}, title = {Pulmonary toxocariasis presenting as migratory pulmonary infiltrates and mediastinal lymphadenopathy: a case report and literature review.}, journal = {BMC pulmonary medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12890-026-04362-4}, pmid = {42177450}, issn = {1471-2466}, abstract = {BACKGROUND: Pulmonary toxocariasis, caused by the nematode Toxocara canis or T. cati, is an underdiagnosed cause of eosinophilic lung disease with highly variable radiological presentation that often mimics malignancy or other eosinophilic conditions.<br><br>CASE PRESENTATION: A 53-year-old female smoker presented with progressive dyspnea and cough. Initial chest CT revealed right lower lobe consolidation with mediastinal lymphadenopathy (station 4R with short-axis diameters 12&#xa0;mm), raising concern for lung cancer. Bronchoscopy with EBUS-TBNA was non-diagnostic. The patient was empirically started on dexamethasone (8&#xa0;mg daily, tapered over 3 months) for suspected organizing pneumonia. During steroid taper, her symptoms recurred with delayed emergence of peripheral eosinophilia (670/&#xb5;L; initial absolute eosinophil count on presentation was 90/&#xb5;L), elevated IgE (456 IU/mL), and serial CT scans demonstrating migratory pulmonary infiltrates involving the right lower, right middle, and left lower lobes. A history of raw beef liver consumption prompted serological testing, which confirmed Toxocara canis infection. Treatment with albendazole alone (400&#xa0;mg twice daily for 14 days, without corticosteroids) resulted in complete clinical and radiological resolution.<br><br>LITERATURE REVIEW: We searched PubMed and Scopus (January 2014 - February 2026) for English- and French-language case reports of pulmonary toxocariasis. Fourteen new cases were identified and analyzed alongside the 12 cases from Ranasuriya et al.'s [1] review. These 26 cases demonstrate marked radiologic heterogeneity: multiple bilateral nodules (50%), consolidations (23%), pleural effusion (27%), and migratory infiltrates (8%). Pleural effusion has emerged as a distinct manifestation in seven recent cases. Delayed eosinophilia occurred in 12% of cases. Immunocompromised states (including primary ciliary dyskinesia, hematologic malignancies, and immunosuppressive therapy) were present in 23% of cases and may predispose to atypical presentations.<br><br>CONCLUSION: Pulmonary toxocariasis should be considered in patients with migratory infiltrates, unexplained eosinophilic pleural effusion, or lung nodules with eosinophilia. A meticulous dietary and exposure history is essential. Diagnosis is confirmed by serology, and patients respond well to albendazole therapy.}, }
@article {pmid42177561, year = {2026}, author = {Sharma, S and Cortés-Pérez, C and Bird, S and Di Curzio, D and Vandenakker, A and Schellenberg, K and Douville, RN}, title = {ERVK activity in CD8[+] T cell immune cell compartment in patients with ALS.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03871-7}, pmid = {42177561}, issn = {1742-2094}, support = {19-IIA-489//ALS Association/ ; 19-IIA-489//ALS Association/ ; }, abstract = {Endogenous retrovirus-K (ERVK) expression has been associated with Amyotrophic Lateral Sclerosis (ALS), and its viral proteins can be detected in affected brain and spinal cord tissues. Despite confirmation of ERVK load in the blood of patients with ALS, few studies have examined ERVK protein expression in immune cells. ERVK produces an enzyme called integrase (IN), which can cause DNA damage during the integration of viral DNA into the host genome. Given that genomic instability is a hallmark of ALS, we hypothesized that the ERVK IN enzyme may also be expressed in lymphoid and myeloid-derived immune cells of patients. Peripheral blood mononuclear cells (PBMC) were isolated from blood specimens using Ficoll isolation, and either flash-frozen for western blot analyses or affixed onto slides using the cytospin technique for subsequent confocal microscopy analysis. Image analysis of confocal micrographs revealed that ERVK IN expression was significantly elevated in CD3[+]CD8[+] T cells from a subset of patients with ALS as compared to controls. CD3[+]CD8[+] T cells in ALS exhibit enhanced number and size of ERVK IN puncta within the nucleus and at the plasma membrane. The DNA damage load, as measured by marker γH2AX, was strongly associated with ERVK IN levels in both controls and patients with ALS. Stratification of molecular data based on clinical parameters showed an association of elevated ERVK IN load in CD8[+] T cells from patients with ALS with lower ALSFRS-R and higher King's scores, as well as a significant decline in lung function metrics. In bulk PBMC from patients with ALS, ERVK IN was associated with expression of immune checkpoint marker PD-1, but not T cell exhaustion marker TOX. ERVK IN in CD14[+]CD11b[+] myeloid cells was also elevated, with ERVK[+] cells exhibiting notable membrane ruffling typical of immune cell activation and increased expression of HLA-DR. However, ERVK IN expression in monocytes was not correlated with clinical metrics in patients with ALS. This work points to the use of ERVK IN in CD8[+] cytotoxic T cells as a blood biomarker for ALS clinical trials, especially those focused on testing the efficacy of antivirals as a therapeutic strategy for ALS.}, }
@article {pmid42177632, year = {2026}, author = {Schimmack, U and Soto, MD}, title = {A response to Pek et al.'s commentary on Z-curve: clarifying the assumptions of selection models.}, journal = {Cognition &amp; emotion}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/02699931.2026.2678998}, pmid = {42177632}, issn = {1464-0600}, abstract = {Pek et al. (2026. What does a Z-curve analysis tell us? Cognition &amp; Emotion, 1-16) comment on Soto and Schimmack (2025. Credibility of results in emotion science: A z-curve analysis of results in the journals Cognition &amp; Emotion and Emotion. Cognition &amp; Emotion) and raise concerns about the use of z-curve to evaluate the credibility of emotion research. Their central criticism is based on simulations showing that z-curve can overestimate the expected discovery rate when selection operates not only at the level of statistical significance but also within the set of significant results as a function of effect size. This point is correct: if researchers selectively publish larger significant effects while suppressing smaller significant ones, selection models that assume threshold-based filtering can be biased. However, this limitation is not unique to z-curve and applies equally to other selection models used in meta-analysis. More importantly, there is currently little empirical evidence for effect-size bias, while there is ample evidence of selection based on significance. Under these more realistic conditions, z-curve provides informative estimates of (a) selection bias, (b) the expected replication rate, and (c) the false positive risk. Our results also demonstrate substantial inflation of effect size estimates in traditional meta-analyses that ignore selection processes. For these reasons, we reject the recommendation to rely solely on standard meta-analytic approaches and advocate for the use of selection models to obtain more realistic estimates.}, }
@article {pmid42178739, year = {2026}, author = {Paquet, A and Touzel-Deschênes, L and Roy, V and Saikali, S and Dupré, N and Gros-Louis, F}, title = {Proteomic Analysis of Corpora Amylacea Extracted From Post-mortem Brain of MAiD-end-of-life Sporadic ALS Patients.}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71486}, doi = {10.1002/brb3.71486}, pmid = {42178739}, issn = {2162-3279}, support = {//tier-1 Canada Research Chair/ ; //CHU de Qu&#xe9;bec Foundation-Desjardins/ ; /CAPMC/CIHR/Canada ; //Canada Foundation for Innovation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Proteomics/methods ; Male ; Female ; Aged ; Middle Aged ; *Brain/metabolism/pathology ; *Inclusion Bodies/metabolism/pathology ; Biomarkers/metabolism ; Aged, 80 and over ; Autopsy ; Proteome ; }, abstract = {PURPOSE: Corpora amylacea (CA) are starch-like inclusions that accumulate in the central nervous system (CNS) with aging and are enriched in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Although often regarded as waste reservoirs, their cellular origins, molecular composition, and pathological significance remain poorly understood.<br><br>METHODS: Here, we performed an unbiased proteomic analysis of purified CAs isolated from post-mortem brains of sporadic ALS patients and controls.<br><br>FINDINGS: In-depth mass spectrometry identified 4,470 proteins, of which 658 were quantified, revealing distinct ALS-specific proteomic signatures. Enriched proteins included markers of cytoskeletal remodeling, mitochondrial dysfunction, and proteostasis disruption, as well as known ALS-associated proteins such as TDP-43 and neurofilament proteins. These findings demonstrate that CAs serve as reservoirs of dysfunctional, disease-relevant proteins and capture key pathological processes in ALS.<br><br>CONCLUSION: By applying an unbiased proteomic approach to purified CAs, this study provides the first comprehensive map of their protein content in ALS, supporting their potential as biomarker sources and as a source of mechanistic insights into neurodegeneration.<br><br>SIGNIFICANCE: Unbiased analyses of CAs in the context of ALS have yet to be undertaken. This study provides the first proteomic profiling of purified CAs, isolated from ALS patient brains using biochemical methods, revealing that CAs harbor disease-relevant proteins implicated in sporadic ALS. By demonstrating that CAs act as reservoirs of dysfunctional proteins related to metabolism, cytoskeletal organization, and proteostasis, our findings highlight their potential as a novel source of ALS-specific mechanistic insight into disease pathology.}, }
@article {pmid42178909, year = {2026}, author = {Debnath, J and Leidal, AM}, title = {Membrane ATG8ylation in secretory autophagy.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/15548627.2026.2676796}, pmid = {42178909}, issn = {1554-8635}, abstract = {Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.}, }
@article {pmid42178983, year = {2026}, author = {Liu, JQ and Liu, H and Sun, YX and Li, Y and Liu, X and Wang, LQ and Yang, Z and Fu, Q and Xu, X and Chen, J and Zhang, Y and Zhou, J and Le, W and Cui, M and Liang, Y}, title = {Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e16846}, doi = {10.1002/advs.202516846}, pmid = {42178983}, issn = {2198-3844}, support = {U1967221//National Natural Science Foundation of China/ ; 32071212//National Natural Science Foundation of China/ ; U1967221//National Natural Science Foundation of China/ ; 22022601//National Natural Science Foundation of China/ ; 2024YFA1307300//National Key Research and Development Program of China/ ; 2023ZD0507202//National Major Science and Technology Projects of China/ ; }, abstract = {Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.}, }
@article {pmid42180530, year = {2026}, author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L}, title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {5}, pages = {2601-2644}, pmid = {42180530}, issn = {2211-3835}, abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.}, }
@article {pmid42181829, year = {2026}, author = {Kuru Çolak, T and Akçay, B and Weiss, HR and Nan, X and Elliott, L and Akkoyunlu, SZ and Borysov, M}, title = {Treatment outcomes across curve patterns and severities in adolescent idiopathic scoliosis treated with a pattern-specific CAD-CAM brace.}, journal = {Frontiers in rehabilitation sciences}, volume = {7}, number = {}, pages = {1826976}, pmid = {42181829}, issn = {2673-6861}, abstract = {BACKGROUND: Whether treatment outcomes differ according to curve pattern or baseline severity in adolescents with idiopathic scoliosis (AIS) remains a subject of debate. In particular, it is unclear whether pattern-specific, CAD-CAM-designed brace systems provide comparable effectiveness across different curvature types. This study aimed to evaluate the influence of curve pattern and initial curve magnitude on treatment outcomes in AIS patients treated with a pattern-specific CAD-CAM-designed brace.<br><br>METHODS: A retrospective analysis was conducted on female AIS patients aged 10-14 years (Risser 0-2) treated between 2015 and 2024. Cobb angle and angle of trunk rotation (ATR) were used as primary outcome measures. Data from four international clinics were analyzed for changes in spinal curvature and curve pattern.<br><br>RESULTS: A total of 145 patients were included (mean age 12.2 years; mean Cobb angle 38.4&#xb0;&#x2009;&#xb1;&#x2009;11.4&#xb0;). Post-treatment, mean Cobb angle and ATR values decreased significantly (p&#x2009;<&#x2009;0.001). The overall treatment success rate was 91%, with no significant differences based on apex vertebra location (p&#x2009;=&#x2009;0.459), ALS patterns (p&#x2009;=&#x2009;0.705), or baseline curve severity (p&#x2009;=&#x2009;0.274).<br><br>CONCLUSION: In this multicenter cohort of skeletally immature adolescents with idiopathic scoliosis, pattern-specific brace treatment was associated with significant reductions in both radiographic curvature and trunk rotation. Improvements were observed across different curve patterns and baseline severities. However, given the retrospective design and absence of a comparison group, these findings should be interpreted with caution. Prospective controlled studies are warranted to further validate these observations.}, }
@article {pmid42172922, year = {2026}, author = {Myers, S and Kraus, E and Davis, ES and Murillo, A and Ng, SC and Sachs, T and Davids, JS and Kenzik, KM}, title = {Ostomy and Anastomotic Leak Differences Among Rural and Urban Surgical Colon Cancer Patients.}, journal = {The Journal of surgical research}, volume = {324}, number = {}, pages = {59-66}, doi = {10.1016/j.jss.2026.04.017}, pmid = {42172922}, issn = {1095-8673}, abstract = {INTRODUCTION: Rural populations experience higher morbidity and mortality after resection of colon cancer (CC) than urban populations. Ostomy creation may obviate or reduce the severity of anastomotic leaks (ALs); however, this practice is surgeon-dependent. Differences in rural-urban ostomy practices and AL following CC resection are unknown.<br><br>METHODS: We identified patients who underwent CC resection between 2014 and 2019 from the Surveillance, Epidemiology, and End Results-Medicare database and characterized ostomy practices. We used multivariable logistic regression to evaluate rural-urban differences in AL and readmissions, with and without ostomies. Oaxaca-Blinder nonlinear effect decomposition was used to analyze the proportion of rural-urban difference in AL explained by age, sex, race, Charlson Comorbidity Index, stage of cancer, surgical approach, surgeon specialty, and ostomy creation.<br><br>RESULTS: Among 28,031 individuals (17.9% rural), rural patients underwent ostomy surgery less often than urban (47.6% versus 52.4%, P< 0.0001). The rate of AL was higher among rural patients with ostomies (8.6% versus 7.0%, P= 0.0069), and rural ostomy patients were discharged with postacute care services less often (43.8% versus 47.3%, P= 0.0034). Resection by a general surgeon was associated with higher odds of AL only among urban patients (versus colorectal, OR = 1.27; 95% CI = 1.13-1.42). Surgical approach explained 37.5% of the rural-urban AL disparity, surgeon specialty explained 21.5%, and ostomy surgery only explained 2.6% of the difference.<br><br>CONCLUSIONS: Ostomy surgery explained a small proportion of the rural-urban AL disparity, while surgical approach explained over a third of the higher AL risk among rural populations. Surgical approach should be prioritized in interventions to improve CC surgical outcomes among rural populations.}, }
@article {pmid42173382, year = {2026}, author = {Braza, AJ and Viñas-Bastart, M and Sureda-Rosich, M and García-Parra, B and Guiu-Segura, JM and Modamio, P}, title = {Tofersen in SOD1-associated amyotrophic lateral sclerosis: From molecular mechanisms to regulatory milestones.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {223}, number = {}, pages = {107563}, doi = {10.1016/j.ejps.2026.107563}, pmid = {42173382}, issn = {1879-0720}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 2% of ALS cases and are associated with toxic protein misfolding and aggregation. Tofersen is an antisense oligonucleotide therapy designed to reduce the synthesis of mutant SOD1 protein through targeted mRNA degradation. While this strategy represents a gene-specific therapeutic approach for a subset of ALS patients, evidence regarding its efficacy, effectiveness and long-term outcomes continues to be evaluated in clinical trials and post-marketing studies.<br><br>OBJECTIVE: First, to describe the molecular mechanisms underlying SOD1-associated ALS and second, to analyze the therapeutic development, clinical outcomes, and regulatory evolution of tofersen.<br><br>METHODS: A narrative review was conducted in PubMed on preclinical and clinical studies published from 2016 through late 2025, complemented by an analysis of public registries and regulatory documentation. Clinical trials were identified through ClinicalTrials.gov and the Clinical Trials Information System (CTIS), and official reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were reviewed to contextualize their development and regulatory evaluation.<br><br>RESULTS: Fifty-three publications were identified, of which 20 met predefined inclusion criteria after screening and full-text review. Preclinical studies showed reduced mutant SOD1 expression and prolonged survival in transgenic models. Phase I-II trials demonstrated safety, favorable pharmacokinetics, and dose-dependent reductions in SOD1 in the cerebrospinal fluid and plasma neurofilament light chain (NfL) levels. Although the phase III VALOR trial did not meet the primary ALSFRS-R endpoint (a validated questionnaire-based functional rating scale-revised for determining ALS disease progression) at 28 weeks, significant reductions in the surrogate biomarker NfL indicated target engagement and supported accelerated regulatory approval. Extension data suggested potential clinical benefit with early treatment. Ongoing studies, including ATLAS in presymptomatic carriers, and real-world European data support continued evaluation, alongside accelerated regulatory approvals by FDA and EMA.<br><br>CONCLUSION: Tofersen marks a paradigm shift in ALS management, establishing the foundation for precision medicine in neurodegenerative diseases. Its ongoing evaluation in the ATLAS trial will determine whether early intervention can prevent or delay disease onset in presymptomatic SOD1 mutation carriers.}, }
@article {pmid42174751, year = {2026}, author = {Grouls, A and Leavell, YL and Mehta, AK and Kojimoto, G and O'Riordan, DL and Maiser, S and Kluger, BM and Pantilat, SZ and Bischoff, KE}, title = {Embedding Palliative Care Clinicians in ALS Teams Improves ALS Clinicians' Confidence in Their Patient Management and Satisfaction With Palliative Care.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70291}, pmid = {42174751}, issn = {1097-4598}, support = {A142921//ALS Association/ ; }, abstract = {INTRODUCTION/AIMS: Specialty palliative care (SPC) can improve symptoms and well-being for people living with ALS. Few studies capture how ALS clinicians utilize or are impacted by SPC. We sought to understand how the presence of SPC clinicians on ALS teams impacts ALS clinicians' referrals to and satisfaction with SPC.<br><br>METHODS: We conducted a survey of interdisciplinary ALS clinicians to understand their confidence in their team's care, SPC referral patterns, and satisfaction with SPC. We compared responses from ALS clinicians with and without SPC in their team.<br><br>RESULTS: 141 ALS clinicians completed the survey, having primarily neurology, nursing, and therapy backgrounds. ALS clinicians who had SPC embedded in their team reported more confidence in their team's ability to address pain (63.3% v 37.4%, p&#x2009;<&#x2009;0.001), dyspnea (88.8% v 70.8%, p&#x2009;=&#x2009;0.05), and end-of-life needs (71.4% v 52.1%, p&#x2009;=&#x2009;0.005). They reported fewer SPC referral barriers and referred to SPC for different reasons. ALS clinicians with SPC on their team were more satisfied with SPC's ability to help with motor symptoms (92.7% v 71.4%, p&#x2009;=&#x2009;0.02), dyspnea (98.3% v 86.7%, p&#x2009;=&#x2009;0.04), and care coordination (90.0% v 73.5%, p&#x2009;=&#x2009;0.04).<br><br>DISCUSSION: The presence of SPC embedded within multidisciplinary ALS teams is associated with ALS clinicians feeling more confident in their team's ability to address certain care needs, more satisfied with the care provided by SPC, and experiencing fewer barriers to involving SPC. Additional research should explore how embedding SPC on ALS teams impacts patient outcomes.}, }
@article {pmid41963935, year = {2026}, author = {Zhang, B and Shang, D}, title = {Commentary on "Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells".}, journal = {Molecular cancer}, volume = {25}, number = {1}, pages = {}, pmid = {41963935}, issn = {1476-4598}, support = {2025AHGXZK40703//Anhui Provincial Department of Education Natural Science Research Youth Project/ ; 2025byjbgs064//Bengbu Medical University "Jie Bang Gua Shuai" Research Project/ ; 82374248//National Natural Science Foundation of China/ ; }, abstract = {We recently carefully read the article titled “Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells” published by Chu-An Wang et al. in Molecular Cancer. While this study provides valuable insights into tumor-immune crosstalk, we raise two points for clarification to enhance its precision. First, the manuscript classifies T2N0M0 samples as stage II pancreatic ductal adenocarcinoma (PDAC), which conflicts with the eighth edition of the AJCC Cancer Staging Manual that designates T2N0M0 as stage IB. Second, the authors used pancreatic stellate cells (PSCs) as a surrogate for fibroblasts to model stromal effects, but accumulating evidence indicates that PSCs and fibroblasts are not equivalent. To address this, we integrated single-cell, spatial, and bulk transcriptomic data from multiple cohorts. Our analyses revealed substantial differences between fibroblasts and stellate cells in abundance (fibroblasts enriched in primary pancreatic cancer tumor tissues), prognostic relevance (high fibroblasts associated with poorer survival, high stellate cells with better prognosis), spatial distribution (fibroblasts localized around malignant tumor cells), and intercellular communication (fibroblasts as stronger signal senders to malignant tumor cells). These findings confirm that PSCs cannot accurately represent fibroblasts in PDAC. We emphasize that clarifying these points will not undermine the study’s significance but will strengthen its rigor and comparability. Wang et al.’s work remains a valuable contribution to understanding PDAC progression, and we anticipate these clarifications will further advance stromal-immune crosstalk research in PDAC.}, }
@article {pmid42168859, year = {2026}, author = {Levin, AB and Joshi, Y and Vaidhya, N and Kantianis, J and Macdonald, PS}, title = {Anaesthetics considerations for organ retrieval in the voluntary assisted dying patient - case report.}, journal = {BMC anesthesiology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12871-026-03921-w}, pmid = {42168859}, issn = {1471-2253}, abstract = {BACKGROUND: Voluntary assisted dying (VAD) is now legalised in several countries. Organ donation after VAD provides unique moral and logistical challenges. This report highlights the role of the anaesthetist in such cases.<br><br>CASE PRESENTATION: A 50-year-old man with end-stage amyotrophic lateral sclerosis underwent VAD and became an organ donor. Anaesthetic and logistical considerations during procurement are described. Advances in organ retrieval after VAD and psychosocial implications are briefly outlined.<br><br>CONCLUSIONS: Organ donation after VAD presents unique opportunities and challenges. The anaesthetist plays a key role in ensuring both dignity for the patient and optimal conditions for organ retrieval.}, }
@article {pmid42169130, year = {2026}, author = {Sarti, A and Mandrioli, J and Costanzini, S and Balbo, GX and Malagoli, C and Martini, N and Despini, F and Violi, F and Malavolti, M and Martinelli, I and Giacchino, M and Donelli, G and Canali, E and Zinno, L and Teggi, S and Vinceti, M and Filippini, T}, title = {Green space exposure and risk of amyotrophic lateral sclerosis: a population-based case-control study in Northern Italy.}, journal = {Environmental health : a global access science source}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12940-026-01311-w}, pmid = {42169130}, issn = {1476-069X}, support = {"PRIN 2022" (No. 2022MHMRPR)//Ministero dell'Universit&#xe0; e della Ricerca/ ; "UNIMORE FAR 2023"//Universit&#xe0; Degli Studi di Modena e Reggio Emilia/ ; }, abstract = {BACKGROUND: The contribution of environmental determinants in the etiology of amyotrophic lateral sclerosis (ALS) is still unclear. Among the various environmental factors, exposure to green spaces, also known as greenness, is attracting considerable interest as many studies have reported its beneficial associations to health outcomes, particularly to neurodegenerative diseases.<br><br>METHODS: To investigate the relation between greenness and ALS risk, we conducted a population-based case-control study in a Northern Italy population (from Modena, Reggio Emilia and Parma provinces), including 499 cases of ALS newly-diagnosed from 1998 to 2011 and 1,935 sex-, age-, and province-matched controls randomly selected from study provinces residents. We evaluated the association between greenness in the proximity of residence and ALS risk, assessing exposure through multiple satellite-based and land-use derived indices, both conventional and novel devised, for a total of six indices, each providing specific information, including annual and seasonal Normalized Difference Vegetation Index (NDVI), NDVI-weighted to green areas, green cover ratio, accessibility index, and their combined Green Exposure Index (GEI). We used conditional logistic regression models to evaluate disease risk for increasing exposure through both fixed-categories and non-linear restricted cubic splines.<br><br>RESULTS: We observed a non-linear U-shaped association between greenness and ALS risk with increased odds ratios at both low and high levels. Results were more defined when using NDVI-based indices, while the associations were smoother when considering GEI. The higher risk at low levels may be related to lower accessibility to green spaces with lower physical activity and higher exposure to outdoor air pollutants, whilst elevated greenness may reflect higher exposure to neurotoxic pesticides. These results were confirmed also after adjustment for potential confounders, namely magnetic fields and light at night. Sex stratified analysis yielded similar results, except for more distinct associations in females for GEI.<br><br>CONCLUSIONS: Despite the limitations due to possible unmeasured confounding and exposure misclassification related to the use of residential data, our results provide evidence of an inverse association between intermediate residential greenness and ALS risk, and may have public health implications including disease prevention and urban planning.}, }
@article {pmid42170697, year = {2026}, author = {Prasun, P and Rasberry, M}, title = {Expanding Spectrum of FIG4-Related Neurological Disorders of Lysosomal Homeostasis: Case Report and Overview of the Potential Genotype-Phenotype Correlations.}, journal = {Clinical genetics}, volume = {}, number = {}, pages = {}, doi = {10.1111/cge.70185}, pmid = {42170697}, issn = {1399-0004}, abstract = {Biallelic loss-of-function variants in FIG4 are associated with Charcot-Marie-Tooth disease type 4J, a progressive peripheral sensorimotor demyelinating polyneuropathy. Biallelic null FIG4 variants cause Yunis-Varon syndrome, a severe neurological disorder characterized by global developmental delay, hypotonia, brain malformations, skeletal defects, dysmorphic facial features, and juvenile lethality. In the past few years, many individuals with combined central and peripheral nervous system disease associated with biallelic FIG4 variants have been described. In addition, certain heterozygous FIG4 variants are associated with amyotrophic lateral sclerosis. We describe an individual with global developmental delay, hypotonia, cerebral hypomyelination, peripheral hypomyelinating polyneuropathy, frequent fractures, and juvenile ossifying fibroma. The spectrum of clinical presentation of FIG4-related disorders is increasingly being recognized. Our observations expand the phenotypic spectrum of FIG4-related neurological disorders. In addition, we provide an overview of the potential genotype-phenotype correlations of this expanding group of disorders of lysosomal homeostasis.}, }
@article {pmid42170793, year = {2026}, author = {Michelon, H and Lefèvre-Dognin, C and Paquereau, J and Guidoni, R and Boudy, V and Ruiz, F and Vallet, T}, title = {Acceptability of Atropine Eyedrops Administered Sublingually for Sialorrhea Treatment Related to Neurological Conditions.}, journal = {Pharmacology research &amp; perspectives}, volume = {14}, number = {3}, pages = {e70250}, doi = {10.1002/prp2.70250}, pmid = {42170793}, issn = {2052-1707}, mesh = {Humans ; *Sialorrhea/drug therapy/etiology ; *Atropine/administration &amp; dosage ; Male ; Middle Aged ; Cross-Sectional Studies ; Female ; Adult ; Ophthalmic Solutions/administration &amp; dosage ; Aged ; Administration, Sublingual ; *Nervous System Diseases/complications ; France ; *Patient Acceptance of Health Care ; *Cholinergic Antagonists/administration &amp; dosage ; }, abstract = {Off-label use of anticholinergic agents (atropine eye drops) administered sublingually are a first-line treatment in standard clinical practice in France to treat sialorrhea in patients with neurological conditions. The ability and willingness to using and administering such medication have become key factors to ensure safe and effective therapy. Given that the critical aspects for ophthalmic product development differ from those for oral medicine, the objectives of this study were to investigate patient acceptability of atropine eye drops for treating sialorrhea. A multi-centric, cross-sectional study using the CAST-ClinSearch Acceptability Score Test methodology was conducted in France between February 2021 and April 2023. In total, 31 evaluations were collected. Most patients were males (74.2%) and the mean age was 51.6 ± 20 years. Poor acceptability was reported in real-life settings. A lack of a suitable administration device combined with excessive saliva flow and patient disabilities made it difficult to ensure the required dose intake. Due to the bitter taste of the drug, poor palatability of the product appeared to be a key concern for oral administration. Designing a suitable form of atropine in accordance with the specificities of patients with neurological disabilities is needed to ensure the effective treatment of sialorrhea.}, }
@article {pmid42170807, year = {2026}, author = {Renou, Q and Néant, N and Destere, A and Lagoutte-Renosi, J and Grégoire, M and Parant, F and Lalanne, S and Lemaitre, F and Gandia, P and Venisse, N and Bouchet, S and Lê, MP and Muret, P and Peytavin, G and Solas, C and Benaboud, S and , }, title = {External Evaluation of Population Pharmacokinetic Models of Cabotegravir, During Its Oral and Intramuscular Administration in HIV-Infected Patients.}, journal = {CPT: pharmacometrics &amp; systems pharmacology}, volume = {15}, number = {6}, pages = {e70180}, doi = {10.1002/psp4.70180}, pmid = {42170807}, issn = {2163-8306}, support = {ANRS 0255//Agence Nationale de Recherches sur le Sida et les H&#xe9;patites Virales (ANRS)/Maladies Infectieuses Emergentes/ ; ANRS 0691b//Agence Nationale de Recherches sur le Sida et les H&#xe9;patites Virales (ANRS)/Maladies Infectieuses Emergentes/ ; }, mesh = {Humans ; *HIV Infections/drug therapy ; Injections, Intramuscular ; *Models, Biological ; Female ; Male ; *Anti-HIV Agents/pharmacokinetics/administration &amp; dosage ; Administration, Oral ; Middle Aged ; Adult ; *Pyridones/pharmacokinetics/administration &amp; dosage ; Prospective Studies ; Diketopiperazines ; }, abstract = {Cabotegravir (CAB), combined with rilpivirine, is the first long-acting injectable therapy approved for HIV-1 maintenance treatment. While adherence and patient satisfaction have been improved, pharmacokinetic (PK) variability remains a concern. Two population PK models have been developed: one based on data from phase I-III trials and the other on routine clinical data. However, neither model has undergone thorough external evaluation. The aim of this study was to evaluate the predictive performance of these models using an independent prospective dataset to evaluate their suitability to support model-informed precision dosing (MIPD). External validation was performed using data from the French observational and multicenter (n = 14) ANRS0255 CARLAPOP study (736 HIV-infected patients, representing 2192 concentrations). Models were implemented using MONOLIX software and evaluated using goodness-of-fit, prediction-based, and simulation-based diagnostics. For Han's model, regarding plasma concentrations following intramuscular administration, Median Prediction Error (MDPE) was -1.2% (PRED) and -4.4% (IPRED); Median Absolute Prediction Error (MDAPE) was 36.6% (PRED) and 17.9% (IPRED). For Thoueille's model, MDPE was -24.2% (PRED) and -9.2% (IPRED); MDAPE was 39.0% (PRED) and 15.3% (IPRED). However, < 70% of predictions were within a 20% error margin with both models. Graphical analyses of Thoueille's model showed systemic bias, particularly in women, nonsmokers, and patients with higher body mass index. Therefore, neither model was considered reliable enough for MIPD application in our population. Although Han et al.'s model demonstrated higher predictive performances, further improvements are required before it can be reliably applied for MIPD in daily routine.}, }
@article {pmid42171198, year = {2026}, author = {Tian, J and Jin, Z and Chi, Y and Wang, P and Sun, H}, title = {Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.}, journal = {Nanoscale}, volume = {}, number = {}, pages = {}, doi = {10.1039/d6nr00300a}, pmid = {42171198}, issn = {2040-3372}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by a progressive and selective loss of motor neurons in the central nervous system, particularly in the brain and spinal cord. However, the main cellular mechanisms and cell death pathways leading to motor neuron degeneration have not yet been clarified. Research indicates evidence of ferroptosis in ALS, and the natural compound kaempferol has been demonstrated to inhibit neuronal ferroptosis. However, damage to the blood-brain barrier (BBB) prevents the drug from penetrating the central nervous system, which significantly reduces its therapeutic efficacy. Here, we developed a targeted delivery system named Eda/Kae@Lip-RGD (EKLR), which consisted of liposome-grafted RGD peptides for the co-delivery of the drugs kaempferol and edaravone, capable of crossing the BBB to provide co-delivery of kaempferol and edaravone for combined treatment of ALS. As expected, treatment with EKLR for one month significantly slowed down weight loss and improved athletic performance in SOD1[G93A] transgenic mice. Mechanistically, this nanomedicine suppressed ferroptosis by upregulating the antioxidant proteins GPX4 and SLC7A11, alongside the downregulation of Nrf2 and ACSL4 levels, thus collectively preserving neuronal integrity. Meanwhile, EKLR restored the normal morphology and the survival rate of neurons and maintained the mitochondrial structure and morphological integrity. Accordingly, this nanoplatform may represent a distinctive and potentially effective strategy for achieving neuroprotection in ALS as well as in other disorders of the central nervous system.}, }
@article {pmid42171508, year = {2026}, author = {Ramos, S and Watson, MD and Lee, JC}, title = {Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.6c00226}, pmid = {42171508}, issn = {1948-7193}, abstract = {Cytosolic inclusions of aggregated TAR DNA-binding protein 43 (TDP-43) are hallmarks of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. A prevailing hypothesis suggests that TDP-43 condensates undergo a liquid-to-solid transition during maturation, involving the formation of β-sheet-rich, amyloid-like aggregates. To test this hypothesis, we sought to study the temporal and spatial evolution of protein secondary structure within individual condensates by Raman spectroscopy. We measured in vitro β-sheet development of the C-terminal domain of TDP-43 (TDP-43CTD) at the single-condensate level under physiological solution conditions. All condensates showed apparent single-exponential kinetics (k = 1.6 × 10[-5] s[-1]) for the disordered-to-β-sheet transformation, as indicated by increased amide-I intensity and a shift of the amide-III band to lower energy. Interestingly, the water bend-libration band exhibited a slower rate (k = 4.0 × 10[-6] s[-1]), suggesting that changes in the water environment lag behind protein conformational rearrangement. Further, Raman maps revealed that protein density is highest near the condensate center, whereas β-sheet content is mostly uniform in the interior of the condensate. The unexpected difference between the spatial distributions of β-sheet content and protein density challenges the typical concentration-dependent model of protein aggregation. Importantly, rare events were captured where condensates exhibited spatially asymmetric β-sheet development, revealing localized structural heterogeneity not detectable by ensemble measurements. Collectively, these results provide insight into the temporal and spatial dynamics of protein structure within TDP-43CTD condensates and demonstrate the utility of Raman spectral imaging for tracking condensate maturation.}, }
@article {pmid42171861, year = {2026}, author = {Condorelli, GA and Iozzia, A and Bonifacio, D and Pelin, A}, title = {TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42171861}, issn = {1573-6903}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/immunology ; Humans ; Acetylation ; *DNA-Binding Proteins/metabolism ; Animals ; *Inflammation/metabolism/immunology ; Blood-Brain Barrier/metabolism ; *Neuroimmunomodulation/physiology ; }, abstract = {Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and mislocalisation, TDP-43 enters the periphery; acetylation shapes its conformation, trafficking and immunogenicity. This narrative review synthesises single-cell transcriptomics, proteomic immunoprofiling and clinical inflammatory phenotyping to examine whether site-specific acetylated TDP-43 species may be associated with peripheral inflammatory signatures relevant to ALS immunopathology. By integrating separate datasets on acetylated TDP-43, monocyte phenotypes and cytokine modules, we propose two provisional endotypes characterised by monocyte reprogramming, cytokine modules and Blood-Brain Barrier (BBB) dysfunction-each representing clinically actionable pathways. Framed as a provisional neuroimmune interface, the acetylation state is considered here as a plausible molecular correlate and potential therapeutic entry point: a measurable clue to inform pharmacological targeting and, potentially, a modifiable target via p300CREB-Binding Protein (CBP)-Histone Deacetylase (HDAC) axes or sirtuin activity. Recasting TDP-43 from neuropathological hallmark to immunoactive sentinel supports a shift from descriptive nosology to stratified immunotherapy, in which treatment allocation is informed by acetylation-defined peripheral signatures.}, }
@article {pmid42166253, year = {2026}, author = {Fung, WY and Agustini, S and Amornvit, J and Chai, J and Damian, LF and Fadli, N and Pg Hj Mohd Yassin, DHN and Keovilayhong, S and Krishnan, D and Kulkantrakorn, K and Nguyen Tran, MD and Ng, K and Nghia, HTT and Ohnmar, O and Pengiran Tengah, DSNA and Prado, M and Remli, R and Rojana-Udomsart, A and Le Tuan, TQ and Yanuar, A and Shahrizaila, N}, title = {Strengthening care and research in ALS in Southeast Asia: a call for action.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2026.2671159}, pmid = {42166253}, issn = {2167-9223}, abstract = {In Southeast Asia (SEA), healthcare resources, infrastructure, and access to therapies in amyotrophic lateral sclerosis (ALS) remain limited compared to other parts of the Asia-Pacific region. Many SEA countries continue to face delays in diagnosis, fragmented care pathways, and limited representation in international research. Beyond health system challenges, ALS in SEA may also differ biologically. Emerging studies suggest that genetic variants and clinical phenotypes in Asian populations are not fully mirrored in Western cohorts. In this report, the authors summarize their country-specific background and status of care in ALS as well as their consensus on future strategies and actions. Key short- and long-term strategies are proposed, highlighting the critical need for regional collaboration and patient engagement to advance ALS care and research in the region.}, }
@article {pmid42166260, year = {2026}, author = {Liu, W and Li, Y and Sun, J and Wang, G and You, K and Xie, L and Chen, J}, title = {Data-Driven Internal Model Control for Output Regulation.}, journal = {IEEE transactions on cybernetics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TCYB.2026.3690605}, pmid = {42166260}, issn = {2168-2275}, abstract = {Output regulation is a fundamental problem in control theory, extensively studied since the 1970s. Traditionally, research has primarily addressed scenarios where the system model is explicitly known, leaving the problem in the absence of a system model less explored. Leveraging recent advances in Willems et al.'s fundamental lemma, data-driven control has emerged as a powerful tool for stabilizing unknown systems. This article tackles the output regulation problem for unknown single and multiagent systems (MASs) using noisy data. Many existing data-driven approaches rely on solving data-based output regulator equations (OREs), which become inadequate for achieving zero tracking error in the presence of noisy data. To overcome this limitation, we advocate the use of a classical tool from robust output regulation, namely, the internal model principle. We first apply this idea to linear time-invariant (LTI) systems and show that exact output regulation, that is, zero tracking error, can be achieved by solving a simple data-based linear matrix inequality (LMI). The framework is then extended to the $k$ th-order output regulation problem for nonlinear systems, followed by applications to both linear and nonlinear MASs. Finally, numerical tests validate the effectiveness of the proposed data-driven controllers.}, }
@article {pmid42166277, year = {2026}, author = {De Los Reyes, A}, title = {Toward integrative, multisource, and multimodal approaches to assessing psychopathology intergenerationally and across the lifespan: Commentary on Caspi et al. (2026).}, journal = {Journal of psychopathology and clinical science}, volume = {135}, number = {4}, pages = {495-497}, doi = {10.1037/abn0001084}, pmid = {42166277}, issn = {2769-755X}, mesh = {Humans ; *Mental Disorders/diagnosis ; *Psychopathology/methods ; }, abstract = {Models of psychopathology contain constructs that cannot be directly observed. Assessing these constructs involves identifying specific behaviors that justifiably serve as "markers" of their presence, thus facilitating their precise and accurate measurement. Examples of these behavioral markers include the destruction of property for conduct disorder, the avoidance of unfamiliar people for social anxiety, and sleeping too much or too little for depression. These and other behavioral markers typify the measurement of both specific mental disorders as well as "p" as a transdiagnostic index of psychopathology. Importantly, researchers commonly implement measurement, methodological, and data-analytic practices that conflict with the data conditions that underlie psychopathology studies. For example, researchers often rely on one source to measure behavioral markers of psychopathology (e.g., self-report), even though 60 years of research indicate that the measurement source robustly dictates the conclusions of psychopathology studies. When researchers measure markers of psychopathology with multiple sources, they often integrate these multisource data using data-analytic strategies that misclassify valid data as measurement error; these misclassifications beget underpowered studies and, by logical extension, replication failures. These issues pertain to psychopathology research more broadly, but they also facilitate interpreting Caspi et al. (see record 2026-80066-001), and the foundation it sets for studying psychopathology both developmentally and intergenerationally. In this commentary, I highlight measurement, methodological, and data-analytic issues inspired by Caspi et al. and summarize work that supports their careful consideration. Caspi et al.'s findings call for developing integrative, multisource, and multimodal assessments that optimize the validity of psychopathology assessments intergenerationally and across the lifespan. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42166281, year = {2026}, author = {Harden, KP}, title = {In praise of scientific open relationships: Commentary on Caspi et al. (2026).}, journal = {Journal of psychopathology and clinical science}, volume = {135}, number = {4}, pages = {505-506}, pmid = {42166281}, issn = {2769-755X}, support = {//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; /DA/NIDA NIH HHS/United States ; }, mesh = {Humans ; *Mental Disorders ; *Biomedical Research ; }, abstract = {This commentary responds to arguments presented in Caspi et al.'s (see record 2026-80066-001) viewpoint article. I endorse the authors' overall argument but note that exactly how many mental disorders one needs to study at a time will likely depend on the specific research question. I also describe how transdiagnostic research requires strong norms of data and credit sharing. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42166316, year = {2026}, author = {Meca, A and Cruz, B and Cruz, I and Hinojosa, Z and Nguyễn, M and Gonzales-Backen, M}, title = {Revisiting the two-factor model of ethnic-racial and U.S. identity exploration among Hispanic college students.}, journal = {Cultural diversity &amp; ethnic minority psychology}, volume = {}, number = {}, pages = {}, doi = {10.1037/cdp0000810}, pmid = {42166316}, issn = {1099-9809}, abstract = {OBJECTIVE: Establishing a positive ethnic-racial identity (ERI) and U.S. identity (USI) is an important cultural asset capable of promoting positive adjustment. Although exploration has been identified as the fundamental process underlying ERI and USI development, existing research has largely utilized a unidimensional conceptualization. The present study sought to replicate Syed et al.'s (2013) findings, which differentiated between two forms of ERI exploration, search (i.e., reflection/talking to others) and participation (i.e., involvement in events/experiences), and extend to USI. Moreover, we sought to examine the unique associations between ERI and USI exploration with resolution and negative affect.<br><br>METHOD: The sample included 416 Hispanic/Latine college students (83.7% female; Mage = 20.57 years) recruited from a psychology department participant pool at a public Hispanic-serving institution in South Florida in 2017. Participants completed the online survey at their convenience in exchange for course credit.<br><br>RESULTS: Findings provided support for the differentiation between ERI and USI search and participation, which were uniquely and differentially associated with resolution and negative affect.<br><br>CONCLUSION: Our study highlights the need to move beyond unidimensional conceptualizations of exploration. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42166520, year = {2026}, author = {Marques Couto, C and De Melo Queiroz, E and Souza Lima, W and Camilla De Lima Santos, S and José Moreira Nascimento, O}, title = {Clinical characterization and natural history of ALS8/VAPB p.Pro56Ser: upper motor neurone signs, survival, and functional milestones in 78 patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2674020}, pmid = {42166520}, issn = {2167-9223}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis type 8 (ALS8), caused by the VAPB p.Pro56Ser mutation, is a rare familial motor neurone disease with an incompletely characterized profile. We aimed to characterize the clinical phenotype, upper motor neurone (UMN) sign prevalence, survival, and functional milestones.<br><br>METHODS: We retrospectively analyzed 78 patients with ALS8 confirmed via molecular testing or familial linkage analysis from 57 apparently unrelated families. UMN signs were assessed using a five-item composite of pyramidal signs. Survival and milestones were estimated using Kaplan-Meier analysis.<br><br>RESULTS: Median age at onset was 44.9&#x2009;years; 51% were men. Onset was lumbar in 94%, proximally predominant. UMN signs were present in 53 patients; none exhibited clonus. At admission, 51% had spinal-onset ALS, 42% progressive muscular atrophy (PMA) and 6% flail leg; 30% of patients with PMA subsequently developed UMN signs. Survival was 21.9&#x2009;years; times to wheelchair dependence and noninvasive ventilation were 7.0 and 10.0&#x2009;years, respectively. Bulbar involvement occurred in 17 (21.8%) patients, predominantly as dysphonia. UMN status did not affect survival (p&#x2009;=&#x2009;0.312). The standardized mortality ratio was 4.54 (95% CI 2.77-7.01), supporting disease-related excess mortality.<br><br>CONCLUSIONS: ALS8 is a slowly progressive motor neurone disease with lumbar onset, ascending progression, and frequent but subtle UMN signs. Survival was markedly prolonged but functional decline followed a predictable sequence. These findings expand the phenotypic characterization of ALS8 and support genetic counseling and anticipatory management.}, }
@article {pmid42167402, year = {2026}, author = {Ballesteros, AL and Rodriguez-Cañamero, S and Martín-Conty, JL and Polonio-López, B and Pozo-Vegas, CD and López-Izquierdo, R and Martín-Rodríguez, F and Sanz-García, A}, title = {Effect of Glycemia and Diabetes on Early Warning Scores Performance in Prehospital Patients With Acute Illness: Multicenter, Prospective, Cohort Study.}, journal = {Mayo Clinic proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mayocp.2026.05.008}, pmid = {42167402}, issn = {1942-5546}, abstract = {OBJECTIVE: To determine how glycemia and diabetes affect the performance of the NEWS and mSOFA scores to predict 30-day mortality in patients with acute illnesses requiring EMS assistance.<br><br>PARTICIPANTS AND METHODS: This prospective, multicenter cohort study evaluated 14,726 adults with acute illness attended by advanced life support (ALS) units and helicopter emergency medical services (HEMS) between January 1, 2019, and December 1, 2025. Associations between glucose levels (hypoglycemia, normoglycemia, hyperglycemia), diabetic status, and 30-day mortality were analyzed. Predictive capacity (area under the receiver operating characteristic curve, AUC-ROC) of NEWS and mSOFA stratified by metabolic groups was assessed and compared.<br><br>RESULTS: A nonlinear U-shaped relationship was observed between glycemia and mortality. mSOFA outperformed NEWS (AUC-ROC 0.877 vs 0.822). Under hyperglycemia, NEWS performance decreased (AUC-ROC 0.764), while mSOFA remained more stable (AUC-ROC 0.815). Both scores performed better in nondiabetic patients (AUC-ROC >0.82) than in diabetics with complications, suggesting stress hyperglycemia in nondiabetics reflects greater acute severity.<br><br>CONCLUSIONS: mSOFA showed greater robustness and more stable predictive performance than NEWS with glycemic variability, particularly in nondiabetic patients with stress hyperglycemia, suggesting glucose serves as a universal biomarker of acute severity across prehospital acute illness. These findings support potential value of prehospital POCT to improve critical patient identification and risk stratification where resources and infrastructure allow.}, }
@article {pmid42168009, year = {2026}, author = {Corcia, P and Bernard, E and de la Cruz, E and Danel, V and Soriani, MH and Guy, N and Esselin, F and Bruneteau, G and Pradat, PF and Goutines, V and Catherine, J and Eyraud, N and Cheve, P and Fernandez, A and Erazo, D and Couratier, P}, title = {Primary Lateral Sclerosis French National Diagnostic and Care Protocol.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2026.04.006}, pmid = {42168009}, issn = {0035-3787}, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative motor neuron disease characterized by progressive and selective involvement of the central motor neuron within the bulbar and spinal regions. It is estimated to account for 1-5% of motor neuron diseases and typically presents in the fifth or sixth decade of life, with a slight male predominance. According to current consensus criteria, the diagnosis relies on the demonstration of progressive upper motor neuron dysfunction in the absence of lower motor neuron involvement, with persistence of isolated upper motor neuron signs for at least four years in order to exclude a slowly progressive upper motor neuron-predominant form of amyotrophic lateral sclerosis (ALS). The French Motor Neuron Disease Network (FILSLAN) developed a National Diagnostic and Care Protocol (PNDS) with the aim of standardizing diagnostic criteria, optimizing differential diagnosis, and providing evidence-based recommendations for therapeutic management and follow-up across the national territory. These recommendations were elaborated in accordance with the methodological framework of the French National Authority for Health for rare diseases. The protocol provides practical guidance for establishing PLS as a diagnosis of exclusion, distinguishing it from ALS and hereditary spastic paraplegias, and organizing appropriate clinical and paraclinical investigations. It also outlines indications for genetic testing in selected cases and defines a multidisciplinary management strategy centered on symptomatic treatment, early rehabilitation, respiratory and nutritional surveillance, and psychosocial support. Given the slower progression of PLS compared with ALS, biannual multidisciplinary follow-up is generally appropriate. This protocol aims to harmonize clinical practice and improve patient care while acknowledging the current absence of disease-modifying therapies.}, }
@article {pmid42159145, year = {2026}, author = {Gray, M and Truong, MT}, title = {Invited Commentary on: Modi et al.'s "Development of a Structured Tool for Evaluation of Auricular Reconstruction for Microtia".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261452864}, doi = {10.1177/26893614261452864}, pmid = {42159145}, issn = {2689-3622}, }
@article {pmid42159474, year = {2026}, author = {Mueller, A and Vallejo, V and Panadés, MP and Hardiman, O and Danel-Brunaud, V and Ajroud-Driss, S and Couratier, P and Shefner, J and Gokey, A and DiCesare, M and Lennox, E and Praestgaard, J and Brujin, L and Allred, P and Miller, R}, title = {Evaluation of Digital Technologies for Home-Based Assessment in People With Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70429}, pmid = {42159474}, issn = {2328-9503}, support = {//Novartis Pharma AG/ ; }, abstract = {OBJECTIVE: Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: This was a longitudinal study in people with ALS who were followed up to 9&#x2009;months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures.<br><br>RESULTS: Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants).<br><br>INTERPRETATION: The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.}, }
@article {pmid42159475, year = {2026}, author = {Sewak, A and Inácio, V and Wuu, J and Benatar, M and Hothorn, T}, title = {Likelihood-based modeling of covariate-specific time-dependent receiver operating characteristic curves.}, journal = {Statistical methods in medical research}, volume = {}, number = {}, pages = {9622802261445416}, doi = {10.1177/09622802261445416}, pmid = {42159475}, issn = {1477-0334}, abstract = {Identifying reliable biomarkers for predicting clinical events in longitudinal studies is important for accurate disease prognosis and for guiding development of new treatments. However, prognostic studies are often observational, making it difficult to account for patient heterogeneity. In amyotrophic lateral sclerosis (ALS), factors such as age, site of onset and genetic status influence both survival and biomarker levels, yet their impact on the prognostic accuracy of biomarkers over time remains unclear. While time-dependent receiver operating characteristic methods have been developed to handle censored time-to-event outcomes, most do not adjust for covariates. To address this, we propose the nonparanormal prognostic biomarker framework, which models the joint distribution of the biomarker and event time while accounting for covariates. This allows estimation of covariate-specific time-dependent receiver operating characteristic curves and related summary measures. We apply the NPB framework to evaluate serum neurofilament light as a prognostic biomarker in ALS, showing that its accuracy varies over time and with patient characteristics. By capturing these covariate-specific effects, the NPB framework supports more targeted risk stratification and can potentially improve the design of clinical trials for new ALS treatments.}, }
@article {pmid42160473, year = {2026}, author = {Kim, S and Curtis, SE and Iacono, D and Mehdiyoun, NF and Mitchell, L and Genge, A and Brandt, AU and ,  and Mancini, M}, title = {Types and frequencies of adverse events across clinical trials for patients with amyotrophic lateral sclerosis: an analysis of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2667290}, pmid = {42160473}, issn = {2167-9223}, abstract = {OBJECTIVE: Symptoms of amyotrophic lateral sclerosis (ALS) may present as adverse events (AEs) in ALS clinical trials. Identifying anticipated AEs independent of investigational drug is crucial for trial design and required by the FDA for safety reporting and assessment in drug development. This study describes anticipated AEs and their predicted incidence in ALS trials, leveraging data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.<br><br>METHODS: Placebo-treated people living with ALS (age &#x2265;18&#x2009;years, disease duration &#x2264;36&#x2009;months, &#x2265;50% of predicted vital capacity at screening) were included. A confirmed diagnosis per the El Escorial criteria was required for a sensitivity analysis. Reported AEs were grouped based on pathophysiology and implications in clinical management and safety monitoring. AEs were further consolidated, with seven anticipated groups pre-specified for analysis. AE incidence proportions (IPs) and rates in person-years were estimated.<br><br>RESULTS: The analysis included 1,388 participants (mean [SD] age: 56.8 [11.3] years; mean [SD] disease duration: 1.4 [0.6] years). IP was &#x2265;5% for 24 AE groups, highest for falls and injuries (18.8%), headaches (13.5%), muscle weakness (13.1%), and gastrointestinal signs and symptoms (13.1%). Of seven pre-specified AE groups, falls, injuries, and fractures were the most frequent (23.0%), followed by severe respiratory failure and disorders including dyspnea (19.1%) and dysphagia (10.5%). Sensitivity analysis results were comparable (n&#x2009;=&#x2009;931), although IPs were generally lower.<br><br>CONCLUSIONS: These new findings will facilitate a systematic approach for safety monitoring and reporting in ALS trials, enable detection of true safety signals that may be obscured by these events, and support clinical development.}, }
@article {pmid42160478, year = {2026}, author = {Cosijn, FS and van Unnik, JWJ and Exalto, LG and de Groot, LN and Weemering, DN and van Rijssen, RC and Vink, RG and van den Berg, LH and van Eijk, RPA}, title = {Clinical drug development in amyotrophic lateral sclerosis: industry-reported challenges and opportunities.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2671167}, pmid = {42160478}, issn = {2167-9223}, abstract = {OBJECTIVE: The pharmaceutical industry plays a pivotal role in amyotrophic lateral sclerosis (ALS) drug development, yet the challenges and priorities remain largely unexplored. This study aims to identify industry-perceived opportunities for ALS and examine industry perspectives on trial design.<br><br>METHODS: A survey study was conducted among pharmaceutical companies involved in ALS drug development. The survey was based on literature review and interviews with industry experts. Final survey topics included scientific and operational challenges as well as preferred design settings for phase 2 and 3 clinical trials. Respondents were asked to rank trial-related topics using Likert scales.<br><br>RESULTS: In total, 53 industry professionals responded, representing 42 international companies. Respondents identified three major scientific challenges: heterogeneity in disease progression, lack of reliable biomarkers, and insensitive efficacy measures. Insufficient funding, high dropout rates, and staffing shortages emerged as main operational barriers. For phase 2 trials, neurofilament light chain was most often prioritized as primary outcome, whereas the ALS Functional Rating Scale-Revised was prioritized for phase 3, although priority rankings varied considerably among respondents. Expected median sample sizes were 100 patients (range 20-300) for phase 2 and 300 patients (range 60-800) for phase 3. Overall, 58% of the respondents indicated that standardizing aspects of trial design could enhance trial quality and success rates.<br><br>CONCLUSIONS: This study provides an overview of the industry-perceived challenges, exposing strategic knowledge gaps related to disease and clinical heterogeneity. Standardization of key trial design elements may help mitigate these challenges and better align ALS drug development efforts.}, }
@article {pmid42160479, year = {2026}, author = {Catley, CS and Hoedt, EC and Pockney, P and Keely, S and Hedley, KE}, title = {Unravelling Anastomotic Leak: Biological Mechanisms Underlying Intestinal Healing After Resection.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajpgi.00071.2026}, pmid = {42160479}, issn = {1522-1547}, support = {//University of Newcastle Australia (UON)/ ; //Australian Government (Federal Government)/ ; G2300020//nswgov | NSW Health (The NSW Health)/ ; }, abstract = {Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases such as the inflammatory, proliferative and remodelling phase may result in severe complications, characterised by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer in understanding the underlying AL aetiology. It is clear that ALs are multifactorial in nature and contributed to by patient, technical and biological-related factors, however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors in failed anastomotic healing and AL aetiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing and the advancements made to improve AL rates by targeting the healing response.}, }
@article {pmid42160515, year = {2026}, author = {Zhang, M and Yang, W and Wang, J and Zou, B and Zheng, JC and Wu, Q and Gao, G}, title = {Immunotherapeutic landscape of amyotrophic lateral sclerosis: A bibliometric analysis of research trends, translational priorities, and collaboration networks (2006-2025).}, journal = {Human vaccines &amp; immunotherapeutics}, volume = {22}, number = {1}, pages = {2664985}, doi = {10.1080/21645515.2026.2664985}, pmid = {42160515}, issn = {2164-554X}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology ; Humans ; *Bibliometrics ; *Immunotherapy/methods/trends ; *Translational Research, Biomedical/trends ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a major therapeutic challenge, with immune dysregulation increasingly recognized as a critical driver of disease progression. Despite extensive mechanistic research, no immunotherapeutic approach has achieved consistent disease-modifying effects, raising questions about whether this translational gap reflects biological complexity or structural misalignment within the research ecosystem. To characterize the intellectual evolution of ALS immunotherapeutics research, identify immune targets with translational potential, and evaluate collaboration patterns that may influence translational efficiency, we performed a bibliometric analysis of 2,256 publications indexed in Web of Science and Scopus using network-based approaches including co-citation clustering, keyword co-occurrence, and citation burst detection implemented in CiteSpace, VOSviewer, and R-Bibliometrix. Publication output increased 8.4-fold over the study period, delineating three developmental phases. Thematic analyses revealed a shift from early emphasis on microglial biology and SOD1-based models toward recent focus areas including the gut-brain axis, C9orf72-associated immune dysregulation, and advanced immunomodulatory strategies. Collaboration networks remain predominantly regional despite strong contributions from the United States, Europe, and Asia, with limited integration between mechanistic research groups and clinical trial consortia. Among immune-directed therapeutic strategies, regulatory T cell modulation and microglial-targeted approaches exhibit the highest translational readiness. These findings suggest that the lack of effective ALS immunotherapeutics reflects not only biological complexity but also structural and strategic misalignment within the research ecosystem. This bibliometric analysis provides a systems-level framework to guide more integrated translational strategies in ALS immunotherapeutics development.}, }
@article {pmid42161327, year = {2026}, author = {Vallikivi, JK and Kooyman, M and ,  and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A}, title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag178}, pmid = {42161327}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.}, }
@article {pmid42161687, year = {2026}, author = {Carter, TE and Gunarathna, I}, title = {Reassessing malaria-transmitting mosquito evolution with a neotropical lens.}, journal = {Trends in parasitology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pt.2026.05.006}, pmid = {42161687}, issn = {1471-5007}, abstract = {Tennessen et al.'s study addresses longstanding knowledge gaps regarding the evolutionary drivers of a major Neotropical malaria vector, Anopheles darlingi. Through extensive whole-genome analysis, they revealed geographically structured An. darlingi populations with no evidence of sympatric species and strong signals of widespread insecticide resistance through convergent evolution.}, }
@article {pmid42161891, year = {2026}, author = {Liu, Y and Shi, K and Zhang, M and Wei, J and Feng, M and Dayan, FE and Tao, X and Feng, Z}, title = {Establishment of a versatile virus-based system for elucidating herbicide resistance in Galium aparine.}, journal = {Plant physiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/plphys/kiag285}, pmid = {42161891}, issn = {1532-2548}, abstract = {Herbicide resistance challenges sustainable weed management in crop fields. However, the lack of gene manipulation tools for weeds hinders studies of herbicide resistance evolution and regulation. Here, we identified that tobacco mosaic virus (TMV) can systemically infect Galium aparine, a noxious broadleaf weed common in wheat and rapeseed fields, among thirteen broadleaf weeds. The TMV-based expression system can be used to elucidate herbicide resistance in G. aparine. We demonstrated that virus-based expression of BAR, ALS and its site-directed mutagenized form in G. aparine plants can impart herbicide resistance. To expand the application of this system in metabolic resistance studies, ten upregulated P450 genes in the tribenuron-methyl-resistant G. aparine population plants were identified. Expression of these P450 genes in G. aparine via this system enhanced tribenuron-methyl resistance in G. aparine plants. Additionally, we confirmed Eleusine indica CYP81A104 functions in herbicide resistance through heterologous expression in G. aparine plants, suggesting that this system can be used to investigate the roles of genes from other weed species. The TMV vector-based assay system enabled the functional validation of weed genes within two months, which is shorter than the time required in other heterologous expression systems (i.e., stable expression of weed genes in rice or Arabidopsis). Thus, this virus-based system provides insights into target-site and/or metabolic-based resistance mechanisms to herbicides in G. aparine and possibly in other weed species.}, }
@article {pmid42162572, year = {2026}, author = {Mehta, AK and Steele, SU and Shah, I and Wang, K and Booth, A and Swain, C and Desai, A and Popli, KA and Maragakis, NJ and Wright, R}, title = {Improving ALS Clinic Care Through Experience-Based Co-Design: A Participatory Action Research Study.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70279}, pmid = {42162572}, issn = {1097-4598}, support = {//Harold Young Scholarship/ ; }, abstract = {INTRODUCTION/AIMS: Multidisciplinary clinics (MDCs) are the standard of care for amyotrophic lateral sclerosis (ALS), yet little is known about how well they meet patient and care partner needs, or how stakeholder engagement can be used to strengthen these services. The aim of this study was to explore the experiences of people living with ALS (pALS), care partners (cALS), and staff in an ALS MDC to identify care gaps and collaboratively develop improvement strategies.<br><br>METHODS: We conducted a six-stage experience-based co-design (EBCD) study comprising narrative interviews with pALS, cALS, and ALS clinic staff, followed by validation events and co-design workshops. Data were analyzed using reflexive thematic analysis. Priority areas for improvement were identified through collaborative ranking and translated into actionable interventions through iterative working groups.<br><br>RESULTS: A total of 11 pALS, eight cALS, and 10 clinic staff participated. Two shared priority domains were identified: (1) communication and relationships across the care continuum, and (2) navigational and supportive resources. Stakeholders unanimously identified communication and relationships between cALS and staff as the highest priority for improving MDC care delivery. Key strategies included pre-visit orientation materials, pacing information delivery aligned with patient readiness, and incorporating digital tools to enhance flexible access to resources.<br><br>DISCUSSION: Curated, iterative education is essential for pALS and cALS across the disease trajectory. Improvement strategies developed through equitable stakeholder partnership may yield different, and potentially more patient-centered priorities for ALS MDC care delivery than strategies developed by any single stakeholder group alone.}, }
@article {pmid42162905, year = {2026}, author = {Alamri, MA and Afzal, M and Pandey, SN and Afzal, O and Akela, MA and Rekha, A}, title = {Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {}, number = {}, pages = {121094}, doi = {10.1016/j.cca.2026.121094}, pmid = {42162905}, issn = {1873-3492}, abstract = {Cerebrospinal fluid protein biomarkers, such as the Aβ42/Aβ40 ratio, phosphorylated tau, and neurofilament light chain, have significantly advanced the diagnostic process for Alzheimer's disease. Nonetheless, these biomarkers face challenges in effectively distinguishing Alzheimer's disease from frontotemporal dementia or Parkinson's disease from dementia with Lewy bodies. This limitation arises from overlapping protein profiles and the variability inherent in immunoassay techniques. A complementary class of analytes is exosomal microRNAs in cerebrospinal fluid, where these non-coding RNAs are secreted by neurons, astrocytes, and microglia, are resistant to RNase degradation, and have a disease-specific expression pattern. This review critically evaluates the existing evidence of cerebrospinal fluid exosomal miRNAs as diagnostic biomarkers in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Exosome isolation techniques and detection platform characteristics were compared using RT-qPCR, droplet digital PCR, and small RNA sequencing. Pre-analytical factors, such as collection protocols, hemolysis contamination, freeze-thaw cycling, and circadian sampling variation, were assessed. miRNA profiling data based on disease stratification, receiver operating characteristic performance of the combinatorial panel, and strategies combining exosomal miRNAs with core cerebrospinal fluid proteins were synthesized. This article brings together disease-specific miRNA signatures, pre-analytical standardization needs, and diagnostic accuracy analyses in a translational model to fill the literature gap and form the basis for developing exosomal miRNA panels for rigorously validated clinical laboratory practice.}, }
@article {pmid42163674, year = {2026}, author = {Qi, M and Fei, L and Cui, W and Ho, PW and Lee, SM and Li, J and Zhang, Z}, title = {Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X431460260227095109}, pmid = {42163674}, issn = {1875-6190}, abstract = {Amyotrophic lateral sclerosis (ALS) is an devastating neurodegenerative disorder with a very fast course and a very high fatality rate. The review discusses the intricate pathophysiology of ALS, such as the alterations caused by the genetic mutations of the C9orf72 and SOD1 genes, the misfolding and aggregation of proteins, oxidative stress, the excitotoxicity of glutamate, neuroinflammation, malfunctions in mitochondria, and axonal transport. Heterogeneity of the disease makes the development of biomarkers in ALS challenging; however, some promising candidates have been identified. Protein aggregation markers, including TDP-43 and SOD1, oxidative stress markers, such as 8-oxodG, neuroinflammatory markers, such as CRP and MCP-1, and neurological injury markers, such as NfL and pNfH, have potential in diagnosis, monitoring, and prediction. The miRNAs and particular metabolites can also provide clues to the molecular basis of ALS. The creation of biomarkers is challenged by the presence of a significant amount of disease heterogeneity and the lack of animal model reliability. The review highlights the importance of further research on biomarkers aimed at improving the diagnosis, treatment, and development of drugs for ALS. It supports the concept of a systematic biomarker development process, including genetic testing and molecular subgroup analysis, to enhance diagnostic accuracy and prognostic prediction capabilities. Exploring the interrelationship between the pathological process of ALS and the treatment based on multi-biomarker strategies is crucial for achieving effective management of this disease. As our understanding of ALS deepens, we expect to discover more new biomarkers in the future. This will significantly improve the diagnosis, treatment, and overall management of this devastating diseas.}, }
@article {pmid42163677, year = {2026}, author = {Tiwari, D and Mukherjee, A and Singh, S}, title = {Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X466249260418090832}, pmid = {42163677}, issn = {1875-6190}, abstract = {Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca[2+] signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca[2+]-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca[2+]-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.}, }
@article {pmid42164014, year = {2026}, author = {Cheung, N}, title = {Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.}, journal = {Cureus}, volume = {18}, number = {5}, pages = {e109147}, pmid = {42164014}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.}, }
@article {pmid42164185, year = {2026}, author = {Albesher, AA and Muflehi, NA and Hakami, YA and Barnawi, JA and Softah, RE and Al Ghalib, LH and Bukhari, MA and Almotiri, RA and Algethami, MS and Mahboob, SW and Hakami, RK and Alsaad, A}, title = {Top 50 Cited Articles on the Treatment of Major Depressive Disorder.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e107337}, pmid = {42164185}, issn = {2168-8184}, abstract = {Major depressive disorder (MDD) is a common mental health disorder and is one of the leading causes of disability. Numerous treatment modalities have been studied for MDD, from interventions to psychotherapies. However, no exhaustive investigation has yet provided an overview of influential research on MDD treatments. Studies do not cover influential efforts occurring in the form of a comprehensive bibliometric review. This bibliometric study aims to fill this gap by thoroughly examining the characteristics of the 50 most cited articles on MDD treatment and providing an essential understanding of the intellectual structure and historical development over time. To guarantee a comprehensive research collection of trends in the treatment of MDD, we reviewed 50 pertinent papers without limiting the search by publication year, and the data collection was performed in a neutral manner. The search focuses on extensive citations from other publications and categorizes them according to their frequencies. Between 1989 and 2018, the top 50 MDD treatment publications received 96-1,837 citations (median 210, IQR 121-299). The 2000s and 2010s had a high level of publication activity (21 articles each, 42% per decade). Geographically, the United States (24, 48%), Canada (12, 24%), and the United Kingdom (5, 10%) dominated the journals. The majority of study types were randomized controlled trials (RCTs) (32, 64%), followed by systematic reviews/meta-analyses (16, 32%) and prospective cohorts (2, 4%). The publications covered a range of treatment modalities, including pharmacological, psychotherapeutic, neurostimulation, and lifestyle/complementary approaches. Elkin et al.'s NIMH Treatment of Depression Collaborative Research Program report (1,738 citations) and Unützer et al.'s IMPACT collaborative care RCT (1,837 citations) were the most referenced publications. Our results shed light on the conceptual framework of MDD treatment research, as current guidelines are shaped by significant randomized trials and systematic reviews. Precision-based and new treatments are growing the field, while traditional therapies continue to play a major role. Global applicability is limited by the geographic concentration of research, underscoring the need for diverse populations, assessment of new treatments, and incorporation of individual patient data to bolster the body of evidence.}, }
@article {pmid42164629, year = {2026}, author = {Akan, T and Aishwarya, R and Bhuiyan, MS and Conrad, SA and Vanchiere, JA and Bhuiyan, MAN}, title = {Computational pathology with dynamic convolutional and adaptive kernels.}, journal = {Journal of pathology informatics}, volume = {21}, number = {}, pages = {100662}, pmid = {42164629}, issn = {2229-5089}, abstract = {Data processing and learning have become essential to the advancement of medicine, with pathology and lab medicine being no exception. Integrating scientific research with clinical informatics into clinical practice facilitates novel methodologies for patient care. Computational pathology is a burgeoning subspecialty in pathology that promises a better-integrated solution to histopathological images and clinical informatics. Deep-learning methods in computational pathology have demonstrated considerable advances in automated histopathological image analysis. However, convolutional neural networks (CNNs) face fundamental limitations when dealing with the significant morphological heterogeneity present in disease tissues. Conventional CNNs use fixed convolutional kernels, which restrict their effectiveness in adaptively extracting features from histopathological images that exhibit diverse pathological patterns, staining intensities, and tissue architecture. To address this substantial limitation, we present an optimized variant of Omni-Dimensional Dynamic Convolution (ODConv) networks for distinguishing diseased tissue from healthy tissue. Compared with prior dynamic convolution methods that attend to a single kernel dimension, ODConv applies multi-dimensional attention across spatial positions, input channels, output channels, and kernel candidates, enabling more flexible and adaptive feature extraction. We evaluated our approach on wheat-germ agglutinin-stained and hematoxylin and eosin-stained skeletal muscle images from multiple disease models, including G93A*SOD1 transgenic mice (amyotrophic lateral sclerosis) and Akita mice (Type I diabetes). ODConv, trained entirely from scratch without ImageNet pretraining, achieved competitive classification performance relative to seven fine-tuned pretrained architectures across both staining modalities, demonstrating the effectiveness of omni-dimensional dynamic kernels in learning discriminative morphological representations directly from domain data. The study reports strong statistical agreement metrics, proving effective class balance handling and stable decision boundaries. These findings confirm ODConv as a strong computational pathology framework that advances automated diagnosis of neurodegenerative and metabolic skeletal muscle disorders.}, }
@article {pmid42165374, year = {2026}, author = {Fernández-Gómez, P and Tosat-Bitrián, C and Marugán, T and Fernández-Hernández, L and Cano, A and Martinez-Mulero, JA and López-Carbonero, JI and Pignatelli, J and Corrochano, S and Palomo, V}, title = {Lighting Up Mislocalized Proteins: Quantum Dot Probes for Multiplexed Cytoplasm-Selective Cell Profiling in Neurodegeneration.}, journal = {ACS sensors}, volume = {}, number = {}, pages = {}, doi = {10.1021/acssensors.5c01941}, pmid = {42165374}, issn = {2379-3694}, abstract = {Semiconductor quantum dots (QDs) provide unique stability, brightness, and multiplexed capacity for biomarker detection in complex diseases; however, their distinctive intracellular distribution has rarely been leveraged for spatially resolved diagnostics. Here, we show how QD-based sensors enable selective detection of cytoplasmic proteins and can quantify nucleo-cytoplasm protein mislocalization in patient-derived samples. We validated this approach labeling TAR DNA-binding protein 43 (TDP-43), a key mislocalized protein in amyotrophic lateral sclerosis (ALS). Spatial resolution is achieved in several patient-derived models and mouse brain tissue, underscoring the nanosensor's versatility across biological systems. Multiplexed QD-based immunolabeling, combined with confocal imaging and high-throughput flow cytometry, enables the detection of distinct cytoplasmic biomarker signatures that discriminate ALS patients from healthy controls. These signatures include variations in TDP-43 mislocalization and protein coexpression patterns, which were further modulated by pharmacological treatment. This work establishes QDs as spatially selective, multiplexable nanosensors capable of resolving subtle yet disease-relevant intracellular phenotypes in patient-derived samples. Compared to organic fluorophores, QDs enhance sensitivity, improve signal stability, and enable simultaneous spatially resolved biomarker quantification, broadening their potential for clinical diagnostics and personalized medicine. These findings establish QDs as powerful tools for neurodegeneration research, disease monitoring, and early biomarker discovery, with potential applications in translational neuroscience and precision medicine.}, }
@article {pmid41965692, year = {2026}, author = {Vergano, M and Craxì, L and Zamperetti, N and Latronico, N}, title = {Sliding doors at the bedside: conditional outcomes and moral judgments in end-of-life care.}, journal = {Critical care (London, England)}, volume = {30}, number = {1}, pages = {}, pmid = {41965692}, issn = {1466-609X}, abstract = {BACKGROUND: Intensive care medicine has increasingly embraced shared decision-making and advance care planning as core components of good clinical practice. Nonetheless, clinical reasoning is sometimes implicitly framed as a linear, biologically driven process. In contexts of prognostic uncertainty, this framing risks obscuring a structural feature of decision-making: the constitutive role of value-based judgments in shaping prognosis and outcomes.<br><br>MAIN BODY: This paper introduces the concept of conditional outcomes to clarify a structural feature of certain clinical situations, in which survival or death does not follow from biology alone but is co-determined within the range of biologically possible trajectories by value-based choices made by patients, families, and clinicians regarding whether and how to intervene. Using the case of Mrs. Elizabeth, a woman with advanced amyotrophic lateral sclerosis, we show how an identical clinical state may be framed as either terminal or amenable to escalation, not because it is assessed differently, but because values and goals are interpreted and enacted differently. Even when shared decision-making is practiced, the way value judgments shape prognostic determinations often remains implicit. Making these assumptions explicit complements shared decision-making and advance care planning, clarifying how clinical outcomes are logically dependent on prior value-based commitments that shape judgments about benefit, burden, and the goals of care.<br><br>CONCLUSIONS: Making the conditional structure of outcomes explicit clarifies that value-based judgments are not ancillary to prognosis but structurally shape prognostic determinations and subsequent outcomes. Recognizing the conditional nature of prognostication strengthens clinical reasoning by integrating biological knowledge with ethical commitments in end-of-life care.}, }
@article {pmid42155171, year = {2026}, author = {Czuba, M and Szafrańska, K and Kolaczkowski, M and Marcinkowska, M}, title = {Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.}, journal = {European journal of medicinal chemistry}, volume = {315}, number = {}, pages = {118951}, doi = {10.1016/j.ejmech.2026.118951}, pmid = {42155171}, issn = {1768-3254}, abstract = {TRPML1, a lysosomal Ca[2+] channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.}, }
@article {pmid42155219, year = {2026}, author = {He, L and Zhu, Z and Liu, W and Lan, J and Lin, S and Shang, J}, title = {A Y-γ segmented linear framework for non-equilibrium UV-Vis titration: stage-resolved exploratory analysis of a chemically evolving EGCG-iron system.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {361}, number = {}, pages = {128073}, doi = {10.1016/j.saa.2026.128073}, pmid = {42155219}, issn = {1873-3557}, abstract = {Non-equilibrium UV-Vis titration data are difficult to interpret when multiple processes overlap and strict equilibrium assumptions no longer hold. We propose a non-equilibrium titration framework that transforms UV-Vis matrices into reaction-progress space using a dimensionless γ and a volume-corrected absorbance Y. Under mass and proton-balance constraints, locally single-process intervals obey Yλ = aλ + bλγ; segmented linear regression then yields wavelength-dependent slope fingerprints (bλ) that delineate coordination stages. In the EGCG-iron system, the Y-γ analysis resolves a progression from low-coordination mononuclear species to higher-coordination complexes, multinuclear/bridged units, and iron-rich aggregates across metal-to-ligand ratios and pH. Single-wavelength initial-rate measurements and solid-state characterization support rapid deprotonation-coordination coupling and the formation of cross-linked multinuclear networks at high γ. To benchmark soft-modeling, we performed MCR-ALS decompositions under weak constraints (post-normalized closure) and strong constraints (iterative simplex projection plus monotonic decay-to-zero of the initial dominant component). Both fits achieve similar residual levels, yet the recovered spectra/concentration profiles differ, evidencing rotational ambiguity and emphasizing the dependence of chemometric solutions on constraint choice. In contrast, the Y-γ segmented linear model relies on explicit stoichiometric/proton-balance transformations, providing robust stage boundaries and compact spectral descriptors while remaining computationally simple. This combined hard/soft analysis offers a practical route to mechanistic interpretation of complex titration spectra and motivates future integration of Y-γ descriptors with advanced chemometrics and hybrid hard-soft modeling.}, }
@article {pmid42155417, year = {2026}, author = {Simpson, J and Zarotti, N}, title = {Distress, not symptoms: Reframing psychological difficulties in neurodegenerative diseases of the motor system.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {200}, number = {}, pages = {262-271}, doi = {10.1016/j.cortex.2026.05.004}, pmid = {42155417}, issn = {1973-8102}, abstract = {Psychological distress is common among people living with neurodegenerative diseases of the motor system (NDMS) such as Parkinson's disease, motor neurone disease/amyotrophic lateral sclerosis, and Huntington's disease. Yet the way psychological difficulties are conceptualised in these populations is heavily shaped by medicalised language. Terms such as 'non-motor symptoms' and 'neuropsychiatric manifestations' were originally introduced to draw attention to difficulties beyond movement changes but they now risk positioning mood, anxiety, apathy, and related experiences solely as direct manifestations of neurological degeneration. This framing can obscure the rich psychosocial contexts in which distress arises, blur distinctions between emotional responses and disease processes, and reinforce deficit-based and disease-focused understandings that privilege biological explanations over person-centred ones. It may also influence clinical communication, treatment decisions, help-seeking behaviour, and access to psychological therapy and psychosocial interventions, contributing to inequities in care. This article argues that linguistic choices are not neutral: they construct the boundaries of what counts as legitimate knowledge, shape expectations about causality, and delimit the interventions considered appropriate. Without critical attention to these assumptions, individuals may experience distress as biologically inevitable and clinicians may overlook psychosocial contributors that are amenable to change. We propose that greater awareness of the power of language, coupled with empirical investigation into its effects, is essential for developing a linguistic reformulation of psychological distress in NDMS and more holistic, contextually grounded approaches to supporting psychological wellbeing.}, }
@article {pmid42156174, year = {2026}, author = {Su, X and Tan, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Wang, S and Wang, J and Feng, H}, title = {COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.1803-25.2026}, pmid = {42156174}, issn = {1529-2401}, abstract = {Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia inducible factor 1 subunit alpha (HIF-1α)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1[G93A] transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.Significance Statement Superoxide dismutase 1 (SOD1) was the first identified mutant gene associated with amyotrophic lateral sclerosis (ALS). Mutations in SOD1 compromise its metal-binding function, resulting in neuronal apoptosis, a hallmark of ALS pathogenesis. Utilizing the SOD1[G93A] models of ALS, our findings revealed that COMMD1 deficiency significantly elevates copper incorporation into SOD1, consequently attenuating cellular apoptosis. These results suggest that targeted inhibition of COMMD1 could represent a potential therapeutic strategy for ALS treatment.}, }
@article {pmid42156213, year = {2026}, author = {Nalepa, M and Skweres, A and Węgrzynowicz, M}, title = {Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.}, journal = {Free radical biology &amp; medicine}, volume = {252}, number = {}, pages = {559-579}, doi = {10.1016/j.freeradbiomed.2026.05.285}, pmid = {42156213}, issn = {1873-4596}, abstract = {Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between arginine and ornithine, is positioned at the crossroads of multiple arginine metabolic pathways, thereby controlling a variety of cellular processes essential for proper brain homeostasis. Chronic disruption of these pathways may lead to dysfunction of neurons and glia ultimately resulting in the induction of neurodegenerative processes. In this review, based on data from patients and experimental models, we synthesize and critically evaluate evidence demonstrating alterations in arginase isoenzymes and associated metabolic pathways in Alzheimer's Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. We discuss mechanisms through which dysregulation of arginase and arginine metabolism may contribute to neurodegeneration, including disturbances in nitrogen metabolism, oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Based on this body of evidence, we propose therapeutic strategies targeting arginase-related pathways, with the aim of preserving cellular metabolic homeostasis to ameliorate disease progression. Finally, we outline directions for future research, emphasizing that a proper understanding of the physiological roles of arginase isoenzymes and their disease-, stage-, and cell-specific dysregulation will be essential for the development of effective metabolically targeted therapies against neurodegenerative diseases.}, }
@article {pmid42156505, year = {2026}, author = {Kerins, C and Lieberam, I and Gentleman, E}, title = {ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-10244-6}, pmid = {42156505}, issn = {2399-3642}, support = {MR/N025865/1//RCUK | Medical Research Council (MRC)/ ; 218452/Z/19/Z//Wellcome Trust (Wellcome)/ ; }, abstract = {Perineuronal nets (PNNs) are extracellular matrix structures that stabilise synaptic inputs and play a role in regulating neuronal plasticity. Although PNN dysregulation is observed in several neurological disorders, their relevance to amyotrophic lateral sclerosis (ALS) remains unclear. In particular, the extent to which PNN alterations reported in ALS animal models are motor neuron (MN)-intrinsic is unknown. We investigated whether human pluripotent stem cell-derived MNs form PNN-like structures in vitro, and whether ALS-associated mutations alter this process. We show that PNN-like structures containing hyaluronan, tenascin-R, and aggrecan form in in vitro co-cultures of iPSC-derived MNs and astrocytes, and that their formation and gene expression were not altered by ALS mutations. To explore whether PNN dysregulation reflects contributions from other cell types or selective MN vulnerability, we conducted meta-analyses of transcriptomic datasets from pluripotent stem cell-derived astrocytes carrying ALS-associated mutations, as well as datasets comparing MN populations with differential susceptibility to ALS. These analyses revealed no consistent differences in PNN-related gene expression within human stem cell-derived MNs. In contrast, transcriptomic analyses of human post-mortem ALS tissues revealed dysregulation of PNN-related genes, including core PNN components. Taken together, these findings indicate that PNN-related alterations described in ALS animal models are not reproduced by ALS-associated mutations in MNs alone, and instead point to a role for additional cellular components within the central nervous system.}, }
@article {pmid42156779, year = {2026}, author = {Shaw, TB and Al Najjar, A and Barth, M and Bollmann, S and Bourgeat, P and Chang, J and Dempsey-Jones, H and Fazlollahi, A and Fripp, J and Garden, N and Guo, CC and Henderson, RD and Kuan, E and Lv, J and McCombe, PA and Narayanan, A and Ngo, ST and Nguyen, V and O'Brien, K and Robinson, G and Robinson, S and Salvado, O and Stewart, A and Steyn, FJ and Bollmann, S}, title = {Multimodal ultra-high-field MRI, clinical, cognitive, and genetic profiles across the ALS-FTD spectrum.}, journal = {Scientific data}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41597-026-07461-3}, pmid = {42156779}, issn = {2052-4463}, support = {PDF2112//Motor Neurone Disease Research Australia/ ; TU2201//Motor Neurone Disease Research Australia/ ; APP2029871//National Health and Medical Research Council/ ; Boosting Dementia Research Leadership Fellowship (APP1135769)//National Health and Medical Research Council/ ; ECR-202503-01848//FightMND/ ; Mid-Career Research Fellowship//FightMND/ ; APP 1088419, DP250103627//National Health and Medical Research Council, Australia/ ; FT140100865, IC170100035, DP200103386, DP250103627//Australian Research Council/ ; DP250103627//Australian Research Council/ ; DP240102161//Australian Research Council/ ; Linkage Grant LP200301393//Australian Research Council, Australia/ ; RTP//University of Queensland Graduate School/ ; Research Development Grant//Brain and Mind Centre, University of Sydney/ ; Fudan Brain and Intelligence Science Alliance Flagship Research Program, Moyira Elizabeth Vine Fund for Research into Schizophrenia Program//University of Sydney/ ; 10.55776/PAT3786024//Austrian Science Fund/ ; 794298//Marie Sklodowska-Curie Actions, European Union/ ; }, abstract = {This dataset was acquired and curated to explore the spectrum of Motor Neuron Disease (MND) and Fronto-Temporal Dementia (FTD) with Ultra-High Field Magnetic Resonance Imaging (7 Tesla) and compare these to non-neurodegenerative disease controls (known colloquially as "The 7 T hEalthy Ageing study [7TEA]"). Twenty people living with neurodegenerative disease and 14 non-neurodegenerative controls underwent a comprehensive multimodal MRI protocol including structural, diffusion, quantitative MRI, resting state, and task fMRI, alongside cognitive testing and genetic screening. This dataset combines detailed imaging phenotypes with extensive clinical characterisations. It facilitates investigations into the spectrum of MND and FTD, has provided a basis for developing novel quantitative biomarkers, and supports the exploration of interactions between imaging features and clinical progression. The availability of this dataset supports various research avenues, from detailed hippocampal subfield analyses, network connectivity assessments, and multimodal genetic, cognitive, and imaging studies. The dataset is published on OpenNeuro (dataset ds007036) and is curated in the Brain Imaging Data Structure (BIDS) standard.}, }
@article {pmid42157222, year = {2026}, author = {Bayer, PA and O'Bryan, SJ and Thomas, HJ and Del Vecchio, A and Jain, G and Farina, D and Ferri, A}, title = {The use of high-density surface electromyography in amyotrophic lateral sclerosis: a scoping review.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12984-026-02022-6}, pmid = {42157222}, issn = {1743-0003}, support = {GNT2021176//National Health and Medical Research Council/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in muscle weakness and atrophy. This neuronal loss is partially compensated for by the collateral sprouting of surviving motor neurons, leading to the formation of enlarged motor units (MUs). These MU adaptations, together with hyperexcitability and altered descending messages from the brain, lead to altered characteristics of the MU action potential shape and discharge pattern, that can be captured using high-density surface electromyography (HDsEMG). The aim of this review is to survey all available literature, investigating how HDsEMG has been used in ALS, and highlight differences in methods and outcomes to allow comparison between studies.<br><br>METHODS: A systematic literature search was conducted using four databases (PubMed, Scopus, IEEE Xplore, and Academic Search Ultimate) to identify studies employing HDsEMG in individuals diagnosed with ALS. Eligible studies were reviewed to examine experimental protocols, hardware and software configurations and reported outcome measures.<br><br>RESULTS: Out of 168 identified articles, 26 were included in this review. High heterogeneity was observed in recording methods, analysis, and reporting strategies. Based on measurable features of MU behaviour and morphology, the outcomes reported in the studies were grouped into five main categories: fasciculations, MU properties, MU discharge characteristics, multiple discharges and number of MUs.<br><br>CONCLUSIONS: HDsEMG represents a promising non-invasive technique that allows for repeated, longitudinal measurements as well as the detection of multiple MUs and their individual analysis, the potential of which has not been fully explored. HDsEMG has a strong potential for clinical use in ALS, but its application should first be based on a clear understanding of disease pathophysiology. The findings of this review highlight the urgent need for a consensus on standardised protocols and reporting practices for the application of HDsEMG in ALS research, along with the development of methods that can sensitively indicate disease-specific physiological changes to improve comparability, reproducibility. This understanding will improve how HDsEMG findings are interpreted and support the translation of HDsEMG into a diagnostic tool.}, }
@article {pmid42158589, year = {2026}, author = {Tran, CM and Reddy, N and Thomas, JK and Venugopal, V and Bowser, R}, title = {CHI3L1 (YKL-40) and Chit-1 expressing glia in the white matter of ALS, FTLD and AD: correlations to pathology and disease duration.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001225}, pmid = {42158589}, issn = {2632-6140}, abstract = {BACKGROUND: Chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Few studies have examined the spatial expression of chitinase-expressing cells with respect to neuropathologic hallmarks of disease.<br><br>METHODS: RNA sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterise the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP-43 pathology.<br><br>RESULTS: Chit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of patients with sALS and C9-ALS when compared with controls. Highest levels of Chit-1[+] glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1[+] glia were only significantly increased in sALS. Neither Chit-1[+] nor CHI3L1[+] glia was in close proximity to phosphorylated TDP-43 (pTDP) containing neurons in the motor cortex grey matter; however, there was a significant co-localisation of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter.<br><br>CONCLUSIONS: Chit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter often contained pTDP. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration.}, }
@article {pmid42149283, year = {2026}, author = {Dey, A and Baumeister, TR and Evans, KC and Koppelmans, V and Luk, C and McLaren, DG and Parnianpour, P and Seres, P and ,  and Kalra, S}, title = {Correction: Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, doi = {10.1007/s00415-026-13768-3}, pmid = {42149283}, issn = {1432-1459}, }
@article {pmid42149299, year = {2026}, author = {Morimoto, S and Takahashi, S and Okano, H}, title = {Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.}, journal = {Japanese journal of radiology}, volume = {}, number = {}, pages = {}, pmid = {42149299}, issn = {1867-108X}, support = {JP21H05278, JP22K15736, JP25H00007//Japan Society for the Promotion of Science/ ; JP26K10434//Japan Society for the Promotion of Science/ ; JP26H02431//Japan Society for the Promotion of Science/ ; JP23bm1123046, JP23kk0305024, JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009, JP22bm0804003, JP22ek0109616, JP23bm1423002, JP25wm0625519//Japan Agency for Medical Research and Development/ ; UBE Academic Foundation//UBE Academic Foundation/ ; the Kato Memorial Trust for Nambyo Research//the Kato Memorial Trust for Nambyo Research/ ; 2024A04//Japan Intractable Diseases Research Foundation/ ; Inamori Foundation//Inamori Foundation/ ; Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology//Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology/ ; Ono Medical Research Foundation//Ono Medical Research Foundation/ ; Nakatomi Foundation//Nakatomi Foundation/ ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.}, }
@article {pmid42149483, year = {2026}, author = {Ozimac, KM and Gonzalez, VV and Blaisdell, AP}, title = {Evidence of the conjunction fallacy in Rats (Rattus norvegicus) following two-lever choice training.}, journal = {Journal of comparative psychology (Washington, D.C. : 1983)}, volume = {}, number = {}, pages = {}, doi = {10.1037/com0000448}, pmid = {42149483}, issn = {1939-2087}, abstract = {The conjunction fallacy, a well-known cognitive bias, occurs when individuals erroneously judge the conjunction of 2 events as more probable than either event occurring independently (Tversky &amp; Kahneman, 1983). Although this fallacy has been extensively studied in humans, recent research from our lab shows that nonhuman animals, such as rats, also demonstrate this bias (González, Sadeghi, et al., 2023). In González et al.'s study, rats were trained in a feature-positive/feature-negative go/no-go discrimination (A-/AX+; B+/BY-, where A and B were auditory cues and X and Y were visual cues, and + and-indicate that lever pressing was reinforced or not). At test, cues A and B were presented on probe trials with cues X and Y either unoccluded and off or occluded by a metal shield. Responding was low to A and high to B when the light was visible (and off). When the light was occluded, however, this pattern reversed, with high responding to A and low responding to B. This indicated a bias toward expecting the occluded light to be present rather than absent, consistent with a conjunction fallacy. In a go/no-go procedure, however, some trial types are rewarded, whereas others are unrewarded. This reward asymmetry may bias attention to the different cue conditions. Thus, the current study replicated this conjunction bias using a 2-alternative choice procedure where reinforcement was available on all trial types, removing this potential bias. Our demonstration of a strong conjunction fallacy replicated our prior results, setting the stage for parallel studies in rats and humans. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid42149647, year = {2026}, author = {Hui, LM and Yu, E and Chung, A and Kwan, BYM}, title = {Artificial intelligence for assessment in competency-based medical education: current practices and future directions.}, journal = {Postgraduate medical journal}, volume = {}, number = {}, pages = {}, doi = {10.1093/postmj/qgaf195}, pmid = {42149647}, issn = {1469-0756}, abstract = {BACKGROUND: Competency-Based Medical Education (CBME) relies on frequent, competency-focused assessments, which can be challenging to implement consistently. Artificial Intelligence (AI) holds promise to improve assessment efficiency, objectivity, and feedback in CBME, but its use remains in early stages with limited understanding of current practices and evaluation methods. This study aims to map existing AI applications in CBME assessments to guide future work.<br><br>METHODS: A comprehensive search was performed in MEDLINE (Ovid), EMBASE (Ovid), PsycINFO, and Scopus using tailored keywords and MeSH terms. Included studies focused on the deployment of AI for assessment within CBME, covering applications in generating, analyzing, or interpreting evaluation data across undergraduate, graduate, and continuing professional education. The PRISMA-ScR guidelines were used to ensure transparent reporting, and findings were synthesized following Levac et&#xa0;al.'s approach.<br><br>RESULTS: Of the 1002 search results, 32 studies met the inclusion criteria. Key findings indicate a wide application of AI from surgical or procedural skill assessment, to clinical note assessment, communication assessment, feedback generation, projected trainee performance, and analysis of narrative feedback from supervisors.<br><br>CONCLUSION: This review highlights potential advantages, such as timely evaluations, and challenges, such as lack of granularity, of AI integration. In conclusion, thoughtful integration of AI into competency-based medical education can complement traditional assessment methods and enhance learner outcomes, provided it is supported by robust infrastructure, ethical oversight, and collaborative policy development.}, }
@article {pmid42149655, year = {2026}, author = {Kapitány-Fövény, M}, title = {A qualitative analysis of addiction components in rhinitis medicamentosa.}, journal = {Journal of behavioral addictions}, volume = {}, number = {}, pages = {}, doi = {10.1556/2006.2025.00530}, pmid = {42149655}, issn = {2063-5303}, abstract = {This commentary evaluates Lakatos et al.'s qualitative study on nasal spray addiction within rhinitis medicamentosa (RM), applying Griffiths' addiction component model. While evidence remains insufficient for formal diagnostic inclusion, the study identifies behavioral and psychological features paralleling core addiction criteria. Case reports and user narratives provide additional support, though counter-evidence persists. Conceptual and methodological challenges highlight the need for research addressing clinical relevance, theoretical embedding, and taxonomic plausibility. Despite limited empirical validation, the significant distress and functional impairment reported by affected individuals underscore the importance of recognizing and addressing this emerging issue.}, }
@article {pmid42151714, year = {2026}, author = {Zwicker, J and Smith, IC and Bush, SH and Rice, J and Murphy, R and Breiner, A and Buenger, U and Zehrt, B and Warman-Chardon, J and Watt, CL}, title = {Lessons Learned From a Feasibility Study of Longitudinal Palliative Care for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70283}, pmid = {42151714}, issn = {1097-4598}, support = {//ALS Society of Canada/ ; //Eric Poulin Centre for Neuromuscular Disease/ ; //University of Ottawa/ ; INS-464765/CAPMC/CIHR/Canada ; 932196//Muscular Dystrophy Canada/ ; }, abstract = {INTRODUCTION/AIMS: The benefits of initial palliative care (PC) consultation for patients with amyotrophic lateral sclerosis (ALS) have been previously described. The aim of this study was to explore the evolution of PC needs of patients with ALS over time through analysis of PC follow-up visits.<br><br>METHODS: Patients followed at a multidisciplinary ALS clinic received PC consultations and follow-ups between October 2020 and April 2022. All patients who received at least one PC follow-up visit were included in this study. Physician documentation of the visits was analyzed for sub-themes and topics. Topics discussed during visits and visit frequency were examined in the context of patient variables.<br><br>RESULTS: The 26 patients had at least one PC follow-up visit (range 1-12 visits). Topics of discussion varied by individual rather than disease status and were often discussed repeatedly. Compared to initial consultations, follow-up visits featured more frequent discussion of sialorrhea and less frequent discussion of constipation, pain, and prognosis (all p&#x2009;<&#x2009;0.05). Care coordination was discussed in 82% of follow-ups. Time between follow-up visits shortened as the disease progressed. Medical assistance in dying (MAID) was discussed by 31% of patients either at initial consultation or follow-up.<br><br>DISCUSSION: Each individual with ALS has unique PC needs. PC specialist resource planning should anticipate higher frequency visits for patients later in the disease course. Given the importance of care coordination and the scarcity of PC specialists, we recommend further study of effective models of care coordination. We recommend that PC specialists be comfortable counseling patients on MAID.}, }
@article {pmid42151746, year = {2026}, author = {Best, JD and Landera, MA and Ma, R and Perry, BJ}, title = {Perceptions of Speech-Language Pathology Care in Amyotrophic Lateral Sclerosis: A Patient-Centered Exploratory Study.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70286}, pmid = {42151746}, issn = {1097-4598}, support = {K23NS123369/NH/NIH HHS/United States ; //MGH Institute of Health Professions/ ; }, abstract = {INTRODUCTION/AIMS: Given limited research on patient perspectives of speech-language pathology (SLP) services in ALS care, this study aimed to assess the satisfaction with, and understanding of, SLP services by people with ALS (pwALS) and to examine the alignment between services received and patient-reported impairments.<br><br>METHODS: A cross-sectional survey assessing pwALS' perceptions of SLPs was distributed from October 2024 to January 2025 through electronic mailing lists of relevant professional organizations. A questionnaire examined pwALS' understanding of the SLP role, satisfaction levels, alignment between patient-reported impairments and SLP interventions, and perceived gaps in care. Responses were analyzed using descriptive statistics, with open-ended items analyzed using qualitative analysis.<br><br>RESULTS: The 81 survey respondents consisted of pwALS (81.5%), caregivers (11.1%), family members (4.9%), and others (2.5%). Overall satisfaction with SLP care was high, though open-ended responses revealed gaps in understanding. Many were unaware of the full scope of SLP services; only 17.3% recognized cognitive evaluation and 8.6% cognitive therapy, compared with speech (77.8%) and swallowing (81.5%) evaluations. Reported services often did not align with communication and swallowing needs, but patients educated about a service were significantly more likely to use it.<br><br>DISCUSSION: Overall satisfaction with SLP care was high; however, open-ended responses revealed gaps in understanding, unmet needs, and limited awareness of the full scope of SLP services. This misalignment highlights the need for improved patient and caregiver education regarding the role and timing of SLP involvement to enhance engagement, appropriate service use, and outcomes in ALS care.}, }
@article {pmid42152795, year = {2026}, author = {Hu, N and Qi, M and Su, N and Zhang, D and Zhang, J and Xu, Y and Wang, K and Xu, Y and Li, Z and Hu, B and Wang, L and Wu, B and Chu, L and Wang, Y and Jiang, H and Lu, Z and Wu, J and Fan, X and Han, F and Tian, F and Yuan, J and Liu, M and Zhu, Y}, title = {Quantitative Gait Analysis Reveals Distinct Patterns Associated With Pyramidal Involvement in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71498}, doi = {10.1002/brb3.71498}, pmid = {42152795}, issn = {2162-3279}, support = {//National Science and Technology Major Project/ ; CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; //Ministry of Industry and Information Technology of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; Female ; Middle Aged ; *Gait Analysis/methods ; Cross-Sectional Studies ; Aged ; *Gait Disorders, Neurologic/physiopathology/etiology ; *Gait/physiology ; Adult ; Machine Learning ; *Pyramidal Tracts/physiopathology ; Motor Neurons/physiology ; Severity of Illness Index ; }, abstract = {OBJECTIVE: To dissect specific gait abnormalities associated with upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS) by controlling for overall disease severity and to develop a multivariate classification model.<br><br>METHODS: We performed 3D gait analysis on 118 ALS patients and 1796 healthy controls (HC). ALS patients were categorized into those with ALS with UMN dysfunction((ALS-UMN), n = 70) and those without ALS without UMN signs ((ALS-Numn), n = 48) lower limb UMN signs based on neurological examination. Gait parameters were compared, and their association with UMN involvement was analyzed using partial correlation (controlling for ALSFRS-R score) and machine learning models (Random Forest and Least Absolute Shrinkage and Selection Operator (Lasso) regression).<br><br>RESULTS: Compared with HC, ALS patients exhibited widespread gait deterioration (e.g., reduced speed, increased step width, p < 0.001). After controlling for ALSFRS-R, specific parameters, including reduced stride, increased step width, prolonged double support, and elevated gait cycle time asymmetry, remained independently associated with UMN severity (PENN score, p < 0.01). A multivariate model incorporating key features demonstrated fair discriminative ability for identifying ALS-UMN patients, with an area under the curve (AUC) of 0.690, a sensitivity of 0.816, and a specificity of 0.418.<br><br>CONCLUSION: Quantitative gait analysis reveals a distinct spatiotemporal pattern linked to UMN dysfunction in ALS. A model based on gait features shows potential, particularly high sensitivity, for identifying patients with pyramidal signs, supporting the exploratory utility of objective gait metrics for motor phenotyping in ALS, pending external validation.}, }
@article {pmid42152867, year = {2026}, author = {Cho, Y and Won, SY and Kim, H and Lee, HK and Cho, SR}, title = {The effects of a mobile healthcare application on speech and swallowing in amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {12}, number = {}, pages = {20552076261452405}, pmid = {42152867}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) impairs oral motor function, negatively affecting patients' speech and swallowing abilities, as well as quality of life.<br><br>OBJECTIVE: This study aims to evaluate the effectiveness of A Successful Swallowing with Effortful Training (ASSET) program, included in the 'The 365 Healthy Swallow Health Coach application' in preserving speech and swallowing abilities in ALS patients through self-training.<br><br>METHODS: In this 8-week quasi-experimental study, 13 participants were allocated to either the app-guided ASSET training group (n=7; three sessions per day, five days per week) or a usual-care control group (n=6) based on their clinical visit schedules. To evaluate changes over time and compare the two groups, linear mixed models were employed. Changes in ALS severity scale (ALSSS), Diadochokinetic (DDK) task, speech intensity, Speech Handicap Index-15, Dysphagia Handicap Index, Swallowing Quality of Life (SWAL-QOL), and Brief Inventory of Swallowing Assessment-15 were assessed.<br><br>RESULTS: ALSSS speech scores was relatively preserved from 5.43 (95% CI 3.01-7.84) to 5.29 (95% CI 2.87-7.70) in the ASSET treatment group, but declined from 6.33 (95% CI 3.73-8.94) to 4.83 (95% CI 2.23-7.44) in the control group, with a significant group-by-time interaction (p=.017). DDK/tuh/and/kuh/were relatively preserved from 11.86 to 11.71 and from 12.29 to 11.57 respectively in ASSET group, but declined from 11.67 to 7.50 and from 11.83 to 7.17 in the control group, with significant interactions in/tuh/(p=.032) and/kuh/(p=.044). SWAL-QOL total score was relatively preserved from 155.86 to 149.71 in ASSET group, but declined from 154.67 to 125.17 in the control group, with a significant interaction (p=.011).<br><br>CONCLUSIONS: The findings suggest that ASSET program may help preserve speech and swallowing function in patients with ALS. Future research should validate the ASSET program with a larger, adequately powered sample size.}, }
@article {pmid42141236, year = {2026}, author = {Maxwell, K and Leung, S and Ozakinci, G}, title = {The psychological impact of using 3D printing and imaging technology for patient education: a scoping review.}, journal = {3D printing in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s41205-026-00327-9}, pmid = {42141236}, issn = {2365-6271}, abstract = {BACKGROUND: The way in which patient education is delivered during clinical consultations can have an impact on cognitive and emotional outcomes in patients. 3D printing and imaging can be used in patient education to improve understanding of the information and satisfaction with care. This scoping review sought to explore the psychological impact of using 3D models in patient education.<br><br>METHODS: Searches were conducted in PsycINFO, PsycARTICLES, PubMed, Medline and CINAHL. Levac et al.'s enhanced version of Arksey &amp; O'Malley's methodological framework for conducting scoping reviews, and the PRISMA-ScR, were used to guide the screening and identification of relevant studies. Studies were included if they investigated the effect of using 3D models in patient education and explored psychological outcomes. Both quantitative and qualitative research were included.<br><br>RESULTS: Eleven studies were included in the review, including 2 qualitative studies. 3D models were most often used in educational consultations preceding a surgical procedure (n&#x2009;=&#x2009;9). Psychological outcomes assessed were anxiety, quality of life, distress relief, and decisional conflict. The results were mixed, showing that using 3D models can have a positive as well as negative effect on psychological outcomes such as fear and disempowerment.<br><br>CONCLUSIONS: Using 3D models in patient education has the potential to improve patient anxiety and other psychological outcomes. However, more research is required to identify which patients and types of consultations 3D models are most useful for. For example, appointments involving important decision-making may benefit from the inclusion of 3D models. It is also essential to consider the communicative approach of the healthcare professional in the delivery of patient education with 3D models, as this factor is key to the outcomes of shared decision-making.}, }
@article {pmid42141322, year = {2026}, author = {Slaghekke, HMJ and Govaarts, R and Mesarosova, L and Mühlebner, A and Beeldman, E and de Visser, M and van Es, MA and van den Berg, LH and van der Kooi, AJ and Pijnenburg, YAL and Aronica, E and Raaphorst, J}, title = {Associations of cognitive and behavioural impairment in ALS with brain pathology: pTDP-43 versus microglial activation.}, journal = {Journal of neurology}, volume = {273}, number = {6}, pages = {}, pmid = {42141322}, issn = {1432-1459}, support = {2013-19//Stichting ALS Nederland/ ; 023.012.055//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/complications/metabolism/psychology ; Male ; Female ; Middle Aged ; *Microglia/pathology/metabolism ; Aged ; *Cognitive Dysfunction/pathology/etiology/metabolism ; Frontotemporal Dementia/pathology/metabolism ; *Brain/pathology/metabolism ; Adult ; Gray Matter/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; }, abstract = {OBJECTIVE: Investigate associations between brain pathology (pTDP-43 inclusions and microglial activation) and cognitive and behavioural impairment in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Based on comprehensive neuropsychological examination and behavioural assessment, 21 ALS patients of whom post mortem brain tissue was obtained, were classified as having 1) no cognitive and/or behavioural impairment (pure motor ALS), 2) mild cognitive and/or behavioural impairment (ALSci/bi), and 3) ALS with behavioural variant frontotemporal dementia (ALS-bvFTD). Immunohistochemical staining of pTDP-43 and HLA-DR-defined microglial activation was semi-quantitatively assessed in grey and/or white matter of the prefrontal cortex, thalamus, hippocampus, and motor cortex.<br><br>RESULTS: Fourteen patients had pure motor ALS, four patients had ALSci/bi, and three patients had ALS-bvFTD. pTDP-43 pathology in the grey matter of the prefrontal cortex and gyrus dentatus differed between groups, especially between pure motor ALS and ALS-bvFTD. For each extra-motor brain region, pTDP-43 severity was highest in patients with ALS-bvFTD and lowest in patients with pure motor ALS, with ALSci/bi in between. This pattern was not observed for microglial activation. Associations between white matter pTDP-43 severity and cognitive/behavioural impairment were less robust than those in grey matter.<br><br>CONCLUSION: Severity of cognitive and/or behavioural impairment in ALS is related to severity of pTDP-43 pathology, in particular in the grey matter of extra-motor brain regions; we did not detect a clear association with microglial activation.}, }
@article {pmid42141969, year = {2026}, author = {Olesen, L and Moèll, SK and Knudsen, L}, title = {Living Outside the ALS Home - Everyday Experiences, Challenges and Needs of Adult Children with a Parent with ALS.}, journal = {Journal of social work in end-of-life &amp; palliative care}, volume = {}, number = {}, pages = {1-27}, doi = {10.1080/15524256.2026.2672970}, pmid = {42141969}, issn = {1552-4264}, abstract = {Adult children of a parent with ALS may be highly burdened and in need of support, but studies of their experiences and needs are scarce. The aim of this study was to explore everyday experiences, challenges and needs of adult children living outside the home of a parent with amyotrophic lateral sclerosis (ALS). The design was qualitative using Interpretive Description methodology and Sense of Coherence as framework. Focus group interviews were conducted with 16 adult children. Participants experienced changes in relationship and roles with siblings and parents when ALS moved into the family. Their parents' disease evoked a need for understanding ALS and its trajectory as the disease raised questions, concerns, and sorrow. Furthermore, having a parent with ALS led to strong and mixed emotions and dilemmas like bad conscience, self-blame, gratitude and closeness and wanting to be there but also not being able to bear witnessing the deterioration of their parent. Adult children experience profound challenges and needs related to their parent's disease. They need information and support from professionals and peers as they struggle to balance the demands related to ALS and everyday life with family, work and leisure. Professionals should provide support for this vulnerable group who appear highly burdened practically and emotionally by the situation.}, }
@article {pmid42142504, year = {2026}, author = {Abd-Eldayem, AM and Mohammed, RA}, title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.}, journal = {Current opinion in pharmacology}, volume = {88}, number = {}, pages = {102632}, doi = {10.1016/j.coph.2026.102632}, pmid = {42142504}, issn = {1471-4973}, abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.}, }
@article {pmid42143042, year = {2026}, author = {Ferrari, V and Tedesco, B and Cozzi, M and Pramaggiore, P and Gagliani, MC and Magdalena, R and Cornaggia, L and Casarotto, E and Chierichetti, M and Mohamed, A and Brodnanovà, M and Milioto, C and Piccolella, M and Galbiati, M and Crippa, V and Provenzani, A and Cortese, K and Rusmini, P and Cristofani, R and Poletti, A}, title = {VCP modulation ameliorates pathological features in C9orf72 models.}, journal = {Cell death &amp; disease}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41419-026-08856-1}, pmid = {42143042}, issn = {2041-4889}, support = {23236//AFM-T&#xe9;l&#xe9;thon (French Muscular Dystrophy Association)/ ; 29514//AFM-T&#xe9;l&#xe9;thon (French Muscular Dystrophy Association)/ ; 29514//AFM-T&#xe9;l&#xe9;thon (French Muscular Dystrophy Association)/ ; GGP19128//Fondazione Telethon (Telethon Foundation)/ ; GMR25T1103//Fondazione Telethon (Telethon Foundation)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022EFLFL8//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; National Center for Gene Therapy and Drugs Based on RNA Technology (CN3) CN00000041//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2020PBS5MJ//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n.//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022KSJZF5//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. P2022B5J32//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Universit&#xe0; degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Universit&#xe0; degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Universit&#xe0; degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; 2025-0708//Fondazione Cariplo (Cariplo Foundation)/ ; 2025-0708//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; Grant 2020//Kennedy's Disease Association (KDA)/ ; Grant 2018//Kennedy's Disease Association (KDA)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.}, }
@article {pmid42143268, year = {2026}, author = {Lonn, H and Ndep, AO and Ekpenyong, BN and Cockburn, L and Chirac, AJ and Tchiaze, ATG and Jingkuo, GHM and Abua, EE and Isho, MC}, title = {Experiences and challenges of caregivers of children with cerebral palsy in Magba subdivision, Cameroon: a qualitative analysis.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-04976-5}, pmid = {42143268}, issn = {1471-2377}, abstract = {BACKGROUND: Cerebral palsy (CP) is one of the most common childhood neurodisability globally and disproportionately affects children in low- and middle-income countries. In Cameroon, limited epidemiological data, weak rehabilitation infrastructure, and entrenched sociocultural beliefs shape how CP is understood and managed. Children with CP often require lifelong support, placing substantial physical, emotional, and economic demands on family-caregivers, most commonly mothers. Understanding caregivers' lived experiences within specific cultural and resource-limited contexts is critical for informing inclusive and effective interventions. This study explored the lived experiences and challenges of family-caregivers of children with CP in Magba Subdivision, West Region of Cameroon.<br><br>METHOD: This study employed a qualitative exploratory design using in-depth interviews and inductive content analysis. Participants were family caregivers of children with CP, purposively recruited through community-based rehabilitation (CBR) services. In-depth, face-to-face interviews were conducted in English or local languages, audio-recorded, transcribed, and translated. Data were analysed using inductive content analysis following Elo and Kyng&#xe4;s' approach. Findings were interpreted using Raina et al.'s multidimensional caregiving model.<br><br>RESULTS: All participants, aged 15-49 years, were family caregivers of children with CP, aged 4-15 years. Six interrelated themes emerged: (1) sociocultural challenges, including stigma, discrimination, and harmful spiritual beliefs framing CP as witchcraft, ancestral punishment, 'snake', or 'marine spirit'; (2) economic constraints arising from inability to engage in paid work and the absence of social protections; (3) physical caregiving burden characterised by exhaustion, chronic pain, and musculoskeletal strain; (4) inadequate specialized services and health information; (5) limited social/family support; and (6) limited access rehabilitation services. These challenges intensified caregiver isolation and emotional distress.<br><br>CONCLUSION: Caregiving for children with CP in Magba is shaped by intersecting sociocultural, economic, and systemic factors that extend beyond individual coping capacity. Strengthening culturally sensitive community-based rehabilitation, improving access to early diagnosis and rehabilitation, and implementing disability- and gender-responsive social protection policies are essential to reduce caregiver burden and promote inclusive child and family wellbeing in Cameroon.}, }
@article {pmid42143797, year = {2026}, author = {Tribhuvan, M and Phatke, SN}, title = {Comment on "Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis".}, journal = {Clinical neurology and neurosurgery}, volume = {268}, number = {}, pages = {109480}, doi = {10.1016/j.clineuro.2026.109480}, pmid = {42143797}, issn = {1872-6968}, }
@article {pmid42145633, year = {2026}, author = {Sonkar, KS and D'Ancona, VL and Cramp, J and Shilling, H and Giles, E and Howell-Bray, T and Fillingham, B and Cudkowicz, ME and Nath, A and Rothstein, JD and Bowser, R and Borroni, B and Padovani, A and Berry, JD and Vakili, GS and Buratti, E and Thrippleton, IP}, title = {Functional Activity of TDP-43: A Direct Biomarker for ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.04.26352054}, pmid = {42145633}, abstract = {TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA-binding activity using synthetic UU rich RNA probes. We analyzed 1,080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 ligation activity was elevated in ALS (mean 390 a.u.) versus controls (304 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); with a 366 a.u threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal likely reflects increased extracellular, probe-competent TDP-43 species. This assay provides direct functional measurement of disease-relevant TDP-43 biology, supporting applications in diagnostic discrimination, genotype stratification, and progression monitoring in prospective studies.}, }
@article {pmid42145639, year = {2026}, author = {Humphrey, J and Oku, A and Byrska-Bishop, M and Basile, AO and Evani, US and Corvelo, A and Tokolyi, A and Bp, K and Réal, A and Kim, Y and Bond, ML and Clarke, WE and Fu, R and Geiger, H and Chang, S and Naito, T and Jang, B and Musunuri, R and Dredge, WH and Al-Abri, R and Hoover, BN and Manaa, D and McClintock, J and Singh, FP and Pedersen, MH and Runnels, A and Propp, N and Fennessey, S and Won, HH and Zody, MC and Narzisi, G and Robine, N and Lappalainen, T and Fagegaltier, D and Gürsoy, G and Knowles, DA and Raj, T and ,  and Harms, MB and Phatnani, H}, title = {The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.29.26350889}, pmid = {42145639}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with substantial genetic and clinical heterogeneity that impedes therapeutic development. Large-scale multi-tissue genomic resources have transformed the study of neuropsychiatric and neurodegenerative diseases, but no equivalent resource exists for ALS. Here we present the full NYGC ALS Consortium dataset, combining whole-genome sequencing from 4,746 donors and bulk RNA-seq from 2,574 samples across 8 brain and spinal cord regions from 695 donors across the ALS disease spectrum. Our catalogue of small variants, structural variants, and short tandem repeats identified likely pathogenic mutations in 15.6% of ALS cases. Gene expression and mRNA splicing analysis across 5 major tissues reveals shared and region-specific features, highlighting microglial and T-cell dysregulation in the spinal cord. Mapping the genetic regulation of expression and splicing across tissues identified associations with 6 ALS risk loci, whereas allele-specific rare variant analysis detected expression effects for C9orf72 and OPTN . All data are immediately publicly available.}, }
@article {pmid42146463, year = {2026}, author = {Chen, X and Yan, H and Wei, H and Sajadi, S and Hu, J and Vasconcellos, V and Kim, A and Shriram, T and Tan, H and Keum, K and Wu, J and Paukert, M and Yang, Y}, title = {Genetic suppression of myeloid receptor Clec7a attenuates microglia neuroinflammation and promotes microglial phagocytosis to delay disease progression in ALS models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.05.04.722437}, pmid = {42146463}, issn = {2692-8205}, abstract = {Microglial activation has been closely associated with accelerated ALS disease progression. However, specific microglial pathways that regulate microglial activation and ALS disease progression remain limitedly understood. Here, we determined the role of Clec7a (or Dectin-1), a core signature gene of disease-associated microglia (DAM) in ALS, in regulating microglial activation and ALS disease progression. Our spinal cord scRNA-Seq results found that Clec7a deficiency specifically attenuated microglial neuroimmune gene expression in SOD1G93A mice and human ALS. In addition, in vivo two-photon imaging of human (h) TDP43 phagocytosis by microglia in the cortex showed that Clec7a deficiency promotes microglial phagocytosis of pathological hTDP43 by enhancing microglial process dynamics. Subsequent survival analysis further showed that selective deletion of Clec7a in microglia mitigates motor neuron degeneration and delays disease progression in SOD1G93A ALS mice. Together, our results establish that Clec7a is a key regulator in shaping disease microglial functions and promotes disease progression in ALS.}, }
@article {pmid42146521, year = {2026}, author = {Shahani, N and Banerjee, R and MacMullen, C and Sharma, N and Habibi, M and Wasserman, HD and Noyes, NC and Zhao, P and Elgendy, B and Cameron, MD and Bannister, TD and Hegazy, L and Finck, BN and Davis, RL}, title = {Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.30.722019}, pmid = {42146521}, issn = {2692-8205}, abstract = {UNLABELLED: Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.<br><br>TEASER: Dipyridamole, an FDA-approved drug, restores mitochondrial function and protects neurons in ALS and Alzheimer's disease.}, }
@article {pmid42147178, year = {2026}, author = {Gough, E and Basu, S and Brubaker, J and DeNeraing, B and Sack, D and Bourgeois, AL and Walker, R and Harro, CD and Chakraborty, S}, title = {Influence of Gut Microbiota on Immune Responses and Protection in Volunteers Receiving the Live Attenuated Oral ETEC Vaccine ACE257 followed by Virulent ETEC H10407 Challenge.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-9284363/v1}, pmid = {42147178}, issn = {2693-5015}, abstract = {Enterotoxigenic Escherichia coli (ETEC) remains a major cause of diarrheal morbidity with no licensed vaccines. Role of gut microbiota in vaccine immunogenicity and protection was investigated using 16S rRNA sequencing from the stool samples of 27 volunteers receiving two doses of the live attenuated oral ETEC vaccine ACE527 followed by virulent ETEC H10407 challenge. Systemic and mucosal IgG and IgA responses to heat-labile toxin-B (LTB) and colonization-factor-antigen-I (CFA/I) were quantified by ELISA in serum and antibody-in-lymphocyte-supernatant (ALS). Microbiome α-diversity, β-diversity, and taxa-immune associations were evaluated using regression models, MiRKAT, and relaxed LASSO. Vaccination increased (~ 25-30%) Eubacterium_brachy_group, Family_XIII_AD3011 and Actinomyces. Higher α-diversity (inverse-Simpson) was associated with reduced ALS anti-LTB and CFA/I IgA responses, whereas β-diversity correlated with increased serum anti-CFA/I IgA. Members of Anaerovoraceae, Peptostreptococcaceae, Oscillospiraceae, and Veillonellaceae enhanced immune responses and protection against severe diarrhea and ETEC colonization, while Ruminococcaceae, Sutterellaceae, Coriobacteria, Clostridia, and Actinobacteria showed antagonistic associations.}, }
@article {pmid42147445, year = {2026}, author = {Arogundade, OA and Lam, KJK and Brown, KA and Jain, T and Issagholian-Lewin, PO and Huang, C and Rae-Hudson, T and Briseno, K and Wyman, SK and Krishnappa, N and George, CA and O'Dare, K and Wilson, RHC and van Eijk, P and Reed, SH and Giannikopoulos, P and Clelland, CD}, title = {Arrayed dual-gRNA CRISPR screening platform for C9orf72 repeat expansion excision in patient iPSCs.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {2}, pages = {201741}, pmid = {42147445}, issn = {3117-387X}, abstract = {An intronic hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of both frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). We have previously demonstrated that CRISPR-Cas9 excision of the repeat expansion in patient iPSCs reverts pathological hallmarks of C9-FTD/ALS. Here, we aim to identify efficient and safe gRNAs for CRISPR-spCas9 dual-gRNA excision of the C9-repeat expansion. Utilizing novel ddPCR and single-molecule sequencing assays, we screened 120 gRNA pairs, comparing 64 bi-allelic, intronic excisions of the repeat region to 56 allele-specific excisions of the mutant allele in patient iPSCs, ranking them by efficiency. Bi-allelic excisions of the intronic repeat region were more efficient than excisions of the mutant allele. Single gRNA indel rates can nominate likely efficient gRNA pairs, but these pairs must be tested empirically. The length of the repeat expansion did not impact excision efficiency; rather, the activity of individual gRNAs drove excision efficiencies. Using whole genome sequencing and INDUCE-seq, we found only one detectable off-target of those nominated by Cas-OFFinder and CHANGE-seq across 4 of the most efficient gRNAs. This study advances the development of targeted therapies for C9-FTD/ALS and establishes a framework for dual-gRNA screening in patient iPSCs applicable to other repeat expansions.}, }
@article {pmid42148083, year = {2026}, author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Chen, X and Tao, L and Gao, Y}, title = {Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1807104}, pmid = {42148083}, issn = {1664-3224}, mesh = {*Ferroptosis/immunology ; Humans ; Animals ; *Central Nervous System Diseases/immunology/metabolism/etiology/pathology ; Iron/metabolism ; }, abstract = {Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-α and IL-1β released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8[+] T cell-derived IFN-γ suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.}, }
@article {pmid42148235, year = {2025}, author = {Naserzadeh, E and Olfati, N and Akhlaghi, S and Emadzadeh, M and Rashidnezhad, A and Nafissi, S and Fatehi, F and Sarraf, P and Haghi-Ashtiani, B and Ziaadini, B and Ansari, B and Okhovat, AA and Basiri, K and Boostani, R}, title = {Translation and psychometric validation of the Persian version of amyotrophic lateral sclerosis cognitive behavioral screen (ALS-CBS) and revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R).}, journal = {Current journal of neurology}, volume = {24}, number = {1}, pages = {16-22}, pmid = {42148235}, issn = {2717-011X}, abstract = {Background: The Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen (ALS-CBS) and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) are widely recognized tools for evaluating cognitive, behavioral, and functional changes in patients with amyotrophic lateral sclerosis (ALS). Given the increasing number of ALS cases in Persian-speaking communities, there is a critical need for culturally and linguistically adapted versions of these instruments. The objective of this study was to translate the ALS-CBS and ALSFRS-R into Persian and evaluate their validity and reliability to ensure their applicability in clinical practice and research. Methods: The Persian versions of the ALS-CBS and ALSFRS-R questionnaires were developed using the translation-back translation method. The translated questionnaires were administered to 36 individuals diagnosed with ALS. To assess content validity, neuromuscular specialists evaluated each item based on relevance, clarity, simplicity, necessity, and comprehensiveness, using content validity ratio (CVR) and content validity index (CVI) measures. Internal consistency reliability was assessed using Cronbach's alpha coefficient. Test-retest reliability was evaluated using the intra-class correlation coefficient (ICC). Statistical analysis was conducted using SPSS software. Results: All questionnaire items demonstrated satisfactory face validity after expert-guided revisions. The minimum acceptable values for CVI (≥ 0.78) and CVR (≥ 0.62) were achieved by correcting items that initially scored below the threshold. Reliability analysis revealed ICC values of 0.969 and 0.816 for the cognitive and behavioral sections of the ALS-CBS, respectively, and 0.909 for the ALSFRS-R. Cronbach's alpha coefficients were 0.791 for the ALS-CBS behavioral section and 0.825 for the ALSFRS-R, indicating acceptable internal consistency. Conclusion: The Persian versions of the ALS-CBS and ALSFRS-R have been shown to be both valid and reliable. These adapted tools provide valuable resources for assessing the cognitive, behavioral, and functional status of patients with ALS in Persian-speaking populations, ultimately supporting more accurate diagnosis, monitoring, and disease management.}, }
@article {pmid42148602, year = {2026}, author = {Du, W and Wu, T and Fan, Y and Zhao, M}, title = {When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {3964-3976}, doi = {10.4103/NRR.NRR-D-25-00808}, pmid = {42148602}, issn = {1673-5374}, abstract = {Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer's disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson's disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson's disease and impairs cellular stress responses in Huntington's disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks-such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe-S clusters, and increased reliance on the tricarboxylic acid cycle-which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.}, }
@article {pmid42137032, year = {2026}, author = {Miura, K and Nishimura, H and Ito, Y}, title = {Enhanced saccharification yields from rice straw by senescence-induced expression of a cytokinin biosynthesis gene in intragenic rice plants.}, journal = {Plant biotechnology (Tokyo, Japan)}, volume = {43}, number = {1}, pages = {145-149}, pmid = {42137032}, issn = {1342-4580}, abstract = {Controlling the digestibility of cellulosic biomass is important for its efficient use. We generated intragenic rice plants showing enhanced saccharification yield of rice straw. The rice cytokinin biosynthesis gene, LONELY GUY, under the control of the rice senescence-inducible STAY GREEN promoter, was introduced into the rice genome via particle bombardment. The rice-derived herbicide resistance gene ALS(G95A) was used as a selection marker gene. Regenerated intragenic rice plants with no foreign sequences showed enhanced saccharification yields from the leaves at harvest, whereas no significant differences were observed at the heading stage. Because the saccharification yields of rice straw are reduced after senescence, which is suppressed by cytokinin, we propose that the enhanced saccharification yields of intragenic rice plants are caused by the delay in senescence of the rice leaves due to the expression of the introduced cytokinin biosynthesis gene upon senescence.}, }
@article {pmid42137113, year = {2026}, author = {Rong, P and Heidrick, L}, title = {An interpretable, clinically grounded framework for digital speech biomarker development in neurodegenerative diseases.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1794169}, pmid = {42137113}, issn = {2673-253X}, abstract = {INTRODUCTION: Communication ability-a key determinant of quality of life-is frequently affected and progressively declines in neurodegenerative diseases. Effective management of progressive communication disorders requires a personalized approach to deliver timely interventions tailored to the evolving profiles of communicative impairment, thereby supporting functional communication throughout the disease course. To this end, reliable tools capable of detecting and quantifying both disease-specific patterns of communicative impairment and within-disease phenotypic variability are urgently needed. This study leverages Artificial Intelligence and advanced data analytics to develop an acoustic-based framework for automated extraction of interpretable, clinically grounded speech markers to enable objective assessment and phenotyping of progressive communication disorders.<br><br>METHODS: Three groups of participants, including 14 individuals with amyotrophic lateral sclerosis (ALS) and 15 individuals with Parkinson's disease (PD), alongside 10 neurologically healthy controls, performed a standardized oral passage reading task, yielding 739 speech samples. Fifty acoustic features were extracted using an automated analytic pipeline and subsequently clustered into six interpretable composite markers. The clinical utility of these markers was evaluated with the recorded speech samples by examining their (1) associations with standardized metrics of cognitive, motor speech, and overall communicative functions, (2) efficacy for detecting and differentiating disease-specific communicative impairment patterns in ALS and PD using supervised machine learning, and (3) utility for within-disease phenotyping and stratification using unsupervised clustering analysis.<br><br>RESULTS: The markers effectively (1) detected subtle subclinical changes across multiple domains prior to substantial declines in functional communication outcomes; (2) differentiated disease-specific patterns of communicative impairment (multiclass area under the curve > 0.90); and (3) identified subgroups with distinct speech profiles within each disease.<br><br>DISCUSSION: The findings support the potential of the proposed framework as a clinically translatable, objective tool to facilitate early detection, differential diagnosis, and phenotyping of progressive communication disorders, ultimately advancing personalized, measurement-based care in neurodegenerative diseases.}, }
@article {pmid42139128, year = {2026}, author = {Hong, J and Rao, P and Wang, W and Najafizadeh, L}, title = {EMBC Special Issue: ChatBCI-Assist: An Intent-Based P300 Speller with A Locally-Deployed LLM and Adaptive Stopping Strategy Enabling Record Online Spelling Performance.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2026.3693965}, pmid = {42139128}, issn = {1558-2531}, abstract = {P300-based speller brain computer interfaces (BCIs) provide promising communication solutions for individuals with severe motor impairments such as those with amyotrophic lateral sclerosis (ALS). However, existing P300 spellers are constrained by slow typing speed and limited efficiency. Here, we present ChatBCI-Assist, an intent-based P300 speller that integrates a locally-deployed large language model (LLM), fine-tuned for the task at hand, with an adaptive stopping strategy for key selection and a graphical user interface (GUI) designed for efficient message composition, to achieve record-level online spelling performance. The LLM, trained on an ALS-specific communication corpus using low-rank adaptation (LoRA), produces context-aware, semantically coherent, and prefix-constrained word and phrase predictions in real time. The proposed GUI supports efficient, user-adaptive message composition, while the adaptive stopping strategy dynamically adjusts stimulus presentation based on each subject's classification performance. Combined with a subject specific stepwise linear discriminant analysis (SWLDA) classifier, ChatBCI-Assist enhances spelling efficiency. Results from online experiments demonstrate that ChatBCI-Assist achieves record performance, with an average information transfer rate (ITR) of 105.2 bits/min, an overall character-level mutual information rate (MIR) of 52.9 bits/min and characters per minute (CPM) of 19.7 in copy-spelling tasks, and 30.7 CPM in semantic spelling tasks. Evaluated using semantic ITR (SITR), a metric proposed to characterize semantic communication efficiency, ChatBCI-Assist achieved SITR of 147.1 bits/min. User experience evaluations further confirm reduced workload and higher usability from LLM-based semantic spelling configurations, compared to traditional copy-spelling paradigms (dictionary or LLM). This work demonstrates that integrating locally-adapted LLMs with intent driven design and subject-specific decoding optimization can substantially improve the speed, efficiency, and user experience of BCI-based communication systems.}, }
@article {pmid42141072, year = {2026}, author = {Cropper, HC and Mir, F and Liu, J and Dachet, F and Srivastava, VR and Ramizuddin, M and Kopecky, K and Mocanu, E and Jiang, QL and Soni, M and Valyi-Nagy, T and Mnatsakanova, D and Abrams, CK and Song, F and Loeb, JA}, title = {Axonal dying back of upper motor neurons in human ALS.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-52496-6}, pmid = {42141072}, issn = {2045-2322}, support = {T32AG057468/AG/NIA NIH HHS/United States ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) typically present with arm, leg, or bulbar weakness. While genetics plays a clear role, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. In this clinicopathological case series, we examined the relationships between UMN/LMN disease in ten ALS patients. Detailed clinical assessments and motor cortex, brainstem, and spinal cord tissues were collected via rapid autopsy. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43, and RNA-sequencing was performed. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and both UMN/LMN involvement. LMN degeneration and microglial activation were highest at disease onset sites. UMN degeneration was present at all spinal cord levels through the medulla, regardless of onset site. Surprisingly, there was no evidence of UMN axonal degeneration above the brainstem. While extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. RNA-sequencing implicated inflammatory pathways at sites of disease onset. Our findings suggest that some ALS patients without FTD have a dying back of UMN axons rather than a primary upper neuronopathy of neurons.}, }
@article {pmid42141160, year = {2026}, author = {Hatano, Y and Nakahara, A and Tada, M and Kakita, A and Onodera, O and Ishihara, T}, title = {APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {42141160}, issn = {1432-0533}, support = {23K14771//Japan Society for the Promotion of Science/ ; 21K07272//Japan Society for the Promotion of Science/ ; JPJS00420240016//JSPS J-PEAKS Program/ ; JP22jm0210097//the AMED-SICORP program/ ; JPMH23FC1008//the Ministry of Health, Labour and Welfare (Research on Rare and Intractable Diseases Program)/ ; JP24zf0127012//AMED MoonShot Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Male ; Female ; Aged ; Middle Aged ; *Apolipoprotein E4/genetics ; Aged, 80 and over ; Brain/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (APOE) ε4 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 - largely restricted to motor regions - and type 2 - characterized by widespread cortical involvement. APOE genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among APOE ε4, temporal clinical parameters, Alzheimer's disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. APOE ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking APOE ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that APOE ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer's disease pathology. Incorporation of APOE genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.}, }
@article {pmid42134658, year = {2026}, author = {Purushotham, SS and Chesworth, R and Keembiyage, N and Münch, G and Gyengesi, E and Buskila, Y}, title = {The impact of long-term feeding with curcuminoids phospholipids enriched diet on disease progression of fALS.}, journal = {Neurochemistry international}, volume = {197}, number = {}, pages = {106183}, doi = {10.1016/j.neuint.2026.106183}, pmid = {42134658}, issn = {1872-9754}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease characterised by the progressive loss of motor functions affecting both upper and lower motor neurons. Although considered multifactorial with an unclear aetiology, it is believed that the interplay between genetic and environmental factors, with neuroinflammation playing a key role in disease progression, contributes to its development. There is currently no effective treatment for ALS. Curcumin has been recently highlighted for its potential therapeutic role in treating neurodegenerative diseases. Curcumin phospholipids, a highly bioavailable form of curcumin that allow the curcumin to be absorbed into the bloodstream more effectively than standard curcumin extracts, is considered as a natural cytokine-suppressive anti-inflammatory compound (CSAID) that is well-known for its therapeutic properties and is considered safe for humans and rodents at low to moderate concentrations. In this study, we investigated whether a long-term feeding regimen incorporating curcuminoids phospholipids-enriched diet early in disease progression could mitigate motor deficits and affect the lifespan of the SOD1 mouse model of familial ALS (fALS). Our results indicate sex-differences regarding the effect of curcumin supplementation on motor deficits and anxiety-like behaviour. While long-term feeding with curcuminoids phospholipids enriched diet had a complex effect on SOD1 female mice expressed as reduced anxiety like behaviour and motor deficits at the walking beam test, it had no effect on SOD1 male mice. Moreover, curcuminoids supplementation had a limited effect on disease onset and progression in SOD1 mice model for fALS.}, }
@article {pmid42134762, year = {2026}, author = {Song, J and Lee, S and Lee, J and Gil, Y and Kim, T and Kim, SY and Cha, SJ and Kim, HJ and Kim, K}, title = {Carboplatin alleviates astrocytic TDP-43 neurotoxicity by inhibiting NF-κB activation.}, journal = {European journal of pharmacology}, volume = {1026}, number = {}, pages = {178968}, doi = {10.1016/j.ejphar.2026.178968}, pmid = {42134762}, issn = {1879-0712}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and progressive motor neuron disease; however, its exact pathogenic mechanisms remain unclear. Currently, no effective treatments are available for this disease. Therefore, in this study, we investigated the anti-inflammatory effects of the anti-cancer agent, carboplatin, on neuronal cells and its potential therapeutic effects against ALS. Carboplatin inhibited NF-κB phosphorylation in the transactive response DNA-binding protein (TDP)-43-transfected astrocytes, reducing pro-inflammatory cytokine levels, without affecting the TDP-43 protein levels. In neuron-astrocyte co-culture models, carboplatin effectively alleviated TDP-43-induced toxicity by restoring mitochondrial integrity, specifically rescuing basal respiration, ATP production, and maximal respiratory capacity. In vivo, carboplatin rescued the locomotor deficits in glial-specific TDP-43-expressing Drosophila, without altering TDP-43 protein levels and subcellular localization. These findings suggest that TDP-43-induced astrocytic damage compromises mitochondrial functions in adjacent neurons, and that carboplatin-mediated restoration of TDP-43-mediated astrocyte damage is critical for neuronal survival and functions. Therefore, carboplatin, a chemotherapeutic agent, represents as a potential therapeutic candidate for TDP-43-associated proteinopathies.}, }
@article {pmid42134826, year = {2026}, author = {Fei, X and Qiu, C and Xiao, P and Du, H and Yang, Q}, title = {From Risk Identification to Risk Mitigation: Expanding the Utility of Ohteru Et al.'s Findings in Institutionalized Older Adults.}, journal = {Geriatrics &amp; gerontology international}, volume = {26}, number = {5}, pages = {e70535}, doi = {10.1111/ggi.70535}, pmid = {42134826}, issn = {1447-0594}, }
@article {pmid42135015, year = {2026}, author = {Bate, J and Fealey, J and Young, C and McArdle, A and Staunton, CA and Close, GL}, title = {Sport-related trauma and motor neurone disease: a scoping review of epidemiology, mechanisms and future directions.}, journal = {British journal of sports medicine}, volume = {}, number = {}, pages = {}, doi = {10.1136/bjsports-2025-111410}, pmid = {42135015}, issn = {1473-0480}, abstract = {OBJECTIVE: To map existing epidemiological evidence assessing the relationship of sport-related trauma and Motor Neurone Disease/Amyotrophic Lateral Sclerosis (MND/ALS), identify potential mechanistic pathways through which athletic exposures may influence disease risk and highlight gaps informing future research priorities.<br><br>DESIGN: Scoping Review. Online databases were used to retrieve data from available sources to 25 September 2025.<br><br>DATA SOURCES: Published and grey literature in English were identified through searches of ProQuest Central, Web of Science, Scopus, Sport Discus and PubMed. Studies were deemed eligible if they examined MND/ALS in the context of sport-related physical trauma.<br><br>METHODS: The scoping review was carried out in accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A three-step search strategy identified primary studies, secondary literature and grey literature. Following screening, data were extracted using a standardised charting tool to develop a descriptive analysis and thematic synthesis.<br><br>RESULTS: The search identified 3307 records, with 45 studies meeting inclusion criteria. General physical activity does not elevate MND/ALS risk; however, professional participation in high-impact sports, particularly those involving repetitive head impacts, has been associated with a 4-15-fold increased risk of MND/ALS. However, current evidence is largely descriptive, correlative and lacks mechanistic insights to verify causation.<br><br>CONCLUSION: This scoping review highlights a plausible association between repeated physical trauma in sport and MND/ALS, particularly in professional sports with high exposure to repeated head impacts. Future research should identify biological mechanisms linking trauma exposure with MND/ALS, integrating biomarker, experimental and longitudinal study designs to clarify causal mechanisms and inform risk mitigation in sport.}, }
@article {pmid42135109, year = {2026}, author = {Yin, X and Zhang, H and Zhang, R and Xue, J and Hou, Y}, title = {Epigenetic noise in the aging brain: tuning neuronal vulnerability to neurodegeneration.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2026.04.006}, pmid = {42135109}, issn = {1878-108X}, abstract = {Aging is the predominant risk factor for neurodegenerative diseases, yet the mechanisms linking biological aging to selective neuronal degeneration remain incompletely understood. Accumulating evidence indicates that aging progressively disrupts epigenetic regulation, manifested as increased epigenetic noise in DNA methylation, histone modifications, and chromatin accessibility, which undermines transcriptional precision and the stability of neuronal identity. Recent advances in single-cell and spatial epigenomics further suggest that these age-associated epigenetic alterations are not merely correlative but can actively shape neuronal vulnerability across brain regions and cell types. In this review, we synthesize emerging evidence showing how epigenetic noise contributes to selective neurodegeneration across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and discuss emerging strategies aimed at stabilizing the aging neuronal epigenome.}, }
@article {pmid42135512, year = {2026}, author = {Zhang, Z and van Olst, L and Alessandrini, F and Wright, M and Edwards, AJ and Boles, J and Nalbandian, A and Forsyth, AV and Shepard, N and Watson, T and Kaspi, E and Mittal, A and Kuruvilla, J and Piehl, N and Ramakrishnan, A and Appel, S and Kiskinis, E and Gate, D}, title = {Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {42135512}, issn = {1546-1726}, support = {R01AG078713//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron (MN) degeneration in the brain and spinal cord. Although neuroinflammation is increasingly recognized as a hallmark of ALS, the precise molecular programs linking immune responses to MN pathology remain poorly defined. Using an integrated approach that combines single-cell and bulk RNA sequencing with spatial proteogenomics, we characterized both shared and distinct immune dynamics in peripheral blood and spinal cord tissues from patients with sporadic ALS and those carrying C9orf72 repeat expansions. Our analysis revealed broad immune remodeling in C9orf72 ALS, ALS subtype-specific and progression-associated differences in monocyte activation and antigen-experienced CD8 effector memory T cells with clonal features consistent with antigen-driven responses. Spatial mapping revealed complement activation and lipid-programmed myeloid states converging at sites of MN loss and TDP-43 pathology. Together, these findings connect peripheral and central immune alterations to ALS heterogeneity and highlight stratified immunomodulation as a potential therapeutic strategy.}, }
@article {pmid42135750, year = {2026}, author = {Tamaki, Y and Kaneko, S and Urushitani, M}, title = {Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04935-4}, pmid = {42135750}, issn = {1741-7015}, support = {24K18702//Japan Society for the Promotion of Science/ ; 23K24211//Japan Society for the Promotion of Science/ ; 25wm0625522h0001//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.<br><br>SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.}, }
@article {pmid42135847, year = {2026}, author = {Sinha, IR and Atkinson, AL and Irwin, KE and Ling, JP and Wong, PC}, title = {TDP-43: [GU]-ardian of the transcriptome.}, journal = {Molecular neurodegeneration}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13024-026-00944-2}, pmid = {42135847}, issn = {1750-1326}, abstract = {TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.}, }
@article {pmid42135897, year = {2026}, author = {Kawazoe, T and Sugaya, K and Hayashi, K and Hino, K and Nakata, Y and Bokuda, K and Shimizu, T and Takahashi, K}, title = {Sex-Stratified Association of Regional Dopamine Transporter Binding With Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70432}, pmid = {42135897}, issn = {2328-9503}, support = {R051201013//Tokyo Metropolitan Hospital Organization/ ; }, abstract = {OBJECTIVE: To clarify the clinical relevance of dopamine transporter single-photon emission computed tomography (DAT-SPECT) abnormalities in amyotrophic lateral sclerosis (ALS), with a prespecified focus on sex-stratified associations with disease progression and short-term prognosis.<br><br>METHODS: Fifty-eight consecutive patients with ALS were prospectively enrolled and underwent [123]I-ioflupane DAT-SPECT, and DAT-SPECT data from 30 patients with essential tremor were analyzed as a reference group. We quantified the specific binding ratio (SBR) and the caudate-to-putamen binding ratio (BR-C/P) as age-adjusted Z-scores. Associations with functional decline (&#x394;ALSFRS-R), respiratory function (forced vital capacity), neuropsychiatric measures, and a 6-month composite endpoint of death or ventilator support were examined using correlation and logistic regression analyses, with prespecified sex-stratified evaluation.<br><br>RESULTS: A significant sex difference in BR-C/P Z-scores prompted sex-stratified analyses. SBR Z-scores were not associated with clinical or neuropsychiatric variables in either sex. In women, lower BR-C/P Z-scores correlated with faster functional decline and were independently associated with a higher risk of death or ventilator support within 6&#x2009;months (odds ratio per 1-unit increase, 0.31; 95% confidence interval, 0.12-0.83). In men, BR-C/P Z-scores correlated with forced vital capacity and respiratory decline. Exploratory voxel-based morphometry suggested limbic and striatal gray matter correlates in women with lower BR-C/P Z-scores.<br><br>INTERPRETATION: Regional dopaminergic imbalance captured by BR-C/P, rather than global SBR, demonstrated sex-stratified associations with disease progression in ALS. These findings support sex-specific interpretation of dopaminergic imaging biomarkers and suggest that BR-C/P may complement clinical measures for identifying higher-risk trajectories, particularly in women. Validation in larger, longitudinal cohorts is required.}, }
@article {pmid42135919, year = {2026}, author = {Baird, LA and McQuown, H and Park, J and Teener, SJ and Webber-Davis, IF and Carter, AD and Jang, DG and Feldman, EL and Goutman, SA and Murdock, BJ}, title = {Peripheral Neutrophil Activation and Extracellular Trap Formation in Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70431}, pmid = {42135919}, issn = {2328-9503}, support = {R01TS000339/ACL/ACL HHS/United States ; U01TS000351/ACL/ACL HHS/United States ; F31NS139629/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; T32AI007413/NH/NIH HHS/United States ; //Richard Stravitz Foundation/ ; //Peter R. Clark Fund for ALS Research/ ; //Coleman Therapeutic Discovery Fund/ ; //Stanford Morris ALS Research Fund/ ; //Michael R. Johns Fund/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //NeuroNetwork for Emerging Therapies/ ; //Scott Pranger ALS Center, the Dr. Randall Whitcomb Fund for ALS Genetics, the Coleman Therapeutic Discovery Fund, James and Margaret Hiller, Eric and Linda Novak/ ; }, abstract = {OBJECTIVES: Peripheral neutrophil levels in amyotrophic lateral sclerosis (ALS) inversely correlate with survival, suggesting a role for neutrophils in disease progression. Here, we characterize markers of several neutrophil activation pathways and evaluate their associations with survival to identify potential mechanisms of disease.<br><br>METHODS: Blood samples were obtained from participants at the University of Michigan ALS Clinic or from healthy controls. Ex&#xa0;vivo neutrophil extracellular trap (NET) formation was quantified via image analysis of primary neutrophils. Neutrophil function markers of general activation (calprotectin), migration (matrix-metalloproteinase 9 [MMP9]), and degranulation (neutrophil gelatinase-associated lipocalin [NGAL]) were then quantified in plasma via ELISA; NET formation (double-stranded DNA [dsDNA]) was assessed via fluorescence assay. These markers were then associated with ALS survival using Cox proportional hazard regression models, and analyses were stratified by sex.<br><br>RESULTS: Spontaneous ex&#xa0;vivo NET formation (N&#x2009;=&#x2009;20 controls, 66 ALS) was increased in ALS (1.0% vs. 9.7%; p&#x2009;=&#x2009;0.017). In plasma (N&#x2009;=&#x2009;233 controls, 178 ALS), calprotectin (294 vs. 372&#x2009;ng/mL; p&#x2009;<&#x2009;0.001), MMP9 (106 vs. 152&#x2009;ng/mL; p&#x2009;<&#x2009;0.001), and NGAL (61 vs. 66&#x2009;ng/mL; p&#x2009;=&#x2009;0.01) were elevated in ALS. Calprotectin, MMP9, and NGAL levels were not associated with ALS survival; however, dsDNA was associated with poorer ALS survival but only in females (HR&#x2009;=&#x2009;1.77 [95% CI, 1.20-2.61]; p&#x2009;=&#x2009;0.004).<br><br>INTERPRETATION: Neutrophil function is altered in ALS, and NET formation is a potential mechanism by which neutrophils contribute to ALS, particularly in females.}, }
@article {pmid42136278, year = {2026}, author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS}, title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249405308251210104405}, pmid = {42136278}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.<br><br>METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.<br><br>RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-&#x3ba;B, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.<br><br>DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.<br><br>CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.}, }
@article {pmid42136293, year = {2026}, author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M}, title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273444679260416064255}, pmid = {42136293}, issn = {1996-3181}, abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.}, }
@article {pmid42136304, year = {2026}, author = {Anjukandan, A and Kaliyaperumal, R}, title = {Challenges in Brain Drug Delivery for Neurodegenerative Disorders and Recent Trends: A Review.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273453002260416115852}, pmid = {42136304}, issn = {1996-3181}, abstract = {INTRODUCTION: Age-related disorders known as neurodegenerative illnesses are defined by uncontrolled neuronal loss that gradually impairs brain function. The majority of age-related neurodegenerative disorders are caused by dementias, in particular. Nowadays, the neurodegenerative disorders are not limited to age and are reported in all age groups. The drug delivery to treat the neurodegenerative disorders is challenging due to the presence of the blood-brain barrier (BBB).<br><br>METHOD: A critical literature review has been conducted across databases such as Scopus, Embase, Cochrane, and PubMed. Blood-brain barrier, neurodegenerative disorders, novel drug delivery system, and targeted drug therapy were the search terms.<br><br>RESULTS: Neurodegenerative Diseases (NDD) impact the peripheral nervous system, nerve cells, muscles, and the nerve-muscle junction. This term broadly encompasses cognitive disorders, such as Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and vascular dementia. Additionally, other neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and spinocerebellar ataxias predominantly impair motor system function and nerves in the limbs. The existing therapeutic approaches to treat neurological diseases exhibit limited efficacy due to the BBB. This highly selective semipermeable membrane permits vital nutrients to enter the brain while blocking the potentially harmful toxins. It makes it very challenging to get medications into the brain. There are several effective approaches to deliver drugs to the brain (nanocarrier systems, intranasal administration, and focused ultrasound) to address the limitations of conventional treatments.<br><br>CONCLUSION: This review discusses neurodegenerative disorders, brain anatomy/physiology, barriers to drug delivery, and strategies to overcome these limitations.}, }
@article {pmid42136825, year = {2026}, author = {Pan, J and Zhang, C and Li, J and Ma, L}, title = {Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.}, journal = {Open life sciences}, volume = {21}, number = {1}, pages = {20251323}, pmid = {42136825}, issn = {2391-5412}, abstract = {Evidence from multiple clinical studies indicates that amyotrophic lateral sclerosis (ALS) frequently evolves into a condition requiring neurocritical care. In advanced stages or during acute complications, ALS can rapidly transition into a neurocritical state characterized by respiratory insufficiency, systemic dysfunction, and accelerated neurological decline. Although current management strategies for advanced-stage ALS are relatively well established, there remains a significant lack of targeted interventions aimed at preventing or attenuating neurocritical deterioration. This review systematically examines the pathophysiological mechanisms underlying neurocritical progression in ALS, including respiratory failure, metabolic imbalance, autonomic dysfunction, and multisystem involvement. We further evaluate emerging and potential therapeutic strategies designed to mitigate disease severity and stabilize critical neurological function. In addition, we analyze clinical and biological factors that increase susceptibility to neurocritical states and discuss evidence-based approaches to delay disease progression. By integrating clinical observations with mechanistic insights, this review aims to improve early recognition, optimize neurocritical management, and ultimately enhance outcomes for patients with ALS.}, }
@article {pmid41922953, year = {2026}, author = {Xing, Z and Cheng, Z and Yang, X and Hu, L and Wang, K and Wang, Y and Hu, D and Wang, YH and Du, J and Wang, L and Li, J}, title = {Integrated genomic and transcriptomic analysis reveals candidate genes underlying herbicide resistance in Sorghum.}, journal = {BMC plant biology}, volume = {26}, number = {1}, pages = {}, pmid = {41922953}, issn = {1471-2229}, support = {32372134//The National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Herbicide-resistant germplasms provide critical genetic resources for improving weed control and understanding resistance mechanisms in crops.<br><br>OBJECTIVE: To screen sorghum accessions for tolerance to ACCase and ALS inhibitor herbicides at the seedling stage, identify the major locus and strong candidate gene associated with feproxydim resistance, and verify the gene expression pattern and genetic variation by quantitative real&#x2011;time PCR (qRT&#x2011;PCR) and KASP genotyping.<br><br>METHOD: A total of 316 sorghum accessions were screened for seedling-stage herbicide tolerance using gradient herbicide treatments. Bulked segregant analysis sequencing (BSA-Seq) was performed on resistant and susceptible gene pools constructed from the F&#x2082; population derived from IS1219 &#xd7; RTx430. Transcriptome sequencing (RNA-Seq) was conducted on leaf tissues after feproxydim treatment to identify candidate genes within the mapped interval. KASP markers were developed for the functional variation site of the key candidate gene for genotyping validation. Quantitative real&#x2011;time PCR (qRT-PCR) was used to measure the relative expression level of the target gene and compare it with the susceptible control line. Protein sequence comparison was used to detect variations in the key candidate gene between resistant and susceptible lines.<br><br>RESULT: In the screening with the ACCase inhibitor 10% feproxydim, IS1219 exhibited high-level resistance. Preliminary screening under the ALS inhibitor mesosulfuron-methyl treatment identified only SJ304 with visible tolerance, which was not subjected to further mapping or validation. BSA-Seq identified a major feproxydim resistance QTL on chromosome 1. RNA-Seq revealed five co-expressed candidate genes in the target interval, among which Sobic.001G431500 (encoding carboxylesterase 17, an &#x3b1;/&#x3b2;&#x2011;hydrolase) was markedly upregulated in the resistant line IS1219 but not in the susceptible line RTx430. Quantitative real&#x2011;time PCR (qRT-PCR) analysis confirmed that Sobic.001G431500 was significantly upregulated in the resistant line IS1219 compared with the susceptible control. KASP genotyping demonstrated that the IS1219 allele cosegregated with feproxydim resistance. Protein sequence comparison showed that the IS1219 allele carried a missense mutation V300A and a deletion P301_P303 at and after position 300.<br><br>CONCLUSION: These findings identify a major QTL and a strong candidate gene Sobic.001G431500 associated with feproxydim resistance in the sorghum line IS1219, based on differential expression, genetic variation, and genotype&#x2013;phenotype cosegregation. This study provides valuable genetic resources and functional markers for marker-assisted selection and breeding of feproxydim-tolerant sorghum varieties.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12870-026-08624-5.}, }
@article {pmid42123994, year = {2026}, author = {Christodoulou, RC and Lorentzen, L and Eller, D and Vassiliou, E}, title = {Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.}, journal = {Nutrients}, volume = {18}, number = {9}, pages = {}, pmid = {42123994}, issn = {2072-6643}, mesh = {*Ferroptosis ; Humans ; *Mitochondria/metabolism ; *Lipid Peroxidation ; *Neurodegenerative Diseases/metabolism ; *Fatty Acids/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Lipid Metabolism ; }, abstract = {Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.}, }
@article {pmid42124861, year = {2026}, author = {Reddy, S}, title = {Foundation for Artificial Intelligence-Driven Democratization of Healthcare Access.}, journal = {Learning health systems}, volume = {10}, number = {}, pages = {e70093}, pmid = {42124861}, issn = {2379-6146}, abstract = {INTRODUCTION: Healthcare systems worldwide face unprecedented challenges, including escalating costs, workforce shortages, and access disparities, which threaten their sustainability. The WHO projects an 18 million healthcare worker deficit by 2030, while financial and geographical barriers prevent millions from receiving necessary care. The integration of Artificial Intelligence (AI) into healthcare delivery systems presents opportunities to transform medical service provision, accessibility, and experiences, potentially democratizing healthcare access.<br><br>METHODS: This perspective analysis employs a theoretical framework combining Levesque et&#xa0;al.'s patient-centered healthcare access model with AI democratization frameworks. The analysis synthesizes current evidence on AI healthcare applications and proposes an implementation framework encompassing four dimensions: accessibility, affordability, usability, and ethical regulation. The framework addresses stakeholder roles and governance mechanisms aligned with international standards including the EU's AI Act and WHO's AI ethics guidance.<br><br>RESULTS: Evidence demonstrates significant democratization potential through the implementation of AI. AI-powered platforms eliminate geographical barriers, reduce diagnostic timeframes, optimize resources, and enhance preventive care. Implementation challenges include algorithmic bias, data privacy concerns, digital divide risks, and regulatory fragmentation.<br><br>CONCLUSION: AI integration holds transformative potential for democratizing healthcare across demographic and socioeconomic boundaries. Successful implementation requires structured, ethically grounded approaches that prioritize accessibility, affordability, usability, and regulation while maintaining a human-centered care approach. The framework offers actionable guidance for healthcare professionals and policymakers on deploying AI technologies to reduce disparities. Continuous research, interdisciplinary collaboration, and robust governance are crucial to ensuring that AI advances healthcare equity while preserving patient autonomy and clinical judgment.<br><br>Patient and Public Involvement and Engagement was not appropriate for this theoretical framework and perspective analysis, as it represents a conceptual synthesis of existing literature and policy frameworks rather than primary research involving human participants. This manuscript establishes a theoretical foundation and an implementation framework for AI-driven healthcare democratization, grounded in published evidence and established models of healthcare access. The work focuses on guiding healthcare policymakers and planning professionals rather than collecting new data from patients or the public. However, the framework explicitly emphasizes the critical importance of patient advocacy organizations and community representation in AI development processes, recognizing that meaningful patient involvement will be essential during the actual implementation phases of AI healthcare technologies described in this theoretical foundation.}, }
@article {pmid42125740, year = {2026}, author = {Tranoulis, I and Stefanakis, A and Giannoudi, M and Ioannidis, K}, title = {Basic life support and use of automated external defibrillator by dentists in Greece: a questionnaire-based cross-sectional study.}, journal = {Resuscitation plus}, volume = {29}, number = {}, pages = {101341}, pmid = {42125740}, issn = {2666-5204}, abstract = {BACKGROUND: Cardiac arrest is a leading cause of death; timely intervention with basic life support (BLS) is crucial for healthcare providers, including dentists. This study aimed to assess awareness, educational level, and knowledge regarding the application of BLS and the use of an automated external defibrillator (AED) among dentists in Greece.<br><br>METHODS: A cross-sectional survey using an online questionnaire was conducted to collect demographic data, knowledge of BLS/Advanced Life Support (ALS), and experience in managing medical emergencies in dental practices. The results were statistically analysed, with the level of significance set at P&#xa0;<&#xa0;0.05.<br><br>RESULTS: Overall, the national response rate among Greek dentists was 2.5%. A total of 354 dentists across Greece participated in the study. Attendance at CPR/AED courses was recorded for 67.5% of participants, while 29.4% reported holding active certification. A small proportion of the surveyed dentists had an AED in their dental practices (8.5%), and 47.4% did not possess a self-injectable adrenaline. Syncope was the most common medical emergency during dental procedures (50.3%). Dentists who attended BLS training sessions demonstrated more appropriate practice in managing medical emergencies (P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: Continuous training and ongoing professional development for dentists are essential for effectively handling medical emergencies. This study promotes a more proactive approach to enhancing competency in emergency care and the appropriate management of medical emergencies in dental practices.}, }
@article {pmid42126073, year = {2026}, author = {Razlan, AN and Ma, W and Dickie, AC and Polgar, E and McFarlane, AG and Yadav, M and Cooper, AH and Strathdee, D and Watanabe, M and Bell, AM and Todd, AJ and Hachisuka, J}, title = {Characterisation of cold-selective lamina I spinal projection neurons in the mouse.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {42126073}, issn = {2050-084X}, support = {10.35802/219433/WT_/Wellcome Trust/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/304005/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Mice ; *Cold Temperature ; TRPM Cation Channels/metabolism/genetics ; *Neurons/physiology ; Optogenetics ; Calbindins/metabolism ; Mice, Inbred C57BL ; *Spinal Cord/physiology/cytology ; Male ; }, abstract = {Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.}, }
@article {pmid42127155, year = {2026}, author = {Sunindyo, WD and Anshori, I and Wiguna, KA and Kahari, MMH and Syafalni, I and Dwiyanti, L and , }, title = {Algorithm-assisted interpretation of cyclic and differential pulse voltammetry for cardiac troponin detection.}, journal = {PloS one}, volume = {21}, number = {5}, pages = {e0348348}, doi = {10.1371/journal.pone.0348348}, pmid = {42127155}, issn = {1932-6203}, mesh = {*Algorithms ; Humans ; *Electrochemical Techniques/methods ; Biomarkers/blood ; Electrodes ; Biosensing Techniques/methods ; *Troponin/analysis ; Reproducibility of Results ; }, abstract = {Cardiovascular disease remains a leading cause of mortality worldwide, and rapid identification of cardiac biomarkers is essential for early detection. Electrochemical voltammetry techniques, particularly cyclic voltammetry (CV) and differential pulse voltammetry (DPV), are widely used for detecting cardiac troponin; however, interpretation of raw voltammetric signals is often affected by baseline drift, signal noise, and operator-dependent analysis. This study proposes an algorithm-assisted analytical framework for automated interpretation of voltammetric data obtained from a screen-printed carbon electrode potentiostat. Polynomial fitting was applied for baseline correction in CV signals, while asymmetric least squares (ALS) was employed for DPV data. Peak-to-baseline current response was extracted as a quantitative indicator of biomarker presence. The proposed method successfully identified characteristic voltammetric peaks and distinguished samples with higher and lower cardiac biomarker responses relative to a predefined detection threshold. The analysis showed close agreement with reference electrochemical analysis software, demonstrating reliable peak detection and baseline estimation. By reducing manual interpretation and improving signal clarity, the framework enhances the reproducibility and accessibility of electrochemical biosensor measurements and supports early screening of cardiac biomarkers.}, }
@article {pmid42127907, year = {2026}, author = {Xu, W and Li, H and Zhang, W and Bai, G and Shen, C and Zhang, K}, title = {S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2026.04.016}, pmid = {42127907}, issn = {1097-4164}, abstract = {TDP43 inclusion bodies are widely present in the majority of patients with familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms regulating TDP43 solubility remain incompletely understood. Here, we report that TDP43 undergoes S-acylation primarily at the Cys244 residue by the S-acyltransferase zDHHC23. This S-acylation maintains the liquid-like properties of TDP43 by reducing the aberrant interaction with poly(ADP-ribose) polymerase 1 (PARP1) and PARylated proteins, thereby countering the pathological condensation of TDP43. S-acylation-deficient TDP43 inclusions sequester the translational machinery and inhibit cytoplasmic protein translation, ultimately resulting in neurotoxicity. Importantly, TDP43 S-acylation is decreased in the familial ALS-associated TDP43 mutants as well as in SOD1-G93A mice and C9orf72-ALS induced pluripotent stem cell (iPSC)-derived neurons, suggesting the widespread involvement of TDP43 S-acylation in ALS pathogenesis. Our findings reveal an undescribed modification of TDP43 and provide deeper insight into the regulation of TDP43 pathological condensation in ALS.}, }
@article {pmid42129145, year = {2026}, author = {Pulst, SM and Paul, S and Nguyen, H and Dansithong, W and Figueroa, KP and Gandelman, M and Bonini, NM and Scoles, DR}, title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.}, journal = {Cell death &amp; disease}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41419-026-08830-x}, pmid = {42129145}, issn = {2041-4889}, support = {R21NS127028//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS137233//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097903//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS097275//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R56NS033123//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R37NS033123//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS127253//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.}, }
@article {pmid42130389, year = {2026}, author = {Thurn, T and Chiò, A and Galvin, M and Stavroulakis, T and Anneser, J}, title = {Beyond the surface: Exploring differing aspects of wishes to hasten death in patients with amyotrophic lateral sclerosis.}, journal = {Palliative &amp; supportive care}, volume = {24}, number = {}, pages = {e147}, doi = {10.1017/S1478951526102673}, pmid = {42130389}, issn = {1478-9523}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Cross-Sectional Studies ; Middle Aged ; Aged ; Longitudinal Studies ; Europe ; *Attitude to Death ; Quality of Life/psychology ; Surveys and Questionnaires ; Adult ; Aged, 80 and over ; }, abstract = {OBJECTIVES: This study investigates differing aspects of wishes to hasten death (WTHD) distinguished by the extent to which WTHD were linked to patients' agency: desire for hastened death (DHD), defined as general wishes for death to come sooner, and hastening death intentions (HDI), defined as thoughts about ending one's life. In particular, this study aims to examine the differences between DHD and HDI in patients with amyotrophic lateral sclerosis (pALS) and identify predictive factors for both.<br><br>METHODS: A cross-sectional nested study was conducted within a multi-center longitudinal study involving pALS from 5 European countries. Data collected included DHD (Schedule of Attitudes toward Hastened Death), HDI ("could you currently imagine ending your life?"), sociodemographic and clinical characteristics, psychological distress, quality of life, and social and spiritual-existential aspects.<br><br>RESULTS: In our sample of 121 pALS, 12.4% (15/121) expressed DHD, and 28.1% (34/121) expressed HDI. Of the 38 patients reporting any WTHD, only 11 experienced both DHD and HDI simultaneously. 23 patients reported HDI without DHD, while 4 patients expressed DHD without HDI. Multivariable logistic regression identified loneliness (OR&#xa0;=&#xa0;1.33, 95% CI 1.03-1.71, p&#xa0;=&#xa0;0.028) and reduced meaning in life (OR&#xa0;=&#xa0;0.89, 95% CI 0.84-0.95, p&#xa0;<&#xa0;0.001) as independent predictors of DHD. For HDI, independent predictors were female gender (OR&#xa0;=&#xa0;3.31, 95% CI 1.37-7.98, p&#xa0;=&#xa0;0.008) and lower spirituality (OR&#xa0;=&#xa0;0.92, 95% CI 0.88-0.95, p&#xa0;<&#xa0;0.001).<br><br>SIGNIFICANCE OF RESULTS: One in 3 pALS expressed WTHD. Our separate analysis of DHD and HDI supports the existence of distinct manifestations of WTHD and varying underlying factors. While DHD and HDI were associated with different predictors, our results point to the crucial role of spiritual-existential factors in the experience of WTHD, identifying these aspects as target points for intervention. This study highlights the importance of a nuanced understanding and communication regarding WTHD.}, }
@article {pmid42131110, year = {2026}, author = {Zhang, M and Su, L and Han, W and Song, F and Fu, Y and Chi, MB and Chen, X and Wu, YH and Gao, SJ}, title = {Single cell Raman spectroscopic profiles predict treatment responses in patients with de novo acute myeloid leukemia.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1767226}, pmid = {42131110}, issn = {2296-634X}, abstract = {INTRODUCTION: Leukemia is a clonal malignant proliferative disease originating from hematopoietic stem cells. Although its treatment strategy has gradually developed from traditional chemotherapy to a multimodal treatment system including novel targeted therapy and immunotherapy, primary drug resistance in particular remains the core clinical problem leading to poor patient prognosis. This clinical dilemma indicates that the traditional genotyping system based on genomics has not been able to fully resolve the molecular heterogeneity of acute myeloid leukemia (AML), and it is urgent to establish a precise stratified model that can dynamically reflect the functional status of tumor cells in the initial stage of treatment.<br><br>METHODS: In this study, Raman spectroscopy (RS) combined with machine learning algorithm was used to construct a metabolic prognosis prediction model for AML chemotherapy response. Bone marrow single cell Raman spectroscopy data of newly diagnosed AML patients were collected, and the molecular fingerprint was analyzed by principal component analysis linear discriminant analysis (PCA-LDA) and multivariate curve resolute alternating least square method (MCR-ALS).<br><br>RESULTS: The results showed that the PCALDA model achieved complete remission or non-remission (CR/NR) classification through 24 principal components (cumulative variance contribution of 90.1%), the accuracy of external validation was 94.8% (sensitivity 97.9%, specificity 92.0%), and the AUC reached 96.27%. Protein, lipid, nucleic acid and mixed components were decomposed by MCR-ALS, and lipid and nucleic acid metabolic pathways were enriched in NR group (P < 0.001).<br><br>DISCUSSION: Studies have shown that RS single-cell metabolic fingerprint can decode the metabolic reprogramming features associated with chemotherapy resistance in AML, providing a new marker-free and highly sensitive tool for real-time prognostic stratification and targeted intervention.}, }
@article {pmid42131159, year = {2026}, author = {Dewan, L and Pal, S and Tibrewal, S}, title = {Letter to the Editor: Comment on Takai et al.'s "Age-Associated Differences in Optic Disc Findings of Leber's Hereditary Optic Neuropathy".}, journal = {Neuro-ophthalmology (Aeolus Press)}, volume = {50}, number = {3}, pages = {292-293}, pmid = {42131159}, issn = {0165-8107}, abstract = {This letter comments on the study by Takai et al examining age-related differences in acute phase optic disc morphology in Leber hereditary optic neuropathy. We highlight methodological considerations in subjective fundus photograph assessment, and discuss additional factors such as refractive status and timing of presentation that may influence the presence of optic disc edema. These points may aid in refining phenotypic interpretation in future LHON studies.}, }
@article {pmid42131356, year = {2026}, author = {Macchietti, L and Carta, M and Delogu, F and Grepioni, F and Emmerling, F and Casali, L}, title = {Scaling up mechanochemical reactions: linking crystalline phase evolution studied via in situ PXRD with kinetics from MCR-ALS.}, journal = {Chemical science}, volume = {}, number = {}, pages = {}, pmid = {42131356}, issn = {2041-6520}, abstract = {This work addresses a key challenge in scaling up mechanochemical synthesis: deriving a kinetic model when unpredictable formation and intricate interaction of multiple crystalline phases occur during solid-state transformations. Reaction kinetics translate our understanding of chemical processes into mathematical rate expressions used for reactor design and evaluation, thus representing a challenge to be addressed for the scale up at the industrial level. Choosing co-crystallization of chloro-3-sulfamoylbenzoic acid (CSBA) and isonicotinamide (INA) as a model system, at first we employ time-resolved in situ powder X-ray diffraction (PXRD) and multivariate curve resolution-Alternating Least Squares (MCR-ALS) analysis to quantify and resolve the evolution of crystalline intermediates under varying methanol-assisted conditions. Our data show that even small changes in the amount of methanol can dramatically alter the kinetic profile, stabilise transient phases (including some that were previously unreported) and alter the overall reaction pathway. We then demonstrate the robust deconvolution of overlapping phases and the extraction of quantitative rate parameters that rationalize the observed behaviour by integrating kinetic modelling as a soft-hard constraint in the MCR-ALS workflow. The validation of the established MCR-ALS workflow is achieved by applying a phenomenological kinetic modelling tailored to rationalize the mechanochemical reaction rates. These results establish a broadly applicable platform for analysing and controlling the complex phase evolution, along with the derivation of a kinetic model instrumental to mechanochemical process development and scaling up, thereby supporting the transition of sustainable solid-state syntheses from the laboratory to industry.}, }
@article {pmid42133017, year = {2026}, author = {Svihlik, J and Rusz, J}, title = {Screening speech disorders in progressive neurological diseases via long-term average spectrum.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42133017}, issn = {1435-1463}, abstract = {The long-term averaged spectrum (LTAS) may provide a universal method for capturing distinct patterns of dysarthria. This study aimed to evaluate the sensitivity of LTAS descriptors in a broad range of neurological diseases and various types and severities of dysarthria. Four spectral moments of spectral mean, spectral standard deviation, spectral skewness and spectral kurtosis based on LTAS were computed for reading passage collected from 461 speakers, including 306 healthy controls and 155 neurological patients secondary to Parkinson's disease (PD), progressive supranuclear palsy, multiple system atrophy (MSA), Huntington's disease, essential tremor, cerebellar ataxia (CA), multiple sclerosis (MS), and amyotrophic lateral sclerosis. Compared to controls, the spectral mean was significantly lower in PD and MS while elevated in CA. Significantly changed LTAS features were observed only in hypokinetic dysarthria and in mixed dysarthrias manifesting hypokinetic elements. Although LTAS features differed between controls and patients with varying degrees of dysarthria, there was no progressive increase in dysarthria severity. Our findings suggest that LTAS-based speech analysis may provide valuable cues to aid differential diagnosis among neurological diseases with overlapping clinical features. LTAS appears more informative when applied to specific diseases than to pooled dysarthria types arising from diverse neurological etiologies.}, }
@article {pmid42134656, year = {2026}, author = {Vassallu, F and López, M and López Ambrosioni, F and Casal, J and Caltana, L and Igaz, LM}, title = {TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {106180}, doi = {10.1016/j.neuint.2026.106180}, pmid = {42134656}, issn = {1872-9754}, abstract = {TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-ΔNLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analyzed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both transgenic TDP-43-ΔNLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-ΔNLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model.}, }
@article {pmid42116599, year = {2026}, author = {Saha, T and Vats, T and Mehan, S}, title = {Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.}, journal = {Immunopharmacology and immunotoxicology}, volume = {}, number = {}, pages = {1-77}, doi = {10.1080/08923973.2026.2671714}, pmid = {42116599}, issn = {1532-2513}, abstract = {Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.}, }
@article {pmid42116669, year = {2026}, author = {Shimizu, T and Myojin, H and Bokuda, K and Kawazoe, T and Morishima, R and Kimura, H and Takahashi, K and Nakayama, Y}, title = {Offset Conduction Velocity Reveals Prognostic Slowing of Motor Axons in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70273}, pmid = {42116669}, issn = {1097-4598}, support = {25293449//Japan Society for the Promotion of Science/ ; 16H05583//Japan Society for the Promotion of Science/ ; }, abstract = {INTRODUCTION/AIMS: Slowing of motor nerve conduction is not classically regarded as a feature of amyotrophic lateral sclerosis (ALS). We introduce a novel electrophysiological parameter, offset motor conduction velocity (offset-MCV), to assess conduction in relatively slower motor axons and investigate its association with survival in ALS.<br><br>METHODS: Motor nerve conduction studies of the median and tibial nerves were performed in 145 patients with ALS and 70 healthy controls. Onset and offset latencies of compound muscle action potentials were measured, and onset- and offset-MCVs were calculated. Patients were followed until death or tracheostomy, and associations between MCV parameters and survival were analyzed.<br><br>RESULTS: Both onset- and offset-MCVs were significantly reduced in patients with ALS compared with controls for the median and tibial nerves (all p&#x2009;<&#x2009;0.0001). Onset-MCVs were not associated with survival. In contrast, reduced offset-MCVs in both nerves were associated with short survival (log-rank test: median nerve, p&#x2009;=&#x2009;0.009; tibial nerve, p&#x2009;=&#x2009;0.021). Multivariate Cox regression analysis identified tibial nerve offset-MCV as an independent prognostic factor (p&#x2009;=&#x2009;0.029).<br><br>DISCUSSION: Pathological slowing of motor nerve conduction occurs in ALS and is associated with poor survival. Offset-MCV may reflect disease-related changes in slower &#x3b1;-motor axons and represents a potential prognostic biomarker in ALS.}, }
@article {pmid42117108, year = {2026}, author = {Jiang, A and Huang, Y and Que, X and Li, C and Lin, Z and Huang, W}, title = {Integrative Transcriptomics Identifies Ubiquitination-Related Genes BIRC2, COPS5, and TBK1 as Novel Biomarkers of T-Cell Dysregulation in Amyotrophic Lateral Sclerosis.}, journal = {Journal of inflammation research}, volume = {19}, number = {}, pages = {585872}, pmid = {42117108}, issn = {1178-7031}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is marked by immune dysregulation; however, the role of T cell-ubiquitination-related genes (TURGs) in its pathogenesis remains unclear. This study aimed to investigate the contribution of TURGs to T-cell dysfunction and ubiquitination imbalance in ALS.<br><br>PATIENTS AND METHODS: Differentially expressed genes were identified through analysis of bulk transcriptomes (GSE112680). CIBERSORT deconvolution and weighted gene co-expression network analysis were employed to define T-cell-associated modules. Integration with ubiquitination-related gene sets yielded T cell-ubiquitination-related differentially expressed genes (TURDEGs). Functional enrichment analysis and protein-protein interaction network construction, combined with multi-algorithm selection, facilitated the development of a risk-prediction model. Mechanistic insights were derived from Gene Set Enrichment Analysis, immune profiling, co-expression and regulatory network analyses, and drug-target prediction. Single-cell transcriptomic analysis provided insights into cellular-level pathogenic mechanisms in ALS. qPCR was used to validate core TURDEGs expression in peripheral blood samples from patients with ALS.<br><br>RESULTS: Thirty-nine TURDEGs were identified and exhibited significant enrichment in pathways related to ubiquitination, immune activation, autophagy, and NOD-like receptor signaling. BIRC2, COPS5, and TBK1 were identified as core genes. The resulting risk-prediction model demonstrated significant potential for clinical application. Immune infiltration analysis revealed positive correlations between core genes and CD4&#x207a; resting memory T cells, as well as negative correlations between COPS5, TBK1, and regulatory T cells. Adavosertib and MRS2211 were identified as potent modulators of TBK1 and BIRC2, respectively. Single-cell transcriptomics highlighted enhanced T cell-neutrophil interactions, suggesting a remodeling of the immune communication network in ALS. qPCR validation confirmed significantly increased expression of these genes in patients with ALS (p<0.05).<br><br>CONCLUSION: TURDEGs-mediated T cell dysfunction and ubiquitination imbalance play critical roles in ALS pathogenesis, unveiling novel biomarkers and potential personalized therapeutic targets.}, }
@article {pmid42117777, year = {2026}, author = {Dong, J and Yan, M and Farmer, A and Jiang, L and Zhen, J and Tong, Y and Dong, Y and Zhang, G and Wu, L and Guo, Y and Yin, X and Fang, L and Xu, Z}, title = {The Impact of Social Isolation on Treatment Burden Among Community-Dwelling Adults With Disability and Multimorbidity: A Longitudinal Qualitative Study in Urban China.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {29}, number = {3}, pages = {e70693}, doi = {10.1111/hex.70693}, pmid = {42117777}, issn = {1369-7625}, support = {2024KY1026//Medical Science and Technology Project of Zhejiang Province/ ; //National Institute of Health and Care Research Oxford Biomedical Research Centre/ ; }, mesh = {Humans ; *Social Isolation/psychology ; Female ; Male ; Longitudinal Studies ; Qualitative Research ; China ; *Persons with Disabilities/psychology/statistics &amp; numerical data ; Aged ; *Multimorbidity ; Middle Aged ; *Independent Living/psychology ; Interviews as Topic ; Urban Population ; *Cost of Illness ; Adult ; Chronic Disease ; }, abstract = {BACKGROUND: Social isolation is a critical social determinant of health that amplifies the significant treatment burden faced by community-dwelling adults with disabilities and multimorbidity. While an association between these factors is established, longitudinal evidence capturing their dynamic interplay is scarce, limiting the development of effective, equitable interventions. This study aimed to longitudinally explore how treatment burden evolves among this population and to elucidate the mechanisms through which social isolation appears to operate through these changes.<br><br>METHODS: We conducted a longitudinal qualitative study using interpretive description in Hangzhou, China. Participants were adults with physician-diagnosed disabilities and &#x2265;&#x2009;2 chronic conditions, recruited via purposive sampling from community health centres. Each participant completed three in-depth, semi-structured interviews over 12 months. We conceptualized treatment burden using Demain et al.'s adaptation of the Cumulative Complexity Model. Data analysis was an iterative process involving constant comparison to identify key themes regarding the interplay of social isolation and treatment burden over time.<br><br>RESULTS: A total of 24 participants (13 were women; median age 67.5 years) completed the study. Our analysis revealed that social isolation was described by participants as dynamically contributing to increased treatment burden through four interconnected mechanisms: (1) Eroding autonomy, leading to passive healthcare decision-making; (2) Compromising emotional well-being, which depleted self-management capacity; (3) Straining relational networks, resulting in the loss of crucial informal support; and (4) Creating navigational barriers, which led to difficulties managing complex treatments. A key cross-cutting theme was the apparent role of depressive symptoms, which participants described as being exacerbated by isolation and, in turn, appearing to contribute to more negative illness perceptions and functional decline. This pattern was consistent with a progressive intensification of treatment burden as emotional and physical challenges fed into each other over time.<br><br>CONCLUSION: Social isolation appeared to function not merely as a passive correlate but as a factor that longitudinally contributed to greater treatment burden, thereby exacerbating health inequities for adults with disabilities and multimorbidity. This pattern appeared to be further shaped by the intersection with depressive symptoms. To mitigate this, multi-level interventions are essential. Priorities should include addressing structural barriers through policies that foster community integration, strengthening mental health support within primary care, and redesigning services to be more relationally-centred and less burdensome.<br><br>Patients, care-givers, people with lived experience or members of the public were not involved in the study design, conduct, data analysis or preparation of the manuscript. However, preliminary findings were shared and discussed with two patient advisors who had lived experience of disability and multimorbidity but were not participants in the interviews. Their feedback helped refine the presentation and contextual relevance of the themes.}, }
@article {pmid42118126, year = {2026}, author = {Ghiasi, S and Röder, T and Schunk, S and Parastar, H and Weller, P}, title = {Separation of Ammonia Isotopologues by Benchtop Drift Tube Ion Mobility Spectrometry and Chemometric Modeling.}, journal = {Journal of the American Society for Mass Spectrometry}, volume = {}, number = {}, pages = {}, doi = {10.1021/jasms.5c00434}, pmid = {42118126}, issn = {1879-1123}, abstract = {This research study assesses the applicability of drift tube ion mobility spectrometry (DTIMS) to resolve ammonia (NH3) from its isotopologue, ammonia-d3 (ND3). DTIMS, known for its rapid response at ambient pressure, was employed to conduct real-time analysis of gaseous samples. Two ammonia introduction methods were evaluated, evaporation of a 3 ppm(v) aqueous ammonia solution and dry gas synthesis. The study tested these methods for the mixture analysis of ammonia and examined their impact on resolution. The resolution of isotopologues and the influence of moisture in the carrier gas on separation were assessed. Individual analysis by evaporation method provided drift times of 6.03 ms for NH3 and 6.17 ms for ND3, from which reduced mobility (K0) values of 2.52 cm[2] V[-1] s[-1] and 2.46 cm[2] V[-1] s[-1] were calculated, respectively. The presence of moisture in the carrier gas was found to significantly reduce the resolution of isotopologue separation. To address this limitation and enhance signal clarity, the application of wavelet denoising was conducted, with universal thresholding based on Symlet, Daubechies, and Coiflet wavelet families systematically evaluated. The Daubechies wavelet (db9) at level 9 was identified as the optimal denoising approach. Following this, multivariate curve resolution alternating least-squares (MCR-ALS) was employed for the decomposition of the complex overlapping signals into their pure ion mobility spectra and corresponding concentration profiles over time. The integration of wavelet-based denoising and MCR-ALS offers a practical strategy for the enhancement of DTIMS performance in complex isotopologue separation, particularly for future studies focused on quantitative analysis. Future work will involve the integration of steady-state isotopic transient kinetic analysis (SSITKA) for a comprehensive kinetic framework for kinetic models.}, }
@article {pmid42118400, year = {2026}, author = {Pi, C and Liu, Y and Jia, Z and Zhang, M and Wang, X and Zhao, H and Dong, Z and Yu, S and Liu, R}, title = {Mechanism of the N87D mutation in SOD1-atypical amyotrophic lateral sclerosis case report and literature review molecular mechanism of N87D mutation in SOD1.}, journal = {Neurogenetics}, volume = {27}, number = {1}, pages = {}, pmid = {42118400}, issn = {1364-6753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Superoxide Dismutase-1/genetics/chemistry ; Molecular Dynamics Simulation ; *Mutation ; Protein Conformation ; Male ; Female ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. This study aimed to investigate the possible molecular mechanisms of ALS by analyzing protein structure and dynamics in a rapidly progressing ALS patient carrying the N87D mutation. A patient with the N87D mutation experienced rapid disease progression and died within one year. We reviewed all known mutations at the 87th position of the superoxide dismutase (SOD1) gene and the clinical characteristics. To investigate the molecular basis of the severe phenotype, we performed protein structure modeling and molecular dynamics (MD) simulations, and compared wild type homodimers, mutant homodimers, and heterodimers in terms of energy, residue fluctuation, number of hydrogen bonds, radius of gyration (Rg), principal component analysis (PCA), free energy landscape (FEL), the contribution of dimer interface residues, solvent-accessible surface area, and metal ion coordination. Our analysis revealed that patients with mutations at the 87th position of the SOD1 gene typically exhibited rapid disease progression. Protein structure modeling and MD simulations demonstrated that the N87D mutation significantly increased the energy and RMSF of SOD1 heterodimers compared to homodimers. Furthermore, Rg, FEL and PCA analyses showed that the heterodimers had a broader and more unstable conformational energy distribution, along with a stronger tendency for aggregation. Additionally, the N87D mutation disrupted metal ion coordination, further destabilizing the heterodimer and promoting protein misfolding. These findings suggest a potential molecular mechanism underlying ALS and support a protein structure based approach for investigating the pathogenic mechanisms of disease causing mutations.}, }
@article {pmid42119241, year = {2026}, author = {Toubasi, AA and Al-Sayegh, TN}, title = {Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Clinical neurology and neurosurgery}, volume = {267}, number = {}, pages = {109466}, doi = {10.1016/j.clineuro.2026.109466}, pmid = {42119241}, issn = {1872-6968}, abstract = {BACKGROUND: Previous studies have suggested that traumatic head injury (THI) is associated with amyotrophic lateral sclerosis (ALS). However, the evidence remains limited and inconsistent, partly due to small sample sizes.<br><br>OBJECTIVES: In this meta-analysis, we aimed to investigate the association between THI and the risk of ALS.<br><br>METHODS: We conducted a systematic review and meta-analysis of studies assessing the relationship between THI and ALS. The exposure of interest was THI, and the outcome of interest was ALS development. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used as effect measures.<br><br>RESULTS: Eighteen studies comprising 578,815 participants were included. THI was associated with an increased risk of ALS (OR = 1.47; 95% CI: 1.23-1.76). The association was consistent across studies conducted in Europe (OR = 1.60; 95% CI: 1.19-2.15) and the Americas (OR = 1.27; 95% CI: 1.12-1.43). Subgroup analysis by sex showed a significant association among males (OR = 2.27; 95% CI: 1.41-3.66) but it was less significant among females (OR = 1.30; 95% CI: 0.78-2.17). Both single (OR = 1.48; 95% CI: 1.18-1.85) and multiple THIs (OR = 1.34; 95% CI: 1.15-1.56) were associated with ALS. Funnel and doi plots demonstrated asymmetry indicating significant publication bias.<br><br>CONCLUSIONS: Our analysis demonstrated an association between THI and ALS, however the lack of dose-response relationship suggests it is less likely to be causative.}, }
@article {pmid42121359, year = {2026}, author = {Goto, S and Singh, S and Zhu, Q and Vyas, SA and Wildsoet, C}, title = {Development of an Optical Defocus-Induced Myopia Model for Guinea Pigs Using Rigid Gas Permeable Contact Lenses.}, journal = {Eye &amp; contact lens}, volume = {}, number = {}, pages = {}, doi = {10.1097/ICL.0000000000001279}, pmid = {42121359}, issn = {1542-233X}, support = {Loris and David Rich Postdoctoral Scholar//International Retina Research Foundation/ ; T32 EY007043/EY/NEI NIH HHS/United States ; R01 EY012392/EY/NEI NIH HHS/United States ; }, abstract = {OBJECTIVES: Guinea pigs are a widely used mammalian model for studies of myopia and early ocular growth regulation more generally. The study reported here covers the development of rigid gas permeable (RGP) contact lenses (CLs) for guinea pigs, as an alternative to spectacle lenses for imposing optical defocus, recognized as an important modulator of eye elongation in young animals.<br><br>METHODS: New Zealand pigmented guinea pigs (Cavia porcellus) were used in this study, with the RGP lens design based on developmental corneal shape profiles derived from anterior segment optical coherence tomography data collected across a range of ages, as typically encountered in such studies. The validity of this CL-based approach was examined in a follow-up study, in which the ocular effects of -10, 0, and +5 diopters [D] RGP lenses, applied as continuous monocular optical defocus treatments, were tracked over 2 weeks, with the fellow untreated eyes of experimental animals serving as contralateral controls. Pretreatment baseline spherical equivalent refractive errors (RE) and axial length (AL) of both eyes were measured, along with follow-up weekly measurements over the wearing period.<br><br>RESULTS: There were no differences in any of the ocular parameters between the three groups at baseline, while after two weeks of lens wear, there were significant differences between the -10 D group compared with 0 D and +5 D groups in both RE (P<0.001) and AL (P<0.05). Importantly, myopia was observed in all of the guinea pigs fitted with -10 D lenses, and overall, eyes fitted with -10 D lenses showed increased ALs and relative myopia compared with their fellows, while those fitted with +5 D lenses showed reduced ALs and relative hyperopia; the plano lens group fell in between (treated-fellow eyes: -10, 0, and +5 D lenses: -8.25, -1.0, and +0.5 D, and +0.16, +0.08, and -0.02 mm, respectively). Also importantly, no significant CL-related adverse ocular effects were observed.<br><br>CONCLUSIONS: This study provides proof of principle that defocusing RGP CLs are a feasible alternative to spectacle lenses for studies of eye growth regulation in young guinea pigs and experimental myopia specifically, with potential application in investigations into novel approaches for controlling myopia progression and underlying mechanisms.}, }
@article {pmid42112934, year = {2026}, author = {Melechovsky, J and Novotny, M and Tykalova, T and Klempir, J and Herremans, D and Rusz, J}, title = {Development of an Interpretable Deep Learning-Based Segmentation Algorithm for Automated Assessment of Oral Diadochokinesis in Progressive Neurological Diseases.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-17}, doi = {10.1044/2026_JSLHR-25-00453}, pmid = {42112934}, issn = {1558-9102}, abstract = {PURPOSE: We aimed to develop a universal, fully automated segmentation algorithm that allows robust analysis of oral diadochokinesis across various neurological diseases, dysarthria types, and dysarthria severities.<br><br>METHOD: Recordings of sequential motion rates were collected from 231 subjects, including 80 healthy controls and 151 patients with neurological diseases such as amyotrophic lateral sclerosis, essential tremor, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and cerebellar ataxia. A robust automatic segmentation algorithm utilizing convolutional neural networks and rule-based postprocessing was developed and evaluated across disease type, dysarthria type, and dysarthria severity. The performance of the developed artificial intelligence-based algorithm was compared with a traditional signal processing-based segmentation approach.<br><br>RESULTS: Our deep learning-based algorithm was able to correctly identify the position of individual syllables with a very high F1 score of 99.1%, compared to a signal processing-based approach with an F1 score of 97.7%. Using a 10-ms tolerance window, the deep learning-based algorithm achieved an average accuracy of 92.0% for the temporal detection of individual phoneme positions. Performance was strongly influenced by dysarthria severity, with accuracy reaching 94.7% in mild, 91.0% in moderate, and 83.1% in severe dysarthria. Disease and dysarthria type did not appear to have a substantial effect on algorithm performance.<br><br>CONCLUSIONS: Our proposed deep learning-based algorithm provides reliable segmentation of syllable and individual phoneme positions during oral diadochokinesis across various disease types, dysarthria types, and dysarthria severities. The deep learning-based segmentation approaches have the potential to outperform the traditional signal processing methods for assessing oral diadochokinesis.}, }
@article {pmid42113315, year = {2026}, author = {Mishra, R and Upadhyay, A}, title = {Exosomes in Amyloid Propagation-Roles in Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42113315}, issn = {1559-1182}, mesh = {*Exosomes/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Amyloid/metabolism ; }, abstract = {Extracellular vesicle (EVs)-mediated cell-to-cell communication is crucial for cell growth, signaling, and metabolism. Exosomes are a subtype of EVs originating from endosomal cellular machinery and have a relatively smaller size (30-150 nM). They carry nucleic acids, proteins, miRNA, lipids, metabolites, and growth factors, making them an exciting research tool for understanding the pathophysiology of complex human diseases. Different brain cells also communicate with themselves by the release of exosomes which helps in overall brain growth and in cell signaling. Recent studies have highlighted the importance of exosomes in neurodegenerative diseases (NDDs) of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion, and Huntington's disease (HD). Exosomes are involved in the spread of amyloid-like protein aggregates formed in these diseases, but a comprehensive understanding of this spread mechanism is limited. In this article, we have analyzed the roles of exosomes in the spread of amyloid protein aggregates in the NDDs. Furthermore, we have discussed possible measures to address several gaps in our current understanding of cross talks between exosomes and protein aggregates in neurodegenerative disorders (NDDs). We have also discussed the therapeutic opportunities to delay or prevent pathogenic amyloid aggregate spread by exploiting exosomal transport. Overall, the review will contribute to develop a better understanding vesicular transport of amyloids and will help contend their propagation in different NDDs.}, }
@article {pmid42113599, year = {2026}, author = {Ravits, J and Ferrey, D and Gundogdu, B and Qayoumi, W and Zale, C}, title = {Amyotrophic Lateral Sclerosis: A Review.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2026.6385}, pmid = {42113599}, issn = {1538-3598}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness due to degeneration of upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord. It affects approximately 25 000 individuals in the United States.<br><br>OBSERVATIONS: Amyotrophic lateral sclerosis is characterized by progressive painless muscle weakness that typically begins in a focal region of the body, such as limb muscle weakness causing hand weakness or foot drop (65%), cranial muscle weakness causing speech or swallowing problems (20%-25%), or axial muscle weakness causing bent posture (5%-10%), and spreads to other body regions over time. The disease usually manifests with dysfunction indicative of both upper motor neurons (causing muscle stiffness and spasticity) and lower motor neurons (causing weakness, fasciculations, atrophy, and flaccidity). After onset, weakness spreads through the musculature and typically causes death due to respiratory muscle weakness. Among people with ALS, approximately 85% have sporadic ALS, which is not associated with known environmental or genetic factors, and 15% have familial ALS. Amyotrophic lateral sclerosis is diagnosed based on clinical features, which can be supported by results of electromyography. More than 60 genes have been associated with ALS, and most are autosomal dominant. Pathogenic variants in chromosome 9 open reading frame 72 (C9orf72) are found in 40% of all familial ALS cases, and pathogenic variants in superoxide dismutase 1 (SOD1) are found in 20% of patients with familial ALS. Patients with ALS survive a mean of 3 to 5 years after diagnosis, and there are currently no curative therapies. Clinical care primarily focuses on symptom management and quality of life. Three US Food and Drug Administration (FDA)-approved disease-modifying therapies are available in the United States. Riluzole and edaravone are oral medications that slow ALS progression by up to 2 to 4 months, and tofersen is an intrathecally administered gene therapy for patients with SOD1 gene variants. Specialized multidisciplinary teams, comprising neurologists, nurses, therapists, dietitians, and social workers, are associated with improved survival (4-7 months) and quality of life.<br><br>CONCLUSIONS AND RELEVANCE: Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disorder of upper and lower motor neurons. No curative therapies exist. Two oral medications, riluzole and edaravone, are approved by the FDA and modestly decrease disease progression in sporadic ALS. Tofersen, an intrathecally administered gene-based therapy, is also FDA approved and slows disease progression in patients with SOD1 pathogenic gene variants.}, }
@article {pmid42114078, year = {2026}, author = {Bareamichael, PI and Babu, S and Hoang, T and Socal, MP}, title = {Bridging the Funding Gap in Drug Development for Amyotrophic Lateral Sclerosis.}, journal = {Neurology. Clinical practice}, volume = {16}, number = {3}, pages = {e200623}, pmid = {42114078}, issn = {2163-0933}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Development/economics ; United States ; Clinical Trials as Topic/economics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with few effective treatments and high clinical trial failure rates. Since 1995, only 3 drugs riluzole, edaravone, and tofersen have gained approval from the Food and Drug Administration, all offering modest benefits. Challenges in ALS drug development include poor translational preclinical models, underpowered early-phase trials, and the high cost of late-stage development. Despite federal initiatives such as the Accelerating Access to Critical Therapies for ALS Act and the ALL ALS Consortium, critical gaps remain in funding large multisite trials and sustaining research networks. Accelerating progress requires strengthening national registries, expanding adaptive trial platforms, integrating existing networks, and adopting innovative funding models such as milestone-based public-private partnerships and reinvestment of licensing revenues. A coordinated, sustainable research and funding ecosystem could transform ALS therapy development and serve as a model for advancing treatments for other rare neurodegenerative and neurogenetic disorders.}, }
@article {pmid42114311, year = {2026}, author = {Shubham,  and Mathur, A}, title = {Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".}, journal = {Journal of the neurological sciences}, volume = {487}, number = {}, pages = {125920}, doi = {10.1016/j.jns.2026.125920}, pmid = {42114311}, issn = {1878-5883}, }
@article {pmid42114427, year = {2026}, author = {Ritu, JR and Uddin, MH and Ferrari, MCO and Chivers, DP}, title = {Ecotoxicological implications of environmental neurotoxin β-N-methylamino-L-alanine (BMAA) in fishes: An emerging concern.}, journal = {Ecotoxicology and environmental safety}, volume = {318}, number = {}, pages = {120252}, doi = {10.1016/j.ecoenv.2026.120252}, pmid = {42114427}, issn = {1090-2414}, abstract = {Harmful algal blooms (HABs), intensified by climate change, eutrophication, and altered hydrological regimes, are expanding globally, releasing cyanotoxins that threaten aquatic ecosystems and human health. β-N-methylamino-L-alanine (BMAA), a non-protein amino acid with neurotoxic potential, has been recognized as a global emerging concern. Following exposure, BMAA is present in both free and protein-bound forms, forming an endogenous toxin reservoir that exacerbates potential neurotoxicity in aquatic organisms and humans. Its presence in aquatic food webs not only elevates ecological risks for wildlife but also raises potential human health concerns, particularly its potential association with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and the ALS/Parkinsonism-dementia complex. This review aims to explore current knowledge of the ecotoxicological impacts of BMAA in fishes, focusing on developmental, behavioural and cognitive perturbations, along with their mechanistic underpinnings. BMAA exposure induces developmental abnormalities, including convulsions, spinal axis malformations, pericardial edema, and altered heart rate, as well as neurodevelopmental impairments, such as reduced motor neuron length and altered neuromuscular colocalization in fishes. Additionally, BMAA exposure affects a wide array of behaviours in fishes, including motor coordination, locomotion, feeding, startle responses, anxiety-like behaviours, and cognitive performance, primarily through excitotoxicity, oxidative stress, apoptosis, metabolic disruption, neuroendocrine modulation, and dysregulated neurotransmitter signalling. Future research should focus on more environmentally relevant exposure scenarios, elucidating BMAA toxicokinetics, and investigating cyanotoxin co-exposure toxicity in fishes. Advancing integrative phenotypic endpoints and knowledge of molecular mechanisms of BMAA toxicity in aquatic organisms is essential for effective ecological risk assessments and for developing regulatory standards to safeguard aquatic ecosystems and human health.}, }
@article {pmid42115692, year = {2026}, author = {Yada, Y and Naoki, H}, title = {Decomposing heterogeneity in disease progression speeds and pathways.}, journal = {NPJ digital medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41746-026-02665-8}, pmid = {42115692}, issn = {2398-6352}, support = {JP23K16994//JSPS Grant-in-Aid for Early-Career Scientists/ ; JP24wm0625416//AMED Brain/MINDS 2.0/ ; JP25wm0625322//AMED Brain/MINDS 2.0/ ; JPMJMS2024//JST Moonshot R D-MILLENNIA Program/ ; JPMJCR25Q2//Japan Science and Technology Agency/ ; }, abstract = {Understanding why patients with the same diagnosis exhibit markedly different disease progression-some rapidly, others slowly, with distinct symptom patterns-remains a major challenge in medicine. Here, we developed a machine learning framework called DiSPAH (Disease-progression Speed and Pathway Analysis based on a Hidden Markov model) to estimate both the pathway and speed of disease progression in individual patients. DiSPAH models disease progression as continuous-time transitions among latent disease states with a patient-specific progression speed. We applied DiSPAH to longitudinal clinical scores from an amyotrophic lateral sclerosis (ALS) cohort and inferred each patient's trajectory of the latent disease states and progression speed. These dynamics were associated with baseline clinical features and enabled prediction of future course from first-visit data. Our results highlight that jointly modeling progression pathway and speed improves prediction of heterogeneous disease courses, offering a powerful tool for personalized care and research in ALS and other chronic conditions.}, }
@article {pmid42115814, year = {2026}, author = {Fang, SY and Jih, KY and Chao, YC and Sytwu, HP and Shih, YC and Liao, YC and Lee, YC}, title = {Clinical and electrophysiological features for differentiating MMN from hand-onset ALS.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {}, number = {}, pages = {}, doi = {10.1097/JCMA.0000000000001387}, pmid = {42115814}, issn = {1728-7731}, abstract = {BACKGROUND: Multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) can be difficult to differentiate, particularly at early disease stages in patients with hand-onset weakness and without upper motor neuron (UMN) signs. This study aimed to identify clinical and electrophysiological features that may facilitate early distinction between MMN and ALS.<br><br>METHODS: We retrospectively analyzed the clinical, laboratory, and electrophysiological characteristics of patients diagnosed with MMN and ALS and receiving identical nerve conduction study protocol comprising extended motor stimulation.<br><br>RESULTS: One hundred and twenty-five patients (74 men and 51 women) were included, consisting of eight patients with MMN and 117 patients with ALS, including 42 with hand-onset ALS. Patients with MMN had a significantly younger mean age at symptom onset than those with ALS (43.1 vs. 58.7 years, p = 0.004). ALS patients had more severe muscle weakness, more frequent muscle atrophy and fasciculation, UMN signs, and body weight loss. Compared with both the overall ALS and the hand-onset ALS groups, MMN patients showed significantly lower serum creatine kinase (CK) level and higher serum IgM levels. Elevated CK levels were observed in approximately one-third of patients with hand-onset ALS, whereas none of the MMN patients had elevated CK. Conduction block (CB) on nerve conduction studies was more common in MMN (87.5%) than in all ALS cases (19.7%, p < 0.001) or hand-onset ALS (31.0%, p = 0.005). MMN patients more frequently exhibited definite CBs involving multiple nerves (85.7%) compared with all ALS (17.4%, p = 0.002) and hand-onset ALS (7.7%, p = 0.001) patients.<br><br>CONCLUSION: Our findings suggest that a combination of clinical features, serum CK and IgM levels, and electrophysiological evidence of CB provides valuable clues for distinguishing MMN from ALS.}, }
@article {pmid42116144, year = {2026}, author = {Li, M and Jin, H and Meng, L and Altay, O and Yuksel, B and Zhang, C and Uhlen, M and Turkez, H and Mardinoglu, A}, title = {WBT-DC pipeline: a cross-cohort and cross-platform disease classification pipeline based on whole-blood transcriptomics.}, journal = {Journal of translational medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12967-026-08254-3}, pmid = {42116144}, issn = {1479-5876}, abstract = {BACKGROUND: Machine-learning models based on tissue transcriptomic data are powerful tools for disease classification. However, their clinical adoption is limited by the invasive nature of tissue sampling. Furthermore, transcriptomic datasets are often affected by batch effects and gene-level noise, which compromise model generalizability across platforms and clinical cohorts.<br><br>METHODS: We developed WBT-DC (Whole Blood Transcriptomics-based Disease Classification), a computational pipeline designed to overcome these challenges. WBT-DC integrates rank-based feature extraction to mitigate batch effects with an ensemble machine-learning framework that incorporates cross-validation and hyperparameter optimization. Its performance was systematically evaluated across five independent cohorts involving 2,164 participants and three disease contexts: Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS). We tested the model's robustness across RNA-sequencing and microarray platforms. Additionally, an internal rheumatoid arthritis (RA) cohort (n&#x2009;=&#x2009;165) was utilized for real-world prospective validation.<br><br>RESULTS: WBT-DC demonstrated high accuracy, achieving ROC-AUC values of 0.90-0.94 in independent datasets when training and testing were conducted on the same platform. In cross-platform evaluations, the pipeline maintained robust performance with ROC-AUC values ranging from 0.71 to 0.84, consistently outperforming conventional gene expression-based models. In the RA validation cohort, WBT-DC achieved an ROC-AUC of 0.81, supporting its applicability in a real-world clinical setting.<br><br>CONCLUSIONS: WBT-DC provides a robust, non-invasive, and platform-agnostic framework for disease classification using whole-blood transcriptomics. By effectively addressing batch effects and platform variability, this pipeline offers a scalable solution for translating systems-level transcriptomic insights into applications.}, }
@article {pmid42116550, year = {2026}, author = {Bae, JH and Kwak, S}, title = {Emergency department visits among patients with neuromuscular diseases receiving home mechanical ventilation: a nationwide population-based study.}, journal = {Journal of Yeungnam medical science}, volume = {43}, number = {}, pages = {32}, doi = {10.12701/jyms.2026.43.32}, pmid = {42116550}, issn = {2799-8010}, abstract = {BACKGROUND: Population-level data on emergency department (ED) utilization in patients with neuromuscular disease (NMDs) receiving home mechanical ventilation (HMV) remain limited. This study investigated the frequency, outcomes, and associated factors of ED visits using a nationwide administrative database.<br><br>METHODS: Using the Health Insurance Review and Assessment Service database, we identified patients with NMDs who received HMV between January 2016 and October 2021, based on diagnostic codes and the MM441 procedure code. ED visits and outcomes were analyzed using claims data. Associations between ED visits and tracheostomy or gastrostomy were evaluated using the chi-square test.<br><br>RESULTS: A total of 1,569 patients were identified; amyotrophic lateral sclerosis (39.7%) and muscular dystrophy (31.0%) were the most common diagnoses. During the study period, 1,009 patients (64.3%) visited the ED at least once, accounting for 5,159 visits (mean 5.1 visits per patient). Among these visits, 36% resulted in hospitalization and 3% resulted in death in the ED. ED visits were more frequent among patients with tracheostomy than in those without tracheostomy (76.6% vs. 59.0%; relative risk [RR], 1.30; 95% confidence interval [CI], 1.21-1.39; p<0.001). In contrast, patients with gastrostomy had a lower proportion of ED visits than those without gastrostomy (22.6% vs. 55.1%; RR, 0.41; 95% CI, 0.35-0.48; p<0.001).<br><br>CONCLUSION: ED utilization is common among patients with NMDs receiving HMV and is frequently associated with hospitalization, highlighting a substantial acute healthcare burden. These findings highlight the need for improved long-term respiratory care and outpatient management.}, }
@article {pmid42116584, year = {2026}, author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S}, title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.}, journal = {Protein and peptide letters}, volume = {33}, number = {1}, pages = {258-274}, doi = {10.2174/0109298665429866260217115717}, pmid = {42116584}, issn = {1875-5305}, mesh = {Humans ; *alpha-Synuclein/metabolism/genetics/antagonists &amp; inhibitors ; *Synucleinopathies/metabolism/therapy/drug therapy/pathology ; *Parkinson Disease/metabolism/therapy/drug therapy/pathology ; Autophagy/drug effects ; Animals ; Oxidative Stress ; }, abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.}, }
@article {pmid41985558, year = {2026}, author = {Navarrete-Dechent, C and Pietkiewicz, P and Voloshynovych, M and Marghoob, AA}, title = {Authors' response to Mart et al's "Response to Navarrete-Dechent et al's 'Ultraviolet-induced fluorescent dermoscopy for the diagnosis of skin tumors: A multicenter study'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.104}, pmid = {41985558}, issn = {1097-6787}, }
@article {pmid42051315, year = {2026}, author = {Nolan, M and Aryal, S and Ndayambaje, IS and Cao, M and Lee, P and Hovde, M and Yun, S and Wlaschin, J and Held, A and Beaussant, H and Wymann, B and Zong-Lee, C and Lim, SM and Jiang, X and Ramesh, N and Agra Almeida Quadros, AR and Boulos, A and Zinter, N and Salem, S and El-Tayar, L and Beccari, M and Presa, M and Jourdan Ferreras Reyes, C and Ruan, YY and Griesman, G and Aguilar, C and Hawrot, J and Wheeler, H and Melamed, Z and Kleinstiver, BP and Albers, M and Cleveland, DW and Tanzi, RE and Lutz, CM and Hubbard, RD and Kobayashi, D and Ward, M and R R Alves, C and Wainger, B and Pichon, CL and Lagier-Tourenne, C}, title = {Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42051315}, issn = {2692-8205}, abstract = {Loss of neuronal regenerative capacity is a common feature of neurodegenerative disease and axonal injury, yet the transcriptional programs governing this state remain poorly defined. Stathmin-2 (STMN2), a tubulin-binding protein essential for axon maintenance and repair, is profoundly depleted following loss of nuclear TDP-43 in neurodegenerative disease. Here, we identify statins as potent inducers of STMN2 expression. Pharmacological and genetic suppression of the mevalonate pathway, and subsequent prevention of protein geranylgeranylation, restored STMN2 levels in TDP-43 deficient cells and promoted neurite growth. STMN2 induction was abrogated when using a statin analogue unable to interact with HMG-CoA reductase, and through co-administration of mevalonate or geranylgeranyl diphosphate substrates. RNA-seq revealed that statins induce a coordinated pro-regenerative transcriptional response, including activation of the AP-1 transcription factor complex gene, ATF3. Loss of ATF3 attenuated STMN2 induction in vitro, and diminished injury-induced Stmn2 upregulation in spinal motor neurons in vivo. These results demonstrate statins as modulators of ATF3 and STMN2 expression and highlight their therapeutic potential in neurodegenerative disease.}, }
@article {pmid42102977, year = {2026}, author = {Zhang, J and Wang, C and Li, Y and Xiao, Z and Cai, Z and Qian, Y and Shi, L and Zhang, Q}, title = {Lipid Dysregulation as a Central Contributor of Neurodegenerative Diseases: Emerging Therapeutic Targets and Strategies.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103159}, doi = {10.1016/j.arr.2026.103159}, pmid = {42102977}, issn = {1872-9649}, abstract = {Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.}, }
@article {pmid42103041, year = {2026}, author = {López-Blanch, R and Oriol-Caballo, M and Estrela, JM and Obrador, E}, title = {Multimodal strategies for diagnosis, stratification, and therapeutic monitoring in ALS.}, journal = {Neuroscience and biobehavioral reviews}, volume = {}, number = {}, pages = {106727}, doi = {10.1016/j.neubiorev.2026.106727}, pmid = {42103041}, issn = {1873-7528}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of motor neurons (MN) that is currently diagnosed through a prolonged process of exclusion, often delaying intervention. This review provides an overview of fluid, imaging, electrophysiological, and genetic biomarkers, explicitly linking each modality to early detection, patient stratification, disease monitoring, therapeutic development, and clinical trial design. Fluid biomarkers (i.e., neurofilament light chain, phosphorylated neurofilament heavy chain, inflammatory cytokines, microRNAs, and proteins in blood or cerebrospinal fluid) reflect neuronal injury and/or disease activity, enabling early identification of pres-ymptomatic individuals and longitudinal tracking of neurodegeneration. Imaging biomarkers, such as structural and diffusion MRI of the motor cortex, corticospinal tracts, and spinal cord, as well as PET imaging neuroinflammation or metabolism, provide objective measures of MN degeneration and extra-motor involvement. Electrophysiological biomarkers, including high-density electromyography, motor unit number, transcranial magnetic stimulation, and electrical impedance myography, quantitatively assess upper and lower MN loss and functional reserve. Genetic biomarkers, encompassing variants in genes such as C9orf72, SOD1, FUS, and TARDBP, enable presymptomatic screening and molecular stratification. In this context, transposable elements have emerged as an additional layer linking genomic variation and RNA dysregulation. We highlight the importance of multimodal and stage-specific biomarker integration to improve diagnostic accuracy and illuminate distinct disease phases. This approach supports stratification by progression rate or molecular subtype, enrichment of clinical trial cohorts, and the development of surrogate endpoints. We conclude by discussing current challenges, including disease heterogeneity and assay standardization, and outline future directions toward biomarker-driven precision medicine in ALS.}, }
@article {pmid42104039, year = {2026}, author = {Jantrapirom, S and Sangphukieo, A and U-On, N and Poonsawas, P and Wongkumool, W and Yeewa, R and Panto, C and Poound, P and Zito, E and Marrazza, A and Lo Piccolo, L}, title = {Discovery of a pyrazolopyridine alkaloid that mitigates neuronal ER stress and age-related decline.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-10226-8}, pmid = {42104039}, issn = {2399-3642}, support = {FF66/061//Chiang Mai University (CMU)/ ; FF67/044//Chiang Mai University (CMU)/ ; FF68/207569//Chiang Mai University (CMU)/ ; 66-124//Health Systems Research Institute (HSRI)/ ; 68-060//Health Systems Research Institute (HSRI)/ ; N42A670768//National Research Council of Thailand (NRCT)/ ; 139/2567//CMU | Faculty of Medicine, Chiang Mai University/ ; }, abstract = {Endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative and age-associated diseases, motivating the search for compounds that enhance ER-stress resilience. Modulation of ER-redox pathways, including those associated with the oxidase ERO1A, can attenuate maladaptive unfolded protein response (UPR) signaling and improve cellular stress tolerance. Here we develop an integrative discovery strategy to identify natural compounds that mitigate ER-stress-associated phenotypes across cellular and organismal models. Structure-informed virtual screening guided by ERO1A biology prioritized the pyrazolopyridine alkaloid S88. In human SH-SY5Y-derived neurons, S88 improves survival and reduces tunicamycin-induced ER-stress markers. In Drosophila, S88 ameliorates neuromuscular and locomotor phenotypes in a UBQLN2-associated ALS model and improves aging-related outcomes. Biochemical assays did not detect inhibition of ERO1A or radical scavenging activity by S88, indicating that its molecular target remains to be identified. Together, these findings identify S88 as a natural-product scaffold that enhances ER-stress resilience across neuronal and in vivo models.}, }
@article {pmid42105306, year = {2026}, author = {Flores, SV and Lillo, P and Briceño-Moya, J and Pedro, AP}, title = {Molecular and genetic landscape of amyotrophic lateral sclerosis in Latin America: a scoping review of pathogenic hypotheses and ancestral heterogeneity.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2668070}, pmid = {42105306}, issn = {2167-9223}, abstract = {Background: The genetic architecture of amyotrophic lateral sclerosis (ALS) has been predominantly characterized in populations of European ancestry, while Latin American populations remain underrepresented despite their complex admixture. Objective: To map the molecular hypotheses explored in ALS research conducted in Latin American populations and identify key methodological and structural gaps. Methods: A scoping review was conducted following Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. Searches were performed in Web of Science, Scopus, PubMed/MEDLINE, SciELO, and LILACS. Studies investigating genetic or molecular aspects of ALS or the ALS-FTD spectrum in Latin American populations were included. Data were extracted using a standardized matrix and synthesized descriptively. Results: Nineteen studies met inclusion criteria. Most were small, single-center investigations employing targeted candidate-gene approaches, predominantly focused on C9orf72 expansions and SOD1 mutations. Reported C9orf72 frequencies varied substantially across countries, indicating population-specific genetic heterogeneity. Only one study incorporated explicit ancestry inference, and no genome-wide association studies or large multicenter ALS genomic cohorts were identified. Conclusions: ALS research in Latin America remains limited, fragmented, and largely candidate-gene driven, with minimal integration of ancestry-informed approaches. The absence of large-scale genomic studies, despite existing regional sequencing capacity, highlights the need for coordinated multicenter initiatives to enable equitable implementation of precision medicine.}, }
@article {pmid42105767, year = {2026}, author = {Sivasubramanian, R and Sterneckert, J}, title = {Restoring miRNA biogenesis in ALS: Enoxacin enhances DICER activity in a first-in-human trial.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2026.04.040}, pmid = {42105767}, issn = {1525-0024}, }
@article {pmid42106156, year = {2026}, author = {Wang, J and Hu, M and Meng, W and Zhang, M and Yuan, Z and Wang, F and Li, S}, title = {Suppressing isovaleric acid off-flavor in Bacillus subtilis fermentation and its consequential effects on secondary metabolism.}, journal = {Bioresource technology}, volume = {455}, number = {}, pages = {134803}, doi = {10.1016/j.biortech.2026.134803}, pmid = {42106156}, issn = {1873-2976}, abstract = {Bacillus subtilis-fermented soybean foods (BFSFs) are nutritious East Asian staples. However, off-flavors dominated by isovaleric acid (IVA), a branched-chain fatty acid, limit consumer acceptance and industrial adoption. Although leucine- and acetolactate-derived pathways have been proposed, key regulatory nodes for IVA in soymilk remain unclear. This study systematically evaluated the key gene nodes controlling IVA biosynthesis during soymilk fermentation by B. subtilis, including bcd (leucine dehydrogenase, Bcd), bkdAB (branched-chain α-keto acid dehydrogenase complex, Bkd), ptb (phosphotransbutyrylase, Ptb), and alsS (acetolactate synthase, ALS). This study utilized B. subtilis 168 (BS168) and a gene-editing approach to construct BS168 mutants lacking bkdAB and alsS, which were combined with previously generated BS168Δbcd and BS168Δptb. IVA was significantly reduced in all mutants, most markedly in BS168Δbcd (-81.85%) and BS168ΔbkdAB (-70.31%). The volatile profile shifted toward higher levels of fruity esters and alcohols and lower levels of acids and ketones, with improved sensory acceptability, particularly in BS168ΔbkdAB. Enzyme assays confirmed Bcd, Bkd, and Ptb as key pathway nodes, while ALS modulated upstream pyruvate flux toward branched-chain amino acid (BCAAs) biosynthesis. Collectively, this work genetically validates IVA pathway control in a real food matrix and shows that targeted disruption of bcd, bkdAB, and ptb is an effective strategy to suppress IVA off-flavor and improve sensory acceptability in B. subtilis-fermented soymilk, providing mechanistic targets for subsequent development and evaluation in food-grade or industrial strains.}, }
@article {pmid42107892, year = {2026}, author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H}, title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.}, journal = {International immunopharmacology}, volume = {182}, number = {}, pages = {116781}, doi = {10.1016/j.intimp.2026.116781}, pmid = {42107892}, issn = {1878-1705}, abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.}, }
@article {pmid42108848, year = {2026}, author = {Jung, YH and Seok, HY and Kang, M and Do, YW and Park, JO and Kim, JH and Park, JS}, title = {Clinical Significance of Plasma Sphingosine-1-Phosphate Decline in Progression of Spinal and Bulbar Muscular Atrophy.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {3}, pages = {327-337}, doi = {10.3988/jcn.2025.0556}, pmid = {42108848}, issn = {1738-6586}, support = {NRF-2022R1C1C1009723/NRF/National Research Foundation of Korea/Korea ; RS-2025-25424215/NRF/National Research Foundation of Korea/Korea ; }, abstract = {BACKGROUND AND PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked neuromuscular disorder characterized by slowly progressive motor decline. However, there is no specific fluid marker that reflects the severity or progression of the disease. Therefore, identifying measurable markers that reflect disease progression remains a major unmet need in SBMA management.<br><br>METHODS: Plasma samples from 21 Korean patients with SBMA were collected at baseline and after 3 years. Untargeted and targeted metabolomics profiling was performed, and plasma sphingosine-1-phosphate (S1P) was the final candidate biomarker. S1P was then quantified using liquid chromatography-mass spectrometry. Associations between longitudinal S1P changes and clinical parameters, including the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), serum creatine kinase (CK), 6-minute walk test (6MWT), and forced vital capacity (FVC), were examined.<br><br>RESULTS: Plasma S1P levels significantly declined in the fast progression group over 3 years, while remaining relatively stable in the slow progression group. Longitudinal changes in plasma S1P showed weak-to-moderate positive trends with clinical measurements, including ALSFRS-R, FVC, and 6MWT, and a negative trend with serum CK at follow-up.<br><br>CONCLUSIONS: Plasma S1P represents a promising quantitative biomarker for monitoring SBMA progression. Validation in larger cohorts and mechanistic studies of S1P regulation are warranted to establish its role in clinical management.}, }
@article {pmid42111077, year = {2026}, author = {Zhou, S and Li, X and Jiao, Y and Wu, J}, title = {Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1754716}, pmid = {42111077}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder for which disease-modifying treatment options remain limited. This study aimed to systematically assess the efficacy and safety of pharmacological and biological therapies for ALS via a network meta-analysis (NMA).<br><br>METHODS: PubMed, EMBASE, Cochrane, and Web of Science were searched until February 25, 2025. Randomized controlled trials (RCTs) evaluating any pharmacological or biological intervention in ALS were eligible. Risk of bias was assessed using the Cochrane RoB 2 tool. A Bayesian NMA was performed in R (gemtc package). Effect estimates were expressed as mean differences (MDs) or risk ratios (RRs) with 95% credible intervals (CrIs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Publication bias was explored with funnel plots (Stata 18.0). Subgroup analyses were conducted for drug classes demonstrating significant efficacy and including at least three RCTs.<br><br>RESULTS: 109 trials involving 16,353 participants were included. The primary outcome was the ALS Functional Rating Scale-Revised (ALSFRS-R); secondary outcomes included forced vital capacity (FVC), mortality, and serious adverse events (SAEs). Compared with placebo, the combination of cell therapy and neuroprotective agents produced the greatest attenuation of ALSFRS-R decline (MD: 3.65, 95% CrI: 1.27-6.05) and was associated with the lowest SAE risk. Receptor agonists ranked highest for preservation of FVC, whereas alkaloids ranked first for mortality reduction; however, no intervention demonstrated a statistically significant survival benefit versus placebo. Within-class subgroup analyses further identified several specific agents, such as masitinib, talampanel, and EH301, as demonstrating relatively consistent efficacy, although substantial heterogeneity remained among enzyme inhibitors.<br><br>CONCLUSION: Cell therapy combined with neuroprotective agents may slow functional decline in ALS. Receptor agonists may help preserve respiratory function. Survival benefits remain inconclusive, underscoring the continued importance of comprehensive supportive care.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000672, identifier CRD420251000672.}, }
@article {pmid42111176, year = {2026}, author = {Li, Y and Yao, Z and Song, Z and Yang, P and Huang, J and Lei, K and Xu, Y}, title = {The intrinsic disorder challenge for AlphaFold: A case study of G3BP1 and pathogenic peptide.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115737}, pmid = {42111176}, issn = {2589-0042}, abstract = {The dipeptide repeat protein GR20 in amyotrophic lateral sclerosis (ALS) exerts neurotoxicity in part by binding to the stress granule protein G3BP1 and disrupting liquid-liquid phase separation (LLPS). However, the structural basis of this interaction remains elusive due to the pervasive intrinsic disorder in both partners. Here, we combine biochemical assays and structure prediction to characterize the G3BP1-GR20 complex. GR20 has high-affinity binding to G3BP1 and modulates LLPS in a concentration-dependent manner. Since the standard AlphaFold (AF) pipeline failed to predict credible models, we employed a constraint-based method AFEX to generate a G3BP1-GR20 complex model with improved confidence and structural plausibility. Our work underscores the necessity of extra efforts for AF predictions on disordered complexes and demonstrates the value of integrative and knowledge-guided approaches for exploring the "invisible proteome" of biomolecular condensates.}, }
@article {pmid42112660, year = {2026}, author = {Kasper, E and Lehto, A and Jürs, A and Nordmann, N and Peters, O and Hellmann, J and Priller, J and Spruth, EJ and Petzold, GC and Voigt, I and Weydt, P and Bernsen, S and Dinter, E and Falkenburger, B and Günther, R and Düzel, E and Glanz, W and Synofzik, M and Beichert, L and Spottke, A and Wagner, M and Brosseron, F and Schmid, MC and Halle, A and Herms, J and Schneider, A and Teipel, S and Prudlo, J and Neumann, M and Hermann, A}, title = {Alzheimer's Disease Co-Pathology and Cognitive Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78227}, pmid = {42112660}, issn = {1531-8249}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) share neuropathological features, including tau, amyloid, and TDP-43 pathology. This study investigated whether AD-related pathological changes are associated with cognitive impairment ALS.<br><br>METHODS: Cerebrospinal fluid (CSF total-tau, phosphorylated-tau, beta-amyloid) and plasma biomarkers (TDP-43; neurofilament light chain [NfL]) were analyzed in 192 individuals with ALS or ALS with frontotemporal dementia (ALS-FTD) and 100 healthy controls. Cognitive performance was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Group comparisons and regression analyses examined associations between biomarker profiles and cognitive status. Autopsy data were available for a subset of participants.<br><br>RESULTS: Compared with healthy controls, patients with ALS - particularly those with cognitive impairment (ALSci) or ALS-FTD - showed elevated AD-related biomarkers. Significant differences in beta-amyloid levels were observed between healthy controls (HCs) and patients with ALSci, but not between controls and cognitively unimpaired patients. CSF p-tau and total-tau levels were strongly associated with domain-specific cognitive performance. In contrast, plasma extracellular vesicle TDP-43 and NfL showed weak or no association with cognition. In vivo biomarkers alone reliably distinguished cognitive impairment only in ALSci and ALS-FTD. Postmortem analyses showed no strong association between ABC scores or overall TDP-43 burden and cognitive state; however, temporal and hippocampal TDP-43 burden was associated with cognitive dysfunction.<br><br>INTERPRETATION: Our findings suggest that tau-related CSF biomarkers, particularly p-tau and total-tau, are associated with cognitive deficits in ALS, indicating that AD-related pathology might be associated to cognitive decline in ALS. However, postmortem data showed even stronger relation of TDP43 pathology to cognitive deficits in ALS. ANN NEUROL 2026 ANN NEUROL 2026.}, }
@article {pmid42101470, year = {2026}, author = {Panchal, D and Solanki, D and Solanki, R and Yadav, AK and Bhatia, D and Yadav, P}, title = {Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.6c00245}, pmid = {42101470}, issn = {1948-7193}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, represent a growing global health crisis characterized by irreversible neuronal loss, protein aggregation, chronic neuroinflammation, and mitochondrial dysfunction. Central to their therapeutic intractability is the blood-brain barrier (BBB), a highly selective neurovascular interface that excludes nearly 98% of conventional pharmacological agents from the central nervous system (CNS). Nanoparticle- and biomaterial-based delivery platforms have emerged as promising strategies to overcome these barriers, encompassing liposomes, polymeric nanoparticles, engineered exosomes, inorganic nanoparticles, and hydrogel scaffolds capable of enabling targeted CNS drug delivery. This Review systematically evaluates the landscape of nanomaterial-based neurotherapeutics across disease-specific pathological contexts, critically analyzing translational failure mechanisms including limited parenchymal brain exposure, receptor saturation during transcytosis, protein corona-mediated immune clearance, and nanoscale toxicity in postmitotic neural tissue. Preclinical-to-clinical translational gaps arising from interspecies BBB transporter heterogeneity and pharmacokinetic divergence are examined alongside manufacturing and regulatory barriers impeding Good Manufacturing Practice (GMP)-scale production. Emerging convergence strategies─including AI-integrated design, hybrid physiologically based pharmacokinetic modeling, theranostic nanoplatforms, and wearable bioresponsive delivery systems─are evaluated for their capacity to address these limitations. The review concludes by proposing a framework for developing clinically viable, disease-modifying CNS nanomedicines.}, }
@article {pmid42102048, year = {2026}, author = {Bombaci, A and Giordano, A and Lavalle, I and Magnino, A and Calvo, A and Chiò, A and Cicolin, A}, title = {"Silent Echoes of the Day: Dream Content Analysis in Amyotrophic Lateral Sclerosis".}, journal = {Brain and behavior}, volume = {16}, number = {5}, pages = {e71387}, pmid = {42102048}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Female ; Male ; Middle Aged ; *Dreams/psychology/physiology ; Aged ; Adult ; Aggression/psychology ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle atrophy, weakness, and respiratory failure. Numerous studies evaluated the impact of diseases on dream content, and the dream content analysis may be considered an interesting tool in the study of the internalization of the consequences of significant life changes. The study of ALS patients' dream content has been mostly neglected in the literature. This study investigated the dream content in a population affected by ALS.<br><br>MATERIAL AND METHODS: We evaluated all consecutive outpatients referred to our ALS Centre using a weekly diary of dreams. Dream contents were coded according to the Hall and Van de Castle coding system.<br><br>RESULTS: Sixty-eight patients completed the study. We collected 127 dreams (females 39.4%) (males 60.6%). Males showed a reduced presence of friends, anatomical elements, aggression, friendship, and sexuality. Instead, we found an increased presence of family members, situations in which the dreamer initiates aggressive action and familiar settings. In the female sample, we found a decreased presence of friends, aggressive and friendly elements, sex-related content, and misfortune, while an increase in animal content.<br><br>CONCLUSIONS: Our results demonstrate that dream content in ALS patients differs from that of healthy subjects, and we noticed some gender differences among ALS patients. The dream content can offer insights into ALS patients' mental state and may improve clinicians' ability to support their patients during their therapeutic course.}, }
@article {pmid42102258, year = {2026}, author = {Di Pede, F and Cabras, S and Manera, U and Vasta, R and Zocco, G and Minerva, E and Matteoni, E and De Mattei, F and Pellegrino, G and Palumbo, F and Pascariu, D and Callegaro, S and Maccabeo, A and Polverari, G and Martino, A and Giuliani, A and Moglia, C and Calvo, A and Chiò, A and Pagani, M and Canosa, A}, title = {King's stages of amyotrophic lateral sclerosis: an 18F-FDG-PET study of brain connectivity.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag159}, pmid = {42102258}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. TDP-43 proteinopathy is the neuropathological signature of the disease, and 18F-FDG-PET serves as a marker of neurodegeneration in vivo. The aim of the present cross-sectional study was to disentangle 18F-FDG-PET correlates of disease severity assessed through the King's staging system, by exploring connectivity changes across motor stages. ALS patients classified as King's stage 1, 2 and 3, who underwent brain 18F-FDG-PET at diagnosis from 2008 to 2022 at the ALS Centre of Turin, were included. A multiple regression analysis to evaluate the relationship between brain metabolism and King's stage was performed. The clusters showing significant results were used as seed regions in an inter-regional correlation analysis (IRCA), performed for each stage. Out of a total of 832 ALS patients, 337 were classified as King's stage 1, 274 as stage 2, and 221 as stage 3. The three groups significantly differed in age at PET, disease duration and total ALSFRS-R score at the time of PET, C9ORF72 status, and the distribution of cognitive categories. We found a decreasing metabolic gradient from King's stage 1 to King's stage 3 in a cluster encompassing motor and cognitive areas. As King's stage increases, we found a decrease of connectivity within the sensorimotor and cognitive areas. The IRCA also showed the connectivity of motor and cognitive regions with temporal and cerebellar regions. The connectivity with temporal regions found in King's stage 1 decreases in King's stage 2 and finally disappears in King's stage 3. The connectivity with the cerebellum occurs in King's stage 2 and decreases in King's stage 3. The changes of connectivity of motor and cognitive areas with temporal and cerebellar regions among different King's stages might reflect the spread of TDP-43 proteinopathy or a compensatory mechanism, respectively. The present study suggests that 18F-FDG-PET imaging of the brain may be integrated with King's staging system to assess the extent of the pathogenic process in the context of clinical trials.}, }
@article {pmid42102284, year = {2026}, author = {Ma, T and Wu, F and Lou, Y and Li, X and Jin, K and Wang, X and Xu, P and Shi, Z and Xu, B}, title = {Enhancing Thermoelectric Performance through Semiconductor-Semimetal Heterostructure via Entropy- and Enthalpy-Driven Phase Regulation in Al/S-Doped BiSbSe3.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.6c00746}, pmid = {42102284}, issn = {1936-086X}, abstract = {This study presents a phase-regulation strategy for enhancing the thermoelectric performance of BiSbSe3-based materials through the controlled formation of a semiconductor-semimetal heterostructure. By incorporating sulfur and aluminum dopants, a hexagonal phase is induced within an orthorhombic BiSbSe3 matrix, thereby establishing a bidirectionally adjustable phase composition through compositional regulation. The hexagonal phase exhibits semimetallic behavior, with a Fermi level positioned higher than that of the semiconductor matrix. This electronic structure difference is consistent with low-barrier interfacial charge transfer and a modulation-doping-like redistribution of electrons across the phase boundaries, contributing to enhanced carrier concentration without severely sacrificing carrier mobility. Moreover, the inherently low thermal conductivity of both phases, combined with enhanced phonon scattering at the interfaces and simultaneous control over grain refinement during phase regulation, effectively suppresses the lattice thermal conductivity. The resulting biphasic structure enables coupled regulation of electronic and thermal transport, synergistically improving thermoelectric performance, achieving a peak thermoelectric figure of merit (zT) of 1.50 at 773 K in Bi0.98Sb0.98Al0.04Se2.8S0.2 under the fixed 2 wt % CuI donor-additive condition. This improvement relative to BiSbSe3 materials demonstrates the effectiveness of phase engineering in decoupling electrical and thermal transport properties. These results highlight interface-engineered semiconductor-semimetal heterostructures as an effective design route for high-performance thermoelectric materials.}, }
@article {pmid42095090, year = {2026}, author = {Tremblay, E and Arbour, D and Vallée, J and Piovesana, R and Vallières, G and Mechichi, E and Robitaille, R}, title = {Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115565}, pmid = {42095090}, issn = {2589-0042}, abstract = {Neuromuscular junction (NMJ) denervation is an early pathological event in amyotrophic lateral sclerosis (ALS) causing motor dysfunction and paralysis. Glial cells at the NMJ, perisynaptic Schwann cells (PSCs), ensure a balance between maintenance and repair via muscarinic receptor signaling. However, in ALS mouse models, PSCs show an aberrant muscarinic hyperactivation. We posited that this excessive activation impairs the PSC capacity to support NMJ repair in ALS. Beginning at symptoms onset, SOD1 [G37R] mice received daily oral administration of darifenacin, a clinically approved type 3 muscarinic receptor antagonist, to reduce PSC hyperactivation. The treatment improved locomotion and preserved NMJ innervation in male mice, with comparable effects observed in females, and extended survival in males. Functional benefits were supported by signs of glial repair and enhanced survival of lumbar motor neurons. These preclinical data indicate that pathological PSC hyperactivity contributes to NMJ denervation in ALS and support therapeutic strategies targeting NMJs in ALS.}, }
@article {pmid42095783, year = {2026}, author = {Gupta, S and Russell, B and Kristensen, LG and de Chant, J and Lu, A and Obst-Huebl, L and Rad, B and Tyler, J and Subramanian, S and Kidd, S and Paul, S and Chen, Y and Petzold, CJ and Kahan, DN and Costello, SM and Nakamura, K and Inman, JL and MacDowell, AA and Spucces, A and Ralston, CY}, title = {Design and commissioning of a new synchrotron beamline dedicated to X-ray footprinting mass spectrometry.}, journal = {Journal of synchrotron radiation}, volume = {}, number = {}, pages = {}, doi = {10.1107/S1600577526003711}, pmid = {42095783}, issn = {1600-5775}, support = {R01GM126218//National Institutes of Health, National Institute of General Medical Sciences/ ; P30GM124169//National Institutes of Health, National Institute of General Medical Sciences/ ; }, abstract = {The structural biology method of X-ray footprinting mass spectrometry (XFMS) is available at two national synchrotron beamlines in the USA: one at the Advanced Light Source (ALS) on the West Coast and the other at the National Synchrotron Light Source II on the East Coast. XFMS is a solution-state technique that utilizes oxidative modifications of proteins at micromolar concentrations in aqueous buffer to extract structural information. X-rays are employed to generate hydroxyl radicals in situ, which covalently modify specific protein side chains. These modifications are subsequently quantified using liquid chromatography and mass spectrometry. Ratiometric changes in modification levels between two protein states (e.g. with and without ligand) generate a relative solvent accessibility map of the protein pairs, which serves to reveal structural features. Up until recently, the XFMS capability was available as part of a shared program at the ALS without a dedicated beamline. In this article, we describe the commissioning of ALS beamline 3.3.1, dedicated to XFMS, including the installation of a new focusing mirror, the design and construction of a new endstation with automated sample handling and exposure capabilities, and the use of accurate empirical dose calculations using Gafchromic film. Finally, we showcase the new beamline capabilities using two protein systems.}, }
@article {pmid42096556, year = {2026}, author = {Copley, KE and Mauna, JC and Danielson, HL and Chen, Q and Ozguney, B and Ngo, M and Xie, L and Smirnov, A and Davis, M and Mayne, L and Linsenmeier, M and Rubien, JD and Bergmann, CA and Portz, B and Lee, BL and Odeh, HM and Lai, L and Chang, YW and Hallegger, M and Ule, J and Pasinelli, P and Poon, Y and Mittal, J and Fawzi, NL and Black, BE and Donnelly, CJ and Jensen, BK and Shorter, J}, title = {Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.}, journal = {Science (New York, N.Y.)}, volume = {392}, number = {6798}, pages = {eadv3301}, doi = {10.1126/science.adv3301}, pmid = {42096556}, issn = {1095-9203}, mesh = {Animals ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; Motor Neurons/metabolism/pathology ; *Protein Aggregation, Pathological/genetics ; *RNA/metabolism/chemistry ; RNA Recognition Motif ; }, abstract = {Aberrant aggregation of the prion-like RNA binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). In this work, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigated aberrant TDP-43 phenotypes in optogenetic models and in ALS patient-derived and control motor neurons. In mice with cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduced pathological aggregation, restored TDP-43 function, and conferred neuroprotection. These results define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.}, }
@article {pmid42096854, year = {2026}, author = {De Avila-Arias, M and Fang, L and Hoyos-Hoyos, V and Harris Ricardo, J and Cadena-Cruz, C and Villarreal-Camacho, JL and Fortich Mesa, N}, title = {Candida-bacteria interactions in peri-implantitis: A narrative review of evidence, mechanisms, and clinical implications.}, journal = {Archives of oral biology}, volume = {188}, number = {}, pages = {106603}, doi = {10.1016/j.archoralbio.2026.106603}, pmid = {42096854}, issn = {1879-1506}, abstract = {OBJECTIVE: To critically synthesize clinical, molecular, and mechanistic evidence on the contribution of the oral mycobiome, particularly Candida albicans, to peri-implantitis, and to evaluate how fungal-bacterial interactions influence biofilm pathogenicity, host responses, and potential therapeutic implications.<br><br>DESIGN: Narrative review of peer-reviewed studies including clinical and epidemiological investigations, molecular analyses (quantitative polymerase chain reaction [qPCR] and next-generation sequencing [NGS] targeting the internal transcribed spacer [ITS] region for fungal profiling and the 16S ribosomal RNA [16S rRNA] gene for bacterial profiling), in vitro and in vivo interkingdom biofilm models, and immunological mechanistic studies. Evidence was evaluated qualitatively, with emphasis on detection methods, study design, and translational relevance.<br><br>RESULTS: Molecular studies detect Candida spp. in a notable fraction of peri-implantitis sites, with higher detection by qPCR/NGS than by culture. Co-occurrence of C. albicans with periodontopathogens (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum) is frequently reported. Mechanistic studies show that C. albicans forms hyphal scaffolds, consumes oxygen to create microanaerobic niches, mediates bacterial adhesion via Als adhesins, and participates in metabolic exchange and cooperative proteolysis. These processes enhance biofilm resilience, promote inflammatory signalling pathways (nuclear factor kappa B [NF-&#x3ba;B] and mitogen-activated protein kinase [MAPK]), activate the NLRP3 inflammasome, and increase antimicrobial tolerance. No randomized controlled trials of antifungal or interkingdom-directed therapies are currently available.<br><br>CONCLUSIONS: Evidence supports an interkingdom, polymicrobial model of peri-implantitis in which fungi contribute to biofilm stability and inflammation. However, heterogeneity in definitions, sampling, and detection methods limits causal inference. Longitudinal and interventional studies are required before mycobiome-directed therapies can be recommended.}, }
@article {pmid42096942, year = {2026}, author = {Mazidi, M and Yong, JL and Grafton, B and MacLeod, C}, title = {Indexing automatic attentional capture by negative information in anxiety using the talking heads attentional bias assessment task.}, journal = {Behaviour research and therapy}, volume = {202}, number = {}, pages = {105066}, doi = {10.1016/j.brat.2026.105066}, pmid = {42096942}, issn = {1873-622X}, abstract = {The Talking Heads Attentional Bias Assessment Task is a recently developed, freely available, methodology for assessing anxiety-linked attentional bias to ecologically relevant emotionally negative information. The task employs video-based stimuli conveying emotionally negative or benign information concerning issues that individuals commonly encounter in daily life. It utilizes a dual-probe methodology with the aim of indexing the degree to which viewers' attention is automatically captured by the more negative videos. When introducing this task, Mazidi et al. (2025) demonstrated that the resulting attentional bias index i. has excellent internal consistency; ii. is significantly correlated with trait anxiety; and iii. mediates the association between trait anxiety and the state anxiety elevation elicited by the emotional videos. However, this prior study did not verify that the anxiety-linked attentional bias indexed by this task is automatic, in the sense that it is independent of volitional viewing preference. The present study was designed to determine the replicability of Mazidi et al.'s original findings, while overcoming this prior limitation. A sample of 170 undergraduate students completed a variant of the Talking Heads Attentional Bias Assessment Task, that now included an additional condition designed to directly measure volitional viewing preference. All of the three effects described above were replicated in full. Moreover, the association between trait anxiety and the resulting index of attentional bias was independent of volitional viewing preference. These findings attest to the capacity of this task to yield a psychometrically appropriate index of trait anxiety-linked bias in automatic attentional capture by emotionally negative information.}, }
@article {pmid42097156, year = {2026}, author = {Gürcan, BA and Gelisken, F and Wenzel, DA and Wenzel, CJ}, title = {[Bilaterale neurosensorische Abhebung als alleinige Manifestation einer posterioren Skleritis].}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2871-6976}, pmid = {42097156}, issn = {1439-3999}, }
@article {pmid42097486, year = {2026}, author = {Deloncle, R}, title = {Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.}, journal = {Experimental neurology}, volume = {}, number = {}, pages = {115812}, doi = {10.1016/j.expneurol.2026.115812}, pmid = {42097486}, issn = {1090-2430}, abstract = {Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.}, }
@article {pmid42099046, year = {2026}, author = {Yang, X and Taghavi, A and Akahori, Y and Pedrini, M and Ishii, T and Disney, MD}, title = {An RNA-Focused DNA-Encoded Library Platform for Discovering Ligands of Pathogenic r(G4C2)[exp] RNA.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.6c00337}, pmid = {42099046}, issn = {1554-8937}, abstract = {Disease-associated RNAs are increasingly recognized as promising therapeutic targets for small-molecule intervention. While DNA-encoded libraries (DELs) have long been established for protein ligand discovery, recent studies have demonstrated their feasibility for identifying RNA-binding small molecules. To further advance RNA-targeted ligand discovery, a diverse, solid-phase DEL enriched in privileged RNA-binding scaffolds was constructed and applied to identify ligands of r(G4C2)[exp], a toxic RNA repeat expansion implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). DEL selection outcomes were analyzed through large-scale molecular docking integrated with physicochemical and structure-activity relationship (SAR) analyses. Correlations were observed between docking predictions and experimental enrichment trends, supporting lead identification. The lead compound was subsequently optimized based on rational design, resulting in analogues with enhanced binding affinity and bioactivity. These findings demonstrate that RNA ligand identification can be effectively achieved by combining DNA-encoded library technology with computational approaches for rational design and analysis and highlight a broadly adaptable platform for RNA-targeted small-molecule discovery.}, }
@article {pmid42099104, year = {2026}, author = {Oriquat, G and Jasim, IK and Gajjar, TB and Hanumanthayya, M and Abdulhameed Ahmad, I and Singh, G and Maharana, L and Bainsal, N}, title = {SUMOylation in Neural Health and Disease: From Cellular Homeostasis to Neurodegeneration.}, journal = {DNA and cell biology}, volume = {}, number = {}, pages = {10445498261444640}, doi = {10.1177/10445498261444640}, pmid = {42099104}, issn = {1557-7430}, abstract = {Neurodegenerative diseases (NDDs) represent a growing global health burden, particularly in aging populations. These disorders primarily affect neurons and are characterized by progressive neuronal dysfunction and loss within specific regions of the central nervous system. Major NDDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and stroke. Although each disorder exhibits distinct genetic backgrounds and pathological protein aggregates, they share common pathogenic mechanisms, including chronic neuroinflammation, impaired autophagy and mitophagy, disrupted proteostasis, telomere instability, and epigenetic alterations. A hallmark feature across NDDs is the accumulation of misfolded proteins, leading to synaptic dysfunction and neuronal degeneration. Small ubiquitin-like modifiers (SUMOs) are a family of ∼100 amino acid proteins, including SUMO1 and the closely related SUMO2/3 isoforms. SUMOylation is a dynamic posttranslational modification that regulates protein function through the covalent attachment or removal of SUMO moieties. This reversible process is mediated by SUMO-specific E1 activating, E2 conjugating, and E3 ligating enzymes and is counterbalanced by SUMO/Sentrin-specific proteases. The SUMOylation status of target proteins depends on the tightly controlled balance between conjugation and deconjugation systems. Acting as a molecular switch, SUMOylation modulates diverse cellular processes such as DNA damage repair, RNA metabolism, transcriptional regulation, and protein quality control, all of which are essential for maintaining cellular homeostasis. Accumulating evidence links dysregulated SUMOylation to the pathogenesis of multiple neurological disorders, including polyglutamine and synucleinopathies. SUMOylation influences neuroinflammation, oxidative stress, protein aggregation, neuroangiogenesis, ischemic injury, and demyelination. This review highlights recent advances in understanding the role of SUMOylation in NDDs and explores its potential as a promising therapeutic target.}, }
@article {pmid42099653, year = {2026}, author = {Zhang, W and Zhao, Y and Ge, N and Hou, F and Li, X and Zhao, C and Fei, H and Shi, X and Wang, W and Wang, S and Liu, X}, title = {Pediatric diamond-blackfan anemia after hematopoietic stem cell transplantation complicated by bronchiolitis obliterans and air-leak syndrome leading to lung transplantation: a case report with multimodal follow-up.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1782188}, pmid = {42099653}, issn = {1664-3224}, mesh = {Humans ; Female ; Child ; *Anemia, Diamond-Blackfan/therapy ; *Bronchiolitis Obliterans/etiology/surgery ; *Lung Transplantation/methods ; Follow-Up Studies ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Syndrome ; *Lung Diseases/etiology/surgery ; Treatment Outcome ; }, abstract = {INTRODUCTION: Bronchiolitis obliterans syndrome (BOS) is a severe, often fatal pulmonary manifestation of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Its progression to air-leak syndrome (ALS) signifies a critical deterioration with exceedingly high mortality. Lung transplantation (LTx) remains a rare salvage option, especially in children, with scarce reports of successful outcomes in those with this complication cascade.<br><br>CASE PRESENTATION: We report the case of a 7-year-old girl with Diamond-Blackfan anemia (DBA) who developed BOS complicated by ALS after allo-HSCT. She developed acute GVHD involving the skin and liver on +100d, which improved following immunosuppressive therapy. On +231d, pulmonary function tests showed severe mixed ventilatory dysfunction (FEV1 37% of predicted value, FEV1/FVC 52%), and high-resolution computed tomography (HRCT) revealed mosaic perfusion and bronchial wall thickening, contributing to the diagnosis of BOS. Despite intensive immunosuppressive therapy, she developed ALS on +360d and type II respiratory failure on +475d. Sequential bilateral LTx was performed on October 28, 2025. Postoperatively, the patient recovered following the management of multidrug-resistant bacterial infections and respiratory complications, with no rejection or recurrence of cGVHD during follow-up.<br><br>CONCLUSION: This report presents the youngest documented DBA case of successful LTx for BOS complicated by ALS after allo-HSCT globally. It demonstrates that dynamic multimodal monitoring is crucial for early BOS detection. LTx is a viable therapy for end-stage pulmonary cGVHD in children. This case underscores the need for proactive monitoring in high-risk patients and provides a paradigm for managing this complex complication.}, }
@article {pmid42101064, year = {2026}, author = {Chae, J and Yoo, SH and Lee, SY and Kim, JS and Sung, JJ and Choi, SJ}, title = {Factors Impacting Tracheostomy Decisions in Korean Individuals With Amyotrophic Lateral Sclerosis: A Cross-Sectional Survey.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70270}, pmid = {42101064}, issn = {1097-4598}, support = {RS-2025-02216164//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-02215165//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-00553428//National Research Foundation of Korea/ ; }, abstract = {INTRODUCTION/AIMS: Decisions regarding tracheostomy are often made under emergent circumstances, although they require complex considerations of patient preferences, quality of life, and prognosis. This study investigated decision-making surrounding tracheostomy in Korean people with amyotrophic lateral sclerosis (pwALS) and factors influencing these decisions.<br><br>METHODS: Eighty participants were recruited from the Korean ALS Association and categorized into those who underwent tracheostomy-invasive ventilation (TIV) and those who did not. Participants completed the Hospital Anxiety and Depression Scale (HADS), the Decisional Conflict Scale (DCS), and the Control Preference Scale (CPS), as well as 27 modified questions from the Columbia University TIV study assessing demographics, disease characteristics, preferences, and reasons for undergoing or declining tracheostomy.<br><br>RESULTS: Forty-two patients underwent TIV. The TIV and non-TIV groups were similar in age and sex, whereas disease duration was longer in the TIV group. Among those in the non-TIV group, King's stage 4a was the most frequent (n&#x2009;=&#x2009;13). Fourteen patients (33%) who underwent TIV reported that they received information about tracheostomy at the time of the procedure, whereas 22 patients in the non-TIV group (58%) reported no prior discussion. DCS and HADS scores did not differ significantly between groups; however, high decisional conflict (DCS &#x2265;&#x2009;25) was associated with higher HADS scores.<br><br>DISCUSSION: Tracheostomy decision-making among Korean pwALS is frequently crisis-driven, limiting opportunities for advance discussion. Timely and structured discussions about end-of-life care are essential for supporting informed, preference-aligned decisions and reducing psychological burden. Using simple, validated questionnaires may help identify decisional uncertainty and clarify patients' preferred roles in decision-making.}, }
@article {pmid42087256, year = {2026}, author = {Harper, NS and Sharpe, JL and Speranza, J and Gulia, R and Chen, JX and Allen, SP and Atwal, MS and Pickering-Brown, S and Livesey, MR and Bennett, CL and Prokop, A and La Spada, AR and West, RJH}, title = {Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02301-2}, pmid = {42087256}, issn = {2051-5960}, support = {630//Alzheimer's Society and The Heather Corrie Impact Fund/ ; Livesey/Oct20/900-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; Livesey/Oct20/900-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; NIH R35 NS122140//National Institutes of Health (NIH)/ ; NIH R35 NS122140//National Institutes of Health (NIH)/ ; 510/ALZS_/Alzheimer's Society/United Kingdom ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2α phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2α phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.}, }
@article {pmid42087754, year = {2026}, author = {van Selms, MKA and Lobbezoo, F and Verhoeff, MC}, title = {[A personal exploration of oral health in amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {133}, number = {5}, pages = {232-238}, doi = {10.5177/ntvt.2026.05.26012}, pmid = {42087754}, issn = {0028-2200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Oral Health ; *Oral Hygiene ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease impairing motor functions, including those of the oral muscles. As a result, oral hygiene and oral care become challenging. Nonetheless, oral health in patients with amyotrophic lateral sclerosis often remains under-addressed. On the basis of interviews with Dr M.K.A. van Selms dental researcher and patient oral health in amyotrophic lateral sclerosis was explored, highlighting care, research and education. Dr van Selms identifies the neglect of oral hygiene in the care of patients with amyotrophic lateral sclerosis, and advocates for patient-informed, functionally tailored guidelines, interdisciplinary collaboration, and improved access to dental services. He also calls for ethically sensitive, patient-centred research; he stresses the relevance of inclusive training for all involved; and recommends developing instructional material for carers and patients. Dr van Selms unique perspective reveals the necessity to integrate oral health into the care for this patient group and offers starting points for improving oral health and quality of life in amyotrophic lateral sclerosis and similar diseases.}, }
@article {pmid42088060, year = {2026}, author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD}, title = {E3 ubiquitin ligases in neurodegenerative diseases.}, journal = {Military Medical Research}, volume = {13}, number = {1}, pages = {100032}, pmid = {42088060}, issn = {2054-9369}, mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use ; *Neurodegenerative Diseases/physiopathology ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.}, }
@article {pmid42091241, year = {2026}, author = {Pronto-Laborinho, AC and Carvalho, M}, title = {Interleukin-6 in ALS: metabolic mediator or marker of ventilatory decline?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2026.2667283}, pmid = {42091241}, issn = {2167-9223}, }
@article {pmid42091714, year = {2026}, author = {Motta, S and Quaremba, G and Aruta, L and Allosso, S and Senerchia, G and Iuzzolino, VV and Dubbioso, R}, title = {The Dysphagia Outcome and Severity Scale (DOSS) and non-instrumental swallowing measures in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {6}, pages = {}, pmid = {42091714}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; *Deglutition Disorders/diagnosis/etiology/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Severity of Illness Index ; Reproducibility of Results ; Deglutition/physiology ; Adult ; ROC Curve ; }, abstract = {PURPOSE: To evaluate reliability of the Dysphagia Outcome and Severity Scale (DOSS) in Amyotrophic Lateral Sclerosis (ALS) patients, and to assess diagnostic accuracy of selected non-instrumental measures in defining swallowing safety in this population.<br><br>METHODS: One hundred and thirteen consecutive ALS patients underwent comprehensive dysphagia evaluation with fiberoptic endoscopic evaluation of swallowing (FEES) and were classified according to DOSS. Safe and unsafe swallowing were defined by DOSS levels 7-6 and 5-1, respectively. Patient-reported measures included ALS Functional Rating Scale-Revised swallow item (I-3) and Eating Assessment Tool-10 (EAT-10). Non-instrumental clinical measures were hyolaryngeal excursion, voluntary cough (VC), voice quality and reflexive cough/throat clearing (VRC), and maximum phonation time (MPT). Inter- and intra-rater reliability were assessed using weighted Cohen's kappa and Fleiss' kappa coefficients. Non-instrumental measures diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.<br><br>RESULTS: Twenty-six of 113 patients (23%) exhibited an unsafe swallowing. Inter- and intra-rater agreement for DOSS classification was excellent across raters. EAT-10 and a composite clinical index derived from VC, VRC, and MPT showed the highest diagnostic accuracy with area under the curve values of 0.790 and 0.832, respectively. Other non-instrumental measures demonstrated lower discriminative performance.<br><br>CONCLUSIONS: The DOSS showed an excellent reliability when applied to FEES in patients with ALS, supporting its use as a functional classification tool with direct nutritional and management implications. Non-instrumental measures should be interpreted with caution and confined to a triage role rather than diagnostic decision-making, particularly in light of the rapid progression of dysphagia in ALS.}, }
@article {pmid42091757, year = {2026}, author = {Puthusseri, SP and Ravivarma, S and Johny, M and Vengellur, A}, title = {Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.}, journal = {Journal of physiology and biochemistry}, volume = {82}, number = {1}, pages = {}, pmid = {42091757}, issn = {1877-8755}, mesh = {*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; Humans ; *Oxidative Stress ; Energy Metabolism ; Animals ; *Neurons/metabolism/pathology ; *Mitochondrial Dynamics ; *Mitochondria/metabolism/pathology ; Homeostasis ; *Nerve Degeneration/metabolism/pathology ; }, abstract = {Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor with an inherently paradoxical biology: under mild-to-moderate hypoxic stress, it functions as a pro-survival regulator, yet under severe or prolonged hypoxia, the same signalling axis promotes apoptotic and autophagic cell death. This duality carries particular significance in neurons, where HIF-1α serves as a critical nexus among neuronal survival, metabolic adaptation, and mitochondrial integrity, and where the consequences of its dysregulation are most profound given their exceptional metabolic demands and limited regenerative capacity. This review examines the molecular determinants governing this protective-to-detrimental switch, integrating key interconnected dimensions: the context-dependent regulation of oxidative stress, the control of mitochondrial bioenergetics, dynamics, mitophagy, and axonal transport; the dual role of HIF-1α in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia; and the therapeutic implications of precision-targeted HIF-1α modulation. Across all these contexts, a consistent pattern emerges: early or acute HIF-1α activation is broadly neuroprotective, while chronic or severe hypoxic stress converts the same pathway into a driver of neurodegeneration. Understanding the determinants of this switch, including hypoxia duration, severity, and cell-type specificity, provides a framework for designing temporally precise therapeutic interventions for hypoxia-related neurological disorders.}, }
@article {pmid42092055, year = {2026}, author = {Azizzadeh, M and Wouters, EFM and Karimi, A and Janssen, DJA and Spaetgens, B and Hartl, S and Breyer-Kohansal, R and Breyer, MK}, title = {Integration of lung function in allostatic load scoring and its impact on mortality prediction.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-48880-x}, pmid = {42092055}, issn = {2045-2322}, abstract = {Allostatic load refers to the physiological "wear and tear" that results from adaptation to stressors over the lifespan. In this study, we integrated lung function (LF) parameters into the calculation of the allostatic load score (ALS) to evaluate changes in its performance for predicting all-cause mortality. Data from 8,775 participants (aged 25-82 years; 52% female) who participated in the first wave of the Austrian LEAD cohort were used. "ALS without LF" was calculated using 12 parameters, including cardiovascular, metabolic, body composition, and bone mineral density measures. Z-scores of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were integrated with the aforementioned parameters for the calculation of "ALS with LF". Participants scored 1 point for each at-risk marker and 1 point for medication use for hypertension, diabetes, and dyslipidaemia. The total points constituted the ALS. Participants were followed-up for death for an average of 7.7 years. The association of ALS, with and without LF, with mortality was investigated using Cox proportional hazards models. ALS increased with age and was higher in males compared to females across all age categories. ALS (as a continuous variable) with LF [hazard ratio (HR): 1.19 (95% confidence interval (CI) 1.14-1.24)] and without LF [HR: 1.16 (95% CI 1.11-1.21)] showed a significant association with mortality in sex- and age-adjusted models. The adjusted models incorporating ALS as a categorical variable showed that individuals with high ALS, with [HR: 2.44 (95% CI 1.41-4.20)] and without [HR: 2.47 (95% CI 1.46-4.80)] LF parameters, had a higher risk of mortality compared to those in the low ALS group. Cox models incorporating "ALS with LF" parameters exhibited higher concordance index and R[2] values, along with a lower Akaike's information criterion indicating superior predictive power compared to models that included "ALS without LF". ALS is strongly associated with mortality, with higher ALS linked to an increased risk of mortality across both continuous and categorical analyses. Models that incorporate ALS with LF parameters demonstrated superior predictive performance and greater robustness, underscoring the added value of including LF in the models.}, }
@article {pmid42092406, year = {2026}, author = {Chen, Q and Zhou, Y and Peng, Y and Lan, J and Kang, Y and Wu, L and Liu, J and Tang, J and Peng, Y}, title = {TRIM16 attenuates TDP43-mediated oxidative injury by coordinating Nrf2 activation and TFR1 autophagic degradation.}, journal = {Free radical biology &amp; medicine}, volume = {252}, number = {}, pages = {132-149}, doi = {10.1016/j.freeradbiomed.2026.05.014}, pmid = {42092406}, issn = {1873-4596}, abstract = {TAR DNA-binding protein 43 (TDP43) aggregation is a well-established pathological hallmark of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders, contributing significantly to oxidative stress and neuronal injury. Here, we report that the M337V mutation in TDP43 exacerbates its proteotoxicity relative to the wild-type protein. Concurrently, multi-omics analysis revealed a pronounced downregulation of TRIM16 in motor neuron-like cells expressing either wild-type or M337V mutant TDP43. Functional studies demonstrated that TRIM16 overexpression effectively mitigated oxidative stress, restored mitochondrial integrity, and suppressed ferroptosis. Mechanistically, TRIM16 promoted the ubiquitination and degradation of Keap1, thereby facilitating the activation of Nrf2-mediated antioxidant genes. Furthermore, we identified the iron import receptor TFR1 as a novel ubiquitination substrate of TRIM16. TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation. Collectively, our findings establish TRIM16 as a pivotal suppressor of TDP43-induced toxicity by orchestrating dual cytoprotective pathways to enhance cellular resilience, highlighting its promising therapeutic potential for TDP43 proteinopathy.}, }
@article {pmid42092970, year = {2026}, author = {Liu, H and Hu, C and Liu, H and Gong, Z and Jiang, S and Xie, J and Li, Y and Liu, C and Wang, Y and Zou, C and Yang, G}, title = {Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03815-1}, pmid = {42092970}, issn = {1742-2094}, support = {2023JJ40952//the Natural Science Foundation of Hunan Province/ ; 2024JJ6618//the Natural Science Foundation of Hunan Province/ ; 82204733//Foundation for Innovative Research Groups of the National Natural Science Foundation of China/ ; 20254677//Health Research Project of Hunan Provincial Health/ ; 82474009//the National Natural Science Foundation of China/ ; }, abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.}, }
@article {pmid42093061, year = {2026}, author = {Abbasi, H and Rasekhi, H and Shafaatdoost, M and Mohajerani, A and Asadollahi, M and Rashidi, M and Malekahmadi, M and Sarraf, P}, title = {Association of dietary inflammatory index with body composition and disease progression in adults with amyotrophic lateral sclerosis: evidence from a cross-sectional study.}, journal = {BMC nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40795-026-01336-x}, pmid = {42093061}, issn = {2055-0928}, support = {IR. TUMS.NI.REC.1401.059//Tehran University of Medical Sciences and Health Services/ ; }, abstract = {BACKGROUND: For decades, diet's pro-inflammatory properties have been considered a potential risk factor in the onset of amyotrophic lateral sclerosis (ALS). This study aimed to explore the association of dietary inflammatory index (DII) with body composition and disease progression in adult individuals with ALS.<br><br>METHODS: Clinically stable adults aged 18 years and older were enrolled for this study from the neuromuscular disorders clinic at Imam Khomeini Hospital. All participants met the EI Escorial criteria for ALS. Participants completed a 153-item dish-based semi-quantitative food frequency questionnaire (FFQ), which was developed and validated for Iranian adults. Multiple linear regression analyses were performed to examine the association between DII and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), Medical Research Council (MRC) score, disease progression rate (DPR), and body composition among adult participants with ALS.<br><br>RESULTS: This cross-sectional study involved 93 adult participants with ALS, comprising 29 women and 64 men (aged 56.95&#x2009;&#xb1;&#x2009;12.05 years). Participants in the third DII tertile had significantly reduced consumption of several nutrients, comprising vitamin E (P&#x2009;<&#x2009;0.001), vitamin A (P&#x2009;<&#x2009;0.001), vitamin B6 (P&#x2009;<&#x2009;0.001), folic acid (P&#x2009;=&#x2009;0.006), vitamin K (P&#x2009;<&#x2009;0.001), fluoride (P&#x2009;=&#x2009;0.009), potassium (P&#x2009;<&#x2009;0.05), and selenium (P&#x2009;=&#x2009;0.003). DPR displayed a significant negative association with the third tertile of DII (&#x3b2;T3 vs. T1= -1.1, 95CI%:-2.2, -0.04; Ptrend= 0.04), signifying a significant relationship after accounting for confounders, including age, gender, BMI, physical activity, and history of ALS.<br><br>CONCLUSION: Our findings suggest that higher inflammatory dietary patterns might be associated with a slower rate of disease progression in adults suffering from ALS. To elucidate these findings, randomized controlled trials are warranted.}, }
@article {pmid42093242, year = {2026}, author = {Torgeman, S and Pincot, DDA and Bjornson, M and Famula, RA and Skillin, P and Krill-Brown, A and Feldmann, MJ}, title = {Genetic architecture of angular leaf spot resistance in cultivated strawberry shaped by epistasis and genotype-by-environment interactions.}, journal = {The plant genome}, volume = {19}, number = {2}, pages = {e70246}, doi = {10.1002/tpg2.70246}, pmid = {42093242}, issn = {1940-3372}, support = {//California Strawberry Commission/ ; FI- 642-24//United States - Israel Binational Agricultural Research and Development Fund/ ; 2024-67013-42591//Agricultural Research Service/ ; 2022-51181-38328//National Institute of Food and Agriculture/ ; }, mesh = {*Fragaria/genetics/microbiology ; *Epistasis, Genetic ; *Disease Resistance/genetics ; *Plant Diseases/genetics/microbiology ; *Gene-Environment Interaction ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Genotype ; Xanthomonas/physiology ; Phenotype ; Quantitative Trait Loci ; }, abstract = {Angular leaf spot (ALS), caused by Xanthomonas fragariae, is a bacterial disease that limits strawberry (Fragaria × ananassa) productivity worldwide. Although major resistance loci have been identified in wild Fragaria species, their introgression into elite germplasm remains constrained by linkage drag and inconsistent inheritance. To dissect the genetic architecture of ALS resistance, we evaluated a diverse panel of n = 241 greenhouse-tested and n = 468 field-tested strawberry accessions representing elite cultivars, breeding materials, and heirloom varieties of cultivated strawberry (F. × ananassa). Plants were evaluated under controlled inoculations and natural field infection using a standardized phenotypic scale and genotyped with 50K single nucleotide polymorphism array. Broad-sense heritability was moderate (H[2] = 0.45), whereas narrow-sense heritability was low (h[2] = 0.10), reflecting the contribution of nonadditive genetic effects such as epistasis. Genome-wide association studies (GWAS) identified two loci on chromosomes 1D and 2D, explaining 4%-5% of phenotypic variance, respectively. A segregating F1 population validated the 2D locus, confirmed by co-localization with the GWAS signal explaining 11.3% of the phenotypic variance. Two-dimensional genome wide scan in this F1 population revealed a significant epistatic interaction between locus on chromosome 2D and an additional locus on chromosome 6B, collectively explaining 27% of the phenotypic variance. Together, these results demonstrate that nonadditive effects in these populations control ALS resistance. Understanding this complexity provides a foundation for developing elite cultivars with durable resistance, such as UCD Royal Royce. Our findings underscore the need for predictive breeding strategies that capture epistatic and environmental variance to accelerate genetic gain for ALS resistance in strawberry.}, }
@article {pmid42093345, year = {2026}, author = {Griffiths, AW and White, S and Norman, P and Coates, E and Hartley, H and Williams, IA and Halliday, V and Beever, D and Hackney, G and Stavroulakis, T and ,  and McDermott, C}, title = {Development of a Complex Intervention to Support High Calorie Diets for People With Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70269}, pmid = {42093345}, issn = {1097-4598}, support = {RP-PG-1016-20006//National Institute for Health and Care Research/ ; }, abstract = {INTRODUCTION: Weight loss in people with amyotrophic lateral sclerosis (pwALS) is a poor prognostic factor. We aimed to develop an intervention to support pwALS to increase calorie intake and explore feasibility and acceptability.<br><br>METHODS: Intervention development was underpinned by the Capability, Opportunity and Motivation (COM-B) model and Person Based Approach (PBA). Phase 1: healthcare professional (HCP) focus groups (n&#x2009;=&#x2009;47), national survey (n&#x2009;=&#x2009;281), mapping review and National Health Service (NHS) organization Freedom of Information requests (n&#x2009;=&#x2009;251) charted current nutritional support. Systematic reviews of correlates (65 studies) and interventions supporting nutritional behaviors (14 studies), and interviews/focus groups with pwALS (n&#x2009;=&#x2009;18), carers (n&#x2009;=&#x2009;18) and HCPs (n&#x2009;=&#x2009;51) identified barriers/facilitators. Phase 2: Think Aloud interviews (verbalizing thoughts whilst using the intervention) with pwALS (n&#x2009;=&#x2009;12), carers (n&#x2009;=&#x2009;10) and HCPs (n&#x2009;=&#x2009;10). Phase 3: three pilot cycles, interviews with pwALS (n&#x2009;=&#x2009;9), carers (n&#x2009;=&#x2009;6) and HCPs (n&#x2009;=&#x2009;5).<br><br>RESULTS: Limited evidence-based nutritional guidelines, late dietetic referral post-diagnosis, little HCP training, and few effective interventions were identified. Key facilitators/barriers included capabilities (physical ability), opportunities (social support), and motivations (dietary beliefs). The intervention was developed and piloted to refine content, presentation, and functionality. Concerns around high calorie diets and increasing intake were addressed. The final intervention comprises: (1) interventionist training, (2) calorie target setting, (3) food diaries, (4) feedback provision, (5) online resources, and (6) oral nutritional supplements. User feedback indicates high usability, acceptability, and feasibility.<br><br>DISCUSSION: The theoretically grounded intervention targets calorie intake through tailored behavior change techniques to support dieticians in practice to deliver personalized care and oral nutritional support for pwALS.}, }
@article {pmid42093834, year = {2026}, author = {Martinez-Nunez, AE and Guo, J and Dorsey, ER and Ruffing, KW and Wymer, J and Okun, MS}, title = {Head trauma and environment progression of amyotrophic lateral sclerosis: long-term data from the National ALS Registry.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001574}, pmid = {42093834}, issn = {2632-6140}, abstract = {BACKGROUND: Environmental exposures have been linked to increased risk of amyotrophic lateral sclerosis (ALS); however, their impact on disease progression remains unclear. This study examined whether prior environmental and occupational exposures influenced functional decline in patients with an established ALS diagnosis.<br><br>METHODS: We conducted a retrospective cohort analysis using the National ALS Registry from 2010 to 2024. Participants with complete exposure histories were included. Disease progression was measured with the ALS Functional Rating Scale-Revised (ALSFRS-R) at baseline and every 3 months. Mixed-effects linear regression models assessed associations between exposures and ALSFRS-R decline, adjusting for age, sex and time since diagnosis.<br><br>RESULTS: The cohort included 8618 participants with ALS. The median time from diagnosis to enrolment was 2 years (IQR= 1.1-2.9), with a median of 1 year of follow-up (IQR=1-4). Exposure to herbicides (&#x3b2;=-0.57. IC95%=-0.86&#x2009;to -0.28, p<0.001), metal dust and fumes (&#x3b2;=-0.28, IC95%=-0.51&#x2009;to -0.04, p=0.020) and oil paint (&#x3b2;=-0.27, IC95%=-0.48&#x2009;to -0.06, p=0.011) prior to diagnosis were each associated with accelerated decline. Head injury was associated with an overall lower ALSFRS-R score (&#x3b2;=-1.74, IC95%=-2.21&#x2009;to -1.27, <0.001), based on our non-linear mixed effects model.<br><br>CONCLUSION: Environmental and occupational exposures, particularly herbicides, metal dust/fumes and oil-based paints, were associated with faster ALS progression, and head injury was associated with overall worse function.}, }
@article {pmid42093907, year = {2026}, author = {Talukder, A and Kelly, M and Gray, D and Sarma, H}, title = {Addressing the double burden of malnutrition in Bangladesh: Evidence from National Policy Documents and gaps in policy integration.}, journal = {Global epidemiology}, volume = {11}, number = {}, pages = {100258}, pmid = {42093907}, issn = {2590-1133}, abstract = {Bangladesh faces a growing double burden of malnutrition (DBM), where persistent undernutrition coexists alongside rapidly rising overweight and obesity. Despite numerous national policies addressing malnutrition, the extent to which these policies explicitly recognize and integrate DBM remains unclear. Objective: This study critically analyzes major national nutrition, food security, health, and agriculture policies in Bangladesh to assess DBM integration and identify gaps requiring urgent policy attention. Methods: We conducted a narrative policy analysis of five purposively selected national policy documents on nutrition implemented between 2015 and 2030. Policies were evaluated using a structured analytical framework informed by Hawkes et al.'s double-duty actions framework, the Essential Nutrition Actions framework of the World Health Organization, and the policy principles of the Global Nutrition Report. The analysis examined three dimensions: (i) recognition and framing of DBM, (ii) intervention design and content, and (iii) implementation systems. Data were extracted using a pre-specified template, verified by a second reviewer, and compared against framework components to identify gaps. Recommendations were then classified into immediate, medium-term, and long-term priorities based on feasibility and urgency. Results: All five policies demonstrated comprehensive undernutrition programming, with measurable targets. However, overnutrition has received minimal attention in all the policies. Only the National Nutrition Policy (2015) explicitly acknowledged DBM, but this fell short of an integrated operational framework. The remaining four policies continued to treat malnutrition as synonymous with undernutrition, leaving overnutrition largely invisible as a policy concern. No policy has provided integrated service delivery models, household-level DBM strategies, life-course surveillance systems, or food environment regulations. Seven critical gap categories were identified: service delivery, monitoring and evaluation, human resources, dietary guidelines, food environment regulation, equity and targeting, and multi-sectoral coordination. Conclusions: Bangladesh's nutrition policies remain structurally misaligned with its evolving DBM burden. Urgent policy actions are needed to explicitly recognize DBM as a distinct policy problem, establish integrated operational frameworks, develop household-level strategies, strengthen food environment regulations, and build multisectoral governance capacity. Phased recommendations spanning immediate, medium-term, and long-term timeframes are proposed to guide systematic DBM policy integration and support progress toward Sustainable Development Goal targets.}, }
@article {pmid42094407, year = {2026}, author = {Flax, R and Lacigová, A and Howell, S and Li, H and Bashore, FM and Čajánek, L and Axtman, AD}, title = {Development of Potent and Cell Active 5-Azaindole-Based Tau Tubulin Kinase Inhibitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.27.721186}, pmid = {42094407}, issn = {2692-8205}, abstract = {We have developed and characterized a potent and cell active tau tubulin kinase 1 and 2 (TTBK1 and TTBK2) inhibitor, 13 . Compound 13 demonstrates in-cell, kinome-wide selectivity, and potently inhibits both TTBK1 and TTBK2. As part of our medicinal chemistry campaign, we also identified a structurally similar negative control, compound 5 , which lacks in-cell affinity for TTBK1 and TTBK2. Based on their substrates, which include TDP-43, tau, and tubulin, TTBK1 and TTBK2 inhibition has been pursued as a therapeutic approach for Alzheimer's disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. TTBK2 is also an effector of ciliogenesis, acting in concert with CEP164, CP110, and CEP83 to initiate the biogenesis of primary cilia. The development of selective chemical tools for these kinases facilitates investigation into TTBK1/2-mediated pathways and potential disease-altering ramifications linked to their pharmacological perturbation.}, }
@article {pmid42094412, year = {2026}, author = {Tilahun, K and Parameswaran, J and Dudley, M and Pun, D and Ma, F and Zhang, J and Bold, T and Jiang, J}, title = {TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.23.719939}, pmid = {42094412}, issn = {2692-8205}, abstract = {TMEM106B is a lysosomal membrane protein and major genetic modifier of multiple neurodegenerative diseases, including frontotemporal lobar degeneration, Alzheimer's disease, and amyotrophic lateral sclerosis. Proteolytically generated C-terminal fragments of TMEM106B assemble into amyloid fibrils that accumulate in the brains of individuals with neurodegenerative disease and in cognitively normal aged adults, yet how these fibrils produce neuronal dysfunction has remained unclear. Here, we show that cytosolic and lysosome-directed TMEM106B C-terminal fragments (CTF and gCTF) form detergent-insoluble amyloid aggregates, drive redistribution of endogenous TDP-43 from the nucleus to the cytoplasm, and accelerate neuronal death. Unbiased proximity proteomics identified the inner nuclear membrane LAP1-TorsinA axis as a fragment-specific interactome, and co-immunoprecipitation confirmed a direct physical interaction between gCTF and LAP1 that was not observed with full-length TMEM106B. Fragment expression disrupted Lamin B1 organization, mislocalized the nuclear import machinery KPNB1 and RanGAP1, and impaired importin-dependent nuclear transport in primary cortical neurons. Critically, neurons harboring endogenous TMEM106B fibrillar pathology in aged human frontal cortex exhibited the same phenotypes, namely disrupted Lamin B1 and LAP1 localization and cytoplasmic redistribution of TDP-43, whereas fibril-negative neurons from the same cases and younger control tissue retained intact nuclear envelope organization. These findings define TMEM106B proteinopathy as an upstream driver of nuclear envelope disruption and nucleocytoplasmic transport failure, linking a widespread feature of brain aging to a central mechanism of neurodegeneration.}, }
@article {pmid42095061, year = {2026}, author = {Hu, Z and Wan, JJ and Yan, QQ and Fan, Y and Liu, J}, title = {Systematic proteomics reveals plasma NEFL as a robust predictor and pathological associate in C9ORF72-related neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1792887}, pmid = {42095061}, issn = {1663-4365}, abstract = {BACKGROUND: The C9ORF72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While neurofilament light chain (NEFL) is an established biomarker of neuroaxonal damage, its specific dose-response relationship with the C9ORF72 expansion and its potential role beyond a passive bystander require systematic investigation. We performed a proteome-wide screen to identify plasma proteins linked to the C9ORF72 expansion and evaluated their predictive value for motor neuron disease (MND).<br><br>METHODS: We utilized whole-genome sequencing and plasma proteomics from the UK Biobank, analyzing 106 individuals with C9ORF72 expansions (defined as >30 repeats) and 212 age- and sex-matched controls. We screened ~3,000 proteins for associations with the continuous repeat count. The top candidate was evaluated using restricted cubic splines (RCS) to assess non-linearity and threshold effects. Its ability to independently predict MND risk was tested using regression models and a machine learning approach.<br><br>RESULTS: Our unbiased screen identified NEFL as the sole protein significantly associated with the C9ORF72 repeat count (FDR-adjusted P = 8.39 &#xd7; 10[-4]). NEFL levels demonstrated a step-wise increase with expansion size, which followed a stable linear trajectory across the repeat spectrum (P non - linear = 0.4435). Elevated NEFL independently predicted MND risk (OR = 2.42; HR = 2.90), even after adjusting for the C9ORF72 repeat count. Our predictive model, combining NEFL and repeat count, achieved an AUC of 0.941 with 100% sensitivity. These findings align with emerging evidence that secreted NEFL may actively modulate neuroinflammation.<br><br>CONCLUSIONS: NEFL emerges as a robust and specific plasma biomarker for C9ORF72-related neurodegeneration. Its strong linear association with repeat burden and independent predictive power, contextualized within its potential role in immune activation, suggest that NEFL is deeply integrated into the C9ORF72 pathological landscape. These findings support NEFL-based screening and monitoring strategies for early intervention in C9ORF72 carriers.}, }
@article {pmid41855303, year = {2026}, author = {Drouin, E and Pereon, Y}, title = {Historical and Clinical Analysis of a Case of Progressive Muscular Atrophy (1853-1871).}, journal = {European neurology}, volume = {}, number = {}, pages = {1-8}, doi = {10.1159/000550658}, pmid = {41855303}, issn = {1421-9913}, abstract = {BACKGROUND: Progressive muscular atrophy (PMA) emerged in the mid-19th century as a distinct clinical entity within the evolving field of French neurology, notably through the work of François Amilcar Aran, Duchenne de Boulogne, and later Jean-Martin Charcot. During this period, uncertainties persisted regarding its nosological status, pathophysiology, and relationship to amyotrophic lateral sclerosis (ALS). Longitudinal clinical observations from this era remain rare but are essential for understanding both the natural history of motor neuron diseases and the historical construction of neurological knowledge.<br><br>SUMMARY: This article presents a historical and clinical analysis of a unique case of PMA observed for over nearly 2 decades (1853-1871) in Parisian hospitals. The case concerns Auguste-Joseph Bellinghen, whose condition was first documented in an unpublished handwritten manuscript in 1853 and later published with photographic illustrations in 1871. Through a comparative analysis of these two observations, the study traces the slow, asymmetrical, and irreversible progression of muscular atrophy, marked by early fasciculations, the absence of sensory disturbances, and eventual severe motor disability. The case is examined within its institutional, nosological, and therapeutic contexts, highlighting hospital circulation, the role of medical interns, and the empirical treatments of the time, including electrotherapy and thermal baths. Reinterpreted in light of contemporary neurology, this historical observation likely corresponds to a spinal-onset motor neuron disease closely related to ALS. Beyond its clinical significance, the case illustrates the transition from descriptive clinical medicine to anatomoclinical correlation and contributes to the historiography of neurology by illuminating how individual patient trajectories shaped medical knowledge in the 19th century.<br><br>KEY MESSAGES: (1) Long-term historical clinical observations provide valuable insights into the natural history of PMA and motor neuron diseases. (2) The Bellinghen case illustrates the evolution of neurological semiology, particularly the early recognition of fasciculations and asymmetrical muscle wasting. (3) This case highlights the transition from Aran's initial clinical description of PMA to Charcot's anatomopathological framework linking PMA to ALS. (4) Historical medical archives offer not only scientific data but also a window into the social consequences of chronic neurological disease in the 19th century. (5) Integrating historical and clinical analysis enriches contemporary understanding of motor neuron disease nosology and medical memory.}, }
@article {pmid42084731, year = {2026}, author = {Pendergast, TH and Maddali, S and Chaluvadi, SR and Qi, P and Vencill, WK and Bennetzen, JL and Devos, KM}, title = {Widespread non-target-site resistance in Setaria viridis to four classes of herbicide.}, journal = {TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik}, volume = {139}, number = {6}, pages = {}, pmid = {42084731}, issn = {1432-2242}, support = {0952177//Directorate for Biological Sciences/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetyl-CoA Carboxylase/genetics ; *Setaria Plant/genetics/drug effects ; Acetolactate Synthase/genetics ; Genotype ; Mutation ; Plant Proteins/genetics ; Alleles ; 3-Phosphoshikimate 1-Carboxyvinyltransferase/genetics ; }, abstract = {Although herbicide resistance in Setaria is rampant and cosmopolitian across four herbicide families, we encountered little evidence of target-site resistance, indicating diverse non-target mechanisms of metabolizing, sequestering, and overwhelming herbicides. Setaria viridis is a cosmopolitan weed and model genetic system with increasing reports of resistance to multiple classes of herbicides. Our goal was to assess the herbicide resistance and allelic diversity in herbicide target genes in a collection of Setaria genotypes from North America and Eurasia, and identify the occurrence of novel and known target-site mutations that led to resistance. A total of 214 Setaria genotypes were exposed to commonly used herbicides that inhibit specific genes: herbicide action class (HRAC) group 1 herbicides targeting acetyl-CoA carboxylase (ACCase), HRAC 2 targeting acetolactate synthase (ALS), HRAC 9 targeting 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, and HRAC 10 targeting glutamine synthetase. ACCase and ALS genes in 53 accessions were PCR-amplified and sequenced. Whole-genome sequencing reads covering the target genes were analyzed for an additional 98 genotypes. Herbicide trials showed that 30% of our accessions set seed following application of at least one herbicide, and 13 accessions were resistant to multiple classes of herbicides. Although there were numerous SNPs, including some known to lead to resistance, in our target genes, SNPs found predominantly in herbicide-resistant genotypes were largely intronic or synonymous. A small number of amino acid substitutions in ALS and ACCase indicated potential and incomplete resistance to HRAC 1 and 2 herbicides, but no SNPs putatively associated with herbicide resistance were identified in the other 6 target-site genes. The broader pattern of herbicide resistance in S. viridis is likely driven by non-target mutations that detoxify or compartmentalize applied herbicides.}, }
@article {pmid42085565, year = {2026}, author = {Singh, K and Ahmad, I and Jain, D and Mim, TJ and Noman, AA and Shihab, MPR and Kondaveeti, SB and Gupta, JK and Wal, P}, title = {Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {5}, pages = {e70880}, doi = {10.1002/jbt.70880}, pmid = {42085565}, issn = {1099-0461}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Wnt Signaling Pathway ; Animals ; Hippo Signaling Pathway ; *beta Catenin/metabolism ; YAP-Signaling Proteins ; *Adaptor Proteins, Signal Transducing/metabolism ; *Protein Serine-Threonine Kinases/metabolism ; *Transcription Factors/metabolism ; Signal Transduction ; }, abstract = {Neurodegenerative diseases (NDs), including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are characterised by impaired cellular homeostasis and progressive neuronal loss. Emerging evidence highlights the critical role of cellular signalling pathways in the progression and pathogenesis of these disorders. With a focus on the NLRP3 inflammasome, Wnt/β-catenin, and Hippo-YAP cascades, this review focuses on new signalling pathways linked to neurodegenerative disorders. Among them, the NLRP3 inflammasome is a crucial mediator of neuroinflammation, causing neuronal damage and persistent immune activation. In contrast, these pathways regulate neurogenesis, synaptic plasticity, and cell survival, offering potential neuroprotective functions. Dysregulation of these pathways disrupts cellular integrity, exacerbates disease progression, and represents a convergence point for therapeutic intervention. In NDs, knowing how these pathways interact offers fresh perspectives on disease processes and finds new targets for the creation of disease-modifying treatments.}, }
@article {pmid42086102, year = {2026}, author = {Chen, M and Huang, X and Li, Y and Hu, L and Lu, R and Li, L}, title = {Microplastics as an emerging environmental pollutant potentially leading to neurodegenerative diseases.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.04.033}, pmid = {42086102}, issn = {1873-7544}, abstract = {Microplastics (MPs), defined as plastic fragments less than 5 mm in diameter, are ubiquitous in the environment. As an emerging environmental pollutant, MPs can infiltrate the human body through multiple pathways, including inhalation, ingestion, dermal contact and bloodborne transmission.Correspondingly, MPs, which can penetrate the blood-brain barrier and enter the central nervous system (CNS), have been linked to the development of neurodegenerative diseases (NDs).In this review, we provide a comprehensive analysis of the environmental distribution of MPs, the pathways of entry into the human body, and the distribution within the CNS. Furthermore, we explore intrinsic factors influencing the neurotoxicity of MPs and elucidate the mechanisms underlying MPs-induced NDs, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Beyond mechanistic insights, we offer a novel perspective by exploring the potential adaptation of emerging environmental MPs detection and removal technologies for CNS applications. Ultimately, elucidating these mechanisms positions the reduction of MPs accumulation as a critical intervention point, highlighting the adaptation of environmental technologies as a promising strategy for the prevention and management of NDs.}, }
@article {pmid42086408, year = {2026}, author = {Ibrahim, M and Hossain, MS and Ooi, L and Hasan, MM and Ahsan, S and Salem, AK and Piazza, GA and Feng, X and Ahsan, F}, title = {Targeting the NAD[+]-PARP1-XRCC1 axis in ALS.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molmed.2026.04.004}, pmid = {42086408}, issn = {1471-499X}, abstract = {Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD[+] depletion contribute to motor neuron degeneration. The NAD[+]-PARP1-XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD[+] support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD[+] metabolites as pharmacodynamic biomarkers.}, }
@article {pmid42086533, year = {2026}, author = {Modafferi, S and Silenzi, V and Garbelli, A and Lazoi, G and Scarian, E and D'Uva, S and Santini, T and Riccardi, A and Cozzolino, M and Pansarasa, O and D'Ambrosi, N and Sabbioneda, S and Morlando, M and Francia, S}, title = {Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.}, journal = {Cell death &amp; disease}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41419-026-08603-6}, pmid = {42086533}, issn = {2041-4889}, support = {PNRR-CN3 642 "National Center for Gene Therapy and Drugs based on RNA Technology"//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2017NWEXEP//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2020CXFL4T//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2022R7LH5T//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2022R7LH5T//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; DN. 1553 11.10.2022//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2017KSZZJW//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2022JA8JY5//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; DSB.AD004.294//Regione Lombardia (Region of Lombardy)/ ; DSB.AD004.294//Regione Lombardia (Region of Lombardy)/ ; DSB.AD004.294//Regione Lombardia (Region of Lombardy)/ ; FOE-2021 DBA.AD005.225//Consiglio Nazionale delle Ricerche (National Research Council)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; FOE-2021 DBA.AD005.225//Consiglio Nazionale delle Ricerche (National Research Council)/ ; RIPREI2023_7c8ae10d783c//Istituto Superiore di Sanit&#xe0; (ISS)/ ; IG2022-27833//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; IG-2020-24316//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; Ricerca Corrente 2025 - 2027//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente 2025 - 2027//Ministero della Salute (Ministry of Health, Italy)/ ; RG12419107CD28D5//Sapienza Universit&#xe0; di Roma (Sapienza University of Rome)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates.}, }
@article {pmid42087223, year = {2026}, author = {Brede, JR and Farbu, BH and Gamberini, L and Thorsen, K and Rehn, M and Rognås, L and Tønsager, K and Sunde, GA and Lauritzen, M and Lupi, C and Tartaglione, M and Skjaerseth, E&#xc5; and Aaen, M and Wiseth, R and Krüger, AJ}, title = {Prehospital resuscitative endovascular balloon occlusion of the aorta in non-traumatic out-of-hospital cardiac arrest (REBOARREST): an international, multicentre, open label, pragmatic, randomised, controlled trial.}, journal = {Critical care (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13054-026-06057-y}, pmid = {42087223}, issn = {1466-609X}, abstract = {BACKGROUND: Most patients with out-of-hospital cardiac arrest do not achieve sustained return of spontaneous circulation (ROSC). Resuscitative endovascular balloon occlusion of the aorta (REBOA) may increase blood pressure proximal to the ballon. If this technique is used during advanced life support (ALS), and occlusion is performed in the thoracic aorta, it may augment aortic pressure and coronary perfusion pressure. We investigated whether prehospital REBOA as an adjunct to ALS increased the rate of ROSC.<br><br>METHODS: REBOARREST was a pragmatic, parallel-group, multicentre, randomised controlled trial conducted at 12 sites in Norway, Denmark, and Italy. Adult patients (18-80 years) with non-traumatic out-of-hospital cardiac arrest were randomly assigned (1:1) to either a control group that received ALS or to an intervention group that received ALS combined with REBOA as an adjunct. Fulfilment of eligibility criteria was determined by the physician on scene and sealed envelopes were used to allocate patients. The statistician that performed the analyses was blinded for group allocation. The primary outcome was sustained ROSC, defined as lasting&#x2009;&#x2265;&#x2009;20&#xa0;min, assessed in the intention-to-treat population.<br><br>RESULTS: From June 7, 2021, to June 28, 2025, 200 patients were randomly assigned to the study groups. Due to lack of consent 21 patients dropped out of the trial, hence data from 179 patients are presented, 88 in the intervention group and 91 in the control group. Most patients were male (76%), with median age of 68 years (IQR 58-74). Median time from arrest to randomisation was 33&#xa0;min (IQR 23-39) in the intervention group and 29&#xa0;min (IQR 23-38) in the control group. Twenty-five of 88 patients (28%) in the intervention group and 24 of 91 patients (26%) in the control group achieved sustained ROSC (adjusted risk difference 1.8% [-11, 15, 95% CI], p&#x2009;=&#x2009;0.78). Adverse events were registered in 19 patients.<br><br>CONCLUSIONS: Among patients with non-traumatic out-of-hospital cardiac arrest, a strategy of prehospital deployment of REBOA as an adjunct to ALS was feasible but did not significantly improve rates of sustained ROSC compared to ALS alone. Deployment of prehospital REBOA is safe and manageable in a two-person team with low procedure time.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov ID NCT04596514. Registered 22.10.2020.}, }
@article {pmid42070188, year = {2026}, author = {Chambers, RL and Lahuerta-Martín, S and Greco, AM and Pattinson, R and Pickles, T and Hassan, J and Mokkink, LB}, title = {Assessing content validity: challenges of conducting systematic reviews of patient-reported outcome measures and recommendations to improve the application of COSMIN guidance.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {35}, number = {6}, pages = {}, pmid = {42070188}, issn = {1573-2649}, abstract = {PURPOSE: Systematic reviews of Patient-Reported Outcome Measures (PROMs) are essential for selecting appropriate measures for research and clinical practice. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines provide a standardised framework for evaluating measurement properties of PROMs, with content validity considered to be the most important property, yet the most complex and poorly reported. This study aimed to report common challenges researchers face when evaluating content validity in systematic reviews on the quality of PROMs, and to provide clear, experience-informed recommendations to overcome them.<br><br>METHOD: A narrative synthesis of challenges in evaluating content validity in systematic reviews of PROMs is presented. Challenges were extracted from Elsman et al.&#x2019;s umbrella review and from stakeholder consultations with the authors of this manuscript, providing practical recommendations and illustrative examples.<br><br>RESULTS: Seven challenges were identified: (1) feasibility of conducting a systematic review on the quality of PROMs, (2) identifying all articles describing PROM development for the target population, (3) managing different versions of PROMs, (4) poor reporting in primary studies (5) ambiguity in classifying studies as PROM development or content validity studies, (6) applying the criteria for content validity, specifically, to the results of development studies, and (7) accurately framing the scope of the PROM and the review. Recommendations include narrowing the scope of the review, conducting supplementary searches, treating PROM versions distinctly, and guidance on how to interpret poorly reported studies.<br><br>CONCLUSION: These insights support consistent application of COSMIN guidelines and improve PROM selection and use, complementing existing COSMIN materials.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11136-026-04261-5.}, }
@article {pmid42081010, year = {2026}, author = {Li, J and Yang, X and Liu, J and Zhao, K}, title = {Unraveling the Pathophysiological Link Between ALS and SCA: The Role of Ischemic Cerebral Vascular Dissection and the Efficacy of Endovascular Therapy.}, journal = {Cerebellum (London, England)}, volume = {25}, number = {3}, pages = {}, pmid = {42081010}, issn = {1473-4230}, support = {YXJL-2022-00351-0183//Neuroscience Innovation Development Research Project/ ; PW2022A-28//Pudong New Area Health Commission/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/physiopathology ; *Spinocerebellar Ataxias/complications/diagnostic imaging/physiopathology ; *Endovascular Procedures/methods ; Young Adult ; *Brain Ischemia/complications/diagnostic imaging/surgery ; *Aortic Dissection/complications/diagnostic imaging/surgery ; Treatment Outcome ; }, abstract = {To explore the role of ischemic cryptogenic vascular dissection (CVD) in a patient presenting with overlapping symptoms of amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA), and the impact of endovascular treatment on posterior circulation hypoperfusion, cerebellar atrophy, and clinical symptoms. A 22-year-old male patient with progressive neurological symptoms underwent MRI, CTA, and genetic testing, revealing cerebellar atrophy, a novel TGM6 gene variation associated with SCA type 35, and SETX gene deletions linked to ALS type 4. Ischemic CVD was diagnosed via dynamic contrast-enhanced CT (DCE-CT) and treated with endovascular stent repair followed by dual antiplatelet therapy. Following endovascular treatment, posterior circulation hypoperfusion and cerebellar atrophy were significantly improved. MRI follow-up showed increased cerebellar size and reduced interlobar spacing, with cerebellar dimensions expanding by up to 26.98% and interlobar spacing narrowing by up to 27.14%. Concurrently, the patient experienced marked improvement in clinical symptoms. At the 21-month follow-up, the patient's Modified Rankin Scale (MRS) score was rated as favorable. Ischemic CVD may underlie overlapping ALS and SCA symptoms, suggesting a genetic-vascular link. Endovascular treatment of CVD led to improvements in posterior circulation hypoperfusion, cerebellar atrophy, and clinical symptoms, supporting further investigation into this potential pathogenic nexus.}, }
@article {pmid42081784, year = {2026}, author = {Zhu, RH and Kalra, S and Dobrowolski, P and Fok, D and DuVal, M and Putko, BN and Johnston, W and Beecher, G}, title = {Medical Assistance in Dying in ALS: Frequency, Survival, and Associations With Patient Characteristics in a Canadian Clinic.}, journal = {Neurology}, volume = {106}, number = {10}, pages = {e218032}, doi = {10.1212/WNL.0000000000218032}, pmid = {42081784}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy ; Female ; Male ; Aged ; Canada/epidemiology ; Middle Aged ; Retrospective Studies ; *Suicide, Assisted/statistics &amp; numerical data ; Gastrostomy/statistics &amp; numerical data ; }, abstract = {OBJECTIVES: Medical assistance in dying (MAiD) has been available across Canada since 2016 for patients with amyotrophic lateral sclerosis (ALS). We aimed to characterize MAiD use, identify associated factors, and compare survival and location of death in a Canadian ALS cohort.<br><br>METHODS: We retrospectively reviewed patients with ALS followed at a Canadian multidisciplinary clinic who died between January 1, 2019 and December 31, 2024. Patient characteristics were described by MAiD status. Factors associated with MAiD utilization were evaluated using regression analyses, and survival and location of death were compared between patients who did and did not pursue MAiD.<br><br>RESULTS: Of 255 patients (median age 67 years [IQR 60-75]; 42% female), 55 (21.6%) underwent MAiD. Percutaneous endoscopic gastrostomy (PEG) use was inversely associated with MAiD utilization (OR 0.34, 95% CI 0.15-0.78), whereas demographic and disease characteristics were not associated with MAiD. Survival from diagnosis to death was shorter among patients who underwent MAiD (median 12 vs 14 months; p = 0.019), with no difference from symptom onset. Death at home was more frequent with MAiD (62% vs 35%; p < 0.001).<br><br>DISCUSSION: MAiD is a common end-of-life option in ALS, reflecting patient values and is associated with lower PEG use, shorter postdiagnosis survival, and more frequent death at home.}, }
@article {pmid42081880, year = {2026}, author = {Schnieders, C and Scholl, C and Hoeflich, A and Schmicke, M}, title = {A pilot study on the influence of early pregnancy interferon τ to the expression of IGF-binding proteins in primary bovine hepatocytes.}, journal = {Domestic animal endocrinology}, volume = {96}, number = {}, pages = {107018}, doi = {10.1016/j.domaniend.2026.107018}, pmid = {42081880}, issn = {1879-0054}, abstract = {The implantation period is crucial for the establishment of pregnancies in cows. Interferon τ (IFNτ) is produced during early implantation and acts in autocrine, paracrine and endocrine fashions on other endocrine systems. One of these is the insulin-like growth factor 1 (IGF-1) system, which is important for cell growth, proliferation, and therefore pregnancy establishment. This study investigated the effect of IFNτ on the expression of hepatic IGF-binding proteins (IGFBPs) in vitro. Primary bovine hepatocytes in a 2D sandwich culture model were stimulated with recombinant bovine IFNτ (rbIFNτ; 0.1-10.0 ng/mL) for six hours. The mRNA expression of IGFBP-1 to -7 and acid labile subunit (ALS) was measured using qRT‒PCR, and protein production was confirmed using western ligand blotting. All the IGFBPs (1-7) and ALS were expressed at basal levels in primary bovine hepatocytes, with IGFBP-2 to -4 secreted at appreciable concentrations in the medium. The expression of IGFBP-2 to -6 was stimulated by IFNτ, (treatment with rbIFNτ vs. control; IGFBP-2: for 0.5 ng/mL rbIFNτ, p = 0.0166; IGFBP-3: for 0.5 ng/mL, 5.0 ng/mL, and 10.0 ng/mL rbIFNτ, p = 0.0293, p = 0.0252, and p = 0.0099; IGFBP-4: for 0.5 ng/mL rbIFNτ, p = 0.0024; IGFBP-5: for 0.5 ng/mL and 10 ng/mL rbIFNτ, p = 0.0008 and p = 0.0421; IGFBP-6: for 0.1-10.0 ng/mL rbIFNτ, p = 0.0498-0.0022). These results indicate modulation of the IGF-system through IFNτ, which may contribute to adaptations supporting the early establishment of pregnancies in cattle.}, }
@article {pmid42082278, year = {2026}, author = {Zhu, Z and Yuan, L and Yang, J and Jiang, S and Cao, Y and Yang, J and Zhang, Y and Mo, Y and Chen, C and Zhang, H and Zhou, J and , }, title = {Healthcare burden of bronchopulmonary dysplasia among very preterm infants in China: a cohort study.}, journal = {BMJ paediatrics open}, volume = {10}, number = {1}, pages = {}, doi = {10.1136/bmjpo-2025-004259}, pmid = {42082278}, issn = {2399-9772}, mesh = {Humans ; *Bronchopulmonary Dysplasia/epidemiology/mortality/economics/therapy ; China/epidemiology ; Infant, Newborn ; Female ; Male ; Prospective Studies ; Intensive Care Units, Neonatal ; Length of Stay/statistics &amp; numerical data ; Infant, Extremely Premature ; Severity of Illness Index ; Infant, Premature ; Gestational Age ; Infant ; Hospitalization/statistics &amp; numerical data/economics ; *Cost of Illness ; }, abstract = {OBJECTIVE: To assess the healthcare burden of bronchopulmonary dysplasia (BPD) among very preterm infants in China.<br><br>DESIGN: A prospective cohort study between 2022 and 2023.<br><br>SETTING: Chinese Neonatal Network (CHNN) participating centres.<br><br>PATIENTS: Infants with gestational age <32 weeks admitted to CHNN neonatal intensive care units.<br><br>MAIN OUTCOME MEASURES: A composite rate of BPD or mortality at 36 weeks' postmenstrual age (PMA), major comorbidities, clinical resources utilisation and outcome at discharge. BPD severity was classified by Jensen et al's criteria.<br><br>RESULTS: Among 17&#x2009;793 eligible infants, 568 (3.2%) infants died before 36 weeks' PMA, 1729 (9.7%) were discharged against medical advice before 36 weeks' PMA, 9895 (55.6%) were classified as no BPD, 2751 (15.5%) developed Grade 1&#x2009;BPD, 2634 (14.8%) developed Grade 2&#x2009;BPD and 216 (1.2%) developed Grade 3&#x2009;BPD. Infants with BPD had significantly longer hospital stays than those without BPD (median (IQR), 67 (52-84) vs 44 (34-56) days) and incurred higher total hospitalisation charges (median (IQR), 127 (91-177) vs 73 (52-103) thousand CNY) and charge per day (median (IQR), 1975 (1638-2361) vs 1714 (1409-2048) CNY). Mortality at discharge increased with BPD severity, with rates of 0.2% (18/9895) for infants without BPD, 0.5% (15/2751) for Grade 1&#x2009;BPD, 2.1% (56/2634) for Grade 2 and 26.9% (58/216) for Grade 3. Similarly, the rates of major comorbidities and the need for home oxygen therapy increased with BPD severity.<br><br>CONCLUSIONS: Greater BPD severity was associated with increased comorbidities, higher in-hospital mortality and greater utilisation of healthcare resources. These findings emphasised the ongoing need to develop cost-saving strategies to reduce the risk and severity of BPD in this vulnerable population and improve overall care.}, }
@article {pmid42082894, year = {2026}, author = {Kipourgos, G and Bakalis, N and Albani, E and Stefanopoulos, N and Lakoumentas, J and Tzenalis, A}, title = {Expert Consensus on Key Attributes of Nurses in Resuscitation Teams: Findings From a Delphi Study.}, journal = {Nursing in critical care}, volume = {31}, number = {3}, pages = {e70506}, doi = {10.1111/nicc.70506}, pmid = {42082894}, issn = {1478-5153}, mesh = {Humans ; Delphi Technique ; *Consensus ; *Clinical Competence ; *Patient Care Team ; *Heart Arrest/nursing/therapy ; Greece ; Female ; Male ; *Resuscitation/nursing ; *Cardiopulmonary Resuscitation/nursing ; Adult ; Middle Aged ; }, abstract = {BACKGROUND: In-hospital cardiac arrest (IHCA) requires coordinated interdisciplinary action. Nurses are often first responders and essential members of resuscitation teams, yet the attributes that define their effectiveness remain unclear. Although team performance has been widely studied, few works have systematically examined nursing competencies in this context. This is the first Delphi-based study in Greece defining key nursing attributes within in-hospital resuscitation teams.<br><br>AIM: To achieve expert consensus on the key attributes characterizing effective nursing participation in IHCA teams.<br><br>STUDY DESIGN: A two-round Delphi study was conducted with experts in resuscitation and critical care. Round one involved thematic analysis of semi-structured interviews. In round two, experts rated attributes on a 10-point Likert scale. Consensus was defined as mean (M) >&#x2009;8 and coefficient of variation (CV) <&#x2009;20%. Descriptive statistics and Kendall's W assessed agreement across domains.<br><br>RESULTS: Thirty-nine attributes were identified and grouped into seven domains: education, experience, physical condition, psychological resilience, technical skills and non-technical skills. Thirty-five attributes met the consensus criteria. Highest agreement was observed for ALS certification, stress resilience, closed-loop communication, adaptability and teamwork. Strongest consensus emerged in non-technical (M&#x2009;=&#x2009;9.75, CV&#x2009;=&#x2009;3.79%) and technical (M&#x2009;=&#x2009;9.61, CV&#x2009;=&#x2009;5.62%) domains.<br><br>CONCLUSIONS: This study provides an evidence-informed framework of competencies and personal qualities underpinning nurses' effectiveness in resuscitation teams, emphasizing both technical expertise and non-technical skills-especially closed-loop communication, composure and collaboration.<br><br>The framework supports clearer role delineation, structured competency development and enhanced team effectiveness in IHCA management.}, }
@article {pmid42082968, year = {2026}, author = {Terrin, F and Faggin, S and Bizzotto, E and Santinello, D and Cerantola, S and Borsato, G and Fabris, F and Scarso, A and Licitra, R and Guella, G and Sales, G and Cagnin, S and Treu, L and Bubacco, L and Giron, MC and Plotegher, N and Dalla Valle, L}, title = {β-Sitosterol β-D-glucoside (BSSG) triggers intestinal inflammation in zebrafish and mouse models prior to neurodegeneration onset.}, journal = {Journal of biomedical science}, volume = {33}, number = {1}, pages = {}, pmid = {42082968}, issn = {1423-0127}, support = {PhD Fellowship 2020//MUR/University of Padova/ ; PostDoc Fellowship 2024//Department of Biology/ ; PostDoc Fellowship ARD-B 2023//Department of Pharmaceutical and Pharmacological Sciences/ ; PostDoc Fellowship ARD-B 2020//Department of Pharmaceutical and Pharmacological Sciences/ ; Seed 2020//Department of Biology Intramural Grant/ ; Seed 2022//Department of Biology Intramural Grant/ ; Project ID: CN00000041 - SP. 3//National Center For Gene Therapy And Drugs Based On RNA Technology Neurodegeneration/ ; UNIPD-DSF-PRID-2023//San Camillo Hospital Grant, Treviso, Italy/ ; }, mesh = {Animals ; Zebrafish ; Mice ; *Sitosterols/adverse effects/toxicity ; Disease Models, Animal ; Gastrointestinal Microbiome/drug effects ; *Intestines/drug effects ; *Glucosides/adverse effects ; *Inflammation/chemically induced ; *Neurodegenerative Diseases/chemically induced ; }, abstract = {BACKGROUND: Glucosylated-sterols can be synthetized endogenously, absorbed through the diet or derive from bacterial infection. Their clinical relevance is currently underestimated, even though their imbalance has been associated with an increased risk of neurodegeneration over the lifespan. We studied the detrimental effects elicited by dietary consumption of the plant-derived β-sitosterol β-D-glucoside (BSSG), known to be associated with the occurrence of ALS-PDC, to elucidate its potential mechanism of action.<br><br>METHODS: Zebrafish larvae and adults, as well as mice, were treated with BSSG administered directly in the water or via customized food pellet, respectively. Since the intestine was identified as the primary target tissue, its morphological and functional characteristics were assessed, together with transcriptional profiling and gut microbiota sequencing. Ex vivo analysis of zebrafish gut contractility was applied to evaluate intestinal neuromuscular responses. Mutant and transgenic zebrafish lines were used to explore a potential BSSG mechanism of action.<br><br>RESULTS: BSSG induced intestinal inflammation in both zebrafish and mouse models. This previously unknown effect was evidenced by gut dysmotility and inflammatory response. Transcriptomic analyses revealed increased expression of inflammation-related genes in the intestine of both zebrafish and mice, while preliminary gut microbiota analyses suggested the onset of dysbiosis. Transgenic and mutant zebrafish lines, depleted of genes involved in glucocorticoids synthesis and activity, evidenced that BSSG likely interacts with the glucocorticoid receptor, potentially impairing its canonical anti-inflammatory activity.<br><br>CONCLUSIONS: We identified novel pathways altered by dietary BSSG exposure. This molecule appears to initially induce gut inflammation, leading to changes in intestinal morphology and function, and may contribute to neurodegeneration through disruption of the well-known gut-brain axis.}, }
@article {pmid42083136, year = {2026}, author = {O'Reilly, &#xc9;J and Bjornevik, K and Furtado, JD and Patel, AV and Wang, Y and Kolonel, LN and Le Marchand, L and Ascherio, A}, title = {Pre-Diagnostic Plasma Carotenoids, Tocopherols and Retinol Levels, and Risk of Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78240}, pmid = {42083136}, issn = {1531-8249}, support = {R01 NS045893/NS/NINDS NIH HHS/United States ; R01 CA49449//Common Fund/ ; U01 CA164973/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Our goal was to examine whether pre-diagnostic plasma carotenoids and tocopherols are associated with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A nested case-control study within 4 United States cohorts, where 154 participants with pre-diagnostic blood-draw, were diagnosed during follow-up with amyotrophic lateral sclerosis&#xa0;(ALS). Controls were randomly selected from participants alive on the date a case was diagnosed, matched 2:1 by cohort, sex, age, race/ethnicity, fasting-status, time of blood-draw. Carotenoid and tocopherol levels were quantified by high-performance liquid-chromatography with diode array-detector. ALS incidence or death rate ratios (RR) were estimated using conditional logistic regression adjusting for body mass index, smoking status, physical activity, cholesterol, and urate levels.<br><br>RESULTS: The association between beta-carotene and ALS varied by sex (p-for-interaction&#x2009;=&#x2009;0.007). After matched- and multivariable-adjustment, women with higher cis-, trans- and total beta-carotene had lower incidence of ALS (RR for 1-standard deviation [SD] increase in total beta-carotene: 0.68; 95% CI: 0.48-0.98; p&#x2009;=&#x2009;0.038), whereas a positive association was seen in men (1-SD increase: RR&#x2009;=&#x2009;1.44; 95% CI: 1.03-2.01; p&#x2009;=&#x2009;0.033). However, after further adjustment for other correlated carotenoids, the association in men was attenuated, whereas it remained significant in women. Women with higher beta-cryptoxanthin, but not men, had a lower risk of ALS (1-SD increase: RR&#x2009;=&#x2009;0.67; 95% CI: 0.48-0.94; p&#x2009;=&#x2009;0.02; p-for-interaction&#x2009;=&#x2009;0.12). Alpha-carotene, lutein-zeaxanthin, lycopene, retinol, and tocopherols were not associated with ALS, except for a borderline inverse association of gamma-tocopherol in men (RR&#x2009;=&#x2009;0.74; 95% CI: 0.54-1.01; p&#x2009;=&#x2009;0.059).<br><br>INTERPRETATION: Higher pre-diagnostic plasma levels of beta-carotene and beta-cryptoxanthin in women and gamma-tocopherol in men were suggestively associated with lower ALS risk. Other carotenoids or tocopherols were not clearly associated with ALS. ANN NEUROL 2026.}, }
@article {pmid42084465, year = {2026}, author = {Farquharson, K and Macrae, T}, title = {Lexical Properties of Stimuli in Standardized Articulation and Phonology Tests: A Short Report.}, journal = {American journal of speech-language pathology}, volume = {}, number = {}, pages = {1-9}, doi = {10.1044/2026_AJSLP-25-00129}, pmid = {42084465}, issn = {1558-9110}, abstract = {PURPOSE: The purpose of the present study was to report the phonological neighborhood density, phonotactic probability, and word frequency of the stimuli in 12 commonly used articulation and/or phonological tests. We extend the work of Macrae (2017), who identified variability in stimulus items across consonant singletons, consonant clusters, vowels, phoneme complexity, and bound morpheme. This study sought to augment that work with a deeper analysis of lexical and sublexical features of these stimuli.<br><br>METHOD: The stimuli from 12 articulation and/or phonological tests were extracted, resulting in 667 stimuli. All stimuli were run through a phonological neighborhood density and phonotactic probability calculator. Word frequency was determined using Moe et al.'s (1982) database.<br><br>RESULTS: Means and ranges for all lexical characteristics were computed across each of the 12 tests. Most stimuli were from sparse phonological neighborhoods, and included common sound sequences. Although the average word frequency value was in the high range, overall, very few test stimuli were high-frequency words.<br><br>DISCUSSION: There was not one articulation and/or phonological test that considered or balanced these three lexical properties. We discuss the linguistic constraints surrounding developing such a test. We also discuss future research opportunities to examine if these lexical properties may result in over- and underidentification of children with speech sound disorders.}, }
@article {pmid42084479, year = {2026}, author = {Liu, X and Dhakal, D and Gu, S and Li, G and Jing, M and Zhang, G and Wang, Y and Zhang, Z and Fan, D}, title = {Relationship between grip strength, functional outcome, and health-related quality of life measurements in amyotrophic lateral sclerosis patients.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2667425}, pmid = {42084479}, issn = {1758-2032}, abstract = {AIM: To explore how grip strength is related to functional status and health-related quality of life (HRQoL) in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: In the phase 2 trial of TBN for treatment of ALS, 148 patients in full analysis set received TBN (600&#x2009;mg or 1200&#x2009;mg) or a placebo for 180&#x2009;days. Outcome measurements included ALS Functional Rating Scale-Revised (ALSFRS-R), 40-item ALS Assessment Questionnaire (ALSAQ-40), grip strength, and forced vital capacity (FVC). Spearman's rank correlation was used to examine associations between grip strength, ALSFRS-R and ALSAQ-40. A principal component analysis-ANCOVA model adjusted for sex was used to further explore the associations.<br><br>RESULTS: Grip strength was strongly correlated with ALSFRS-R fine motor function domain (rs&#x2009;=&#x2009;0.740) and moderately correlated with ALSAQ-40 activities of daily living (ADL) domain (rs&#x2009;=&#x2009;-0.637) (p&#x2009;<&#x2009;0.05). Weak correlations were observed between FVC and both ALSFRS-R total score (rs&#x2009;=&#x2009;0.355) and respiratory domain (rs&#x2009;=&#x2009;0.229) and ALSAQ-40 domains. Grip strength was a strong predictor of ALSFRS-R fine motor and ALSAQ-40 ADL domains.<br><br>CONCLUSION: Grip strength was associated with functional status and HRQoL, supporting its potential role as a meaningful clinical outcome measure in patients with ALS.}, }
@article {pmid42084503, year = {2026}, author = {Shino, Y and Muraki, N and Kobatake, Y and Kamishina, H and Kosuge, H and Nakakido, M and Tsumoto, K and Furukawa, Y}, title = {Structural analysis of Cu/Zn-superoxide dismutase linked to neurodegenerative disease by antibody-guided cryo-EM.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {6}, pages = {e70615}, doi = {10.1002/pro.70615}, pmid = {42084503}, issn = {1469-896X}, support = {19H05765//Ministry of Education, Culture, Sports, Science and Technology/ ; 22H02768//Ministry of Education, Culture, Sports, Science and Technology/ ; 22K19389//Ministry of Education, Culture, Sports, Science and Technology/ ; }, mesh = {Dogs ; Animals ; *Superoxide Dismutase-1/chemistry/metabolism/genetics ; Cryoelectron Microscopy ; *Antibodies, Monoclonal/chemistry/metabolism ; Humans ; *Neurodegenerative Diseases/enzymology ; Models, Molecular ; Dog Diseases/enzymology ; Amyotrophic Lateral Sclerosis ; }, abstract = {Accumulation of misfolded proteins is a hallmark of many neurodegenerative diseases. To characterize such misfolded species in vivo, conformation-specific antibodies are widely used; however, limited knowledge of antibody-epitope interactions often hampers mechanistic insight. To address this, we determined the cryo-electron microscopy structure of the complex between a monoclonal antibody, 19A9, and Cu/Zn-superoxide dismutase (SOD1), a protein associated with canine degenerative myelopathy (DM), which is related to human amyotrophic lateral sclerosis. Biochemical analyses confirmed that 19A9 specifically recognizes monomeric SOD1, and the structure revealed binding near the interface normally used for homodimerization in native SOD1, with steric hindrance preventing interaction when the protein is in its homodimeric form. Immunofluorescence staining of spinal cord sections revealed that 19A9 stained a subset of motoneurons in DM-affected dogs, but not in asymptomatic controls. Structural characterization of the 19A9-monomeric SOD1 complex enabled us to propose that SOD1 monomers can arise in vivo under pathological conditions.}, }
@article {pmid42069087, year = {2026}, author = {Zecca, C and Urso, D and Dell'Abate, MT and Borlizzi, F and Rollo, E and Logroscino, G}, title = {Neurofilament light and GFAP predict survival in frontotemporal dementia spectrum: A population-based study.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107421}, doi = {10.1016/j.nbd.2026.107421}, pmid = {42069087}, issn = {1095-953X}, abstract = {BACKGROUND: Survival estimates for frontotemporal lobar degeneration (FTLD)-related syndromes by incorporating fluid biomarkers are essential to better assess their prognostic value and explore how they might inform long-term outcomes in FTLD. Population-based registries provide valuable data for these predictions. The aim of the present study was to assess whether NfL and GFAP levels correlate with mortality risk in a population-based registry of incident FTLD.<br><br>METHODS: Incident cases with FTLD-spectrum, occurring between 2018 and 2020, were followed for up to six years. Survival and hazard analysis according to biomarkers levels were conducted.<br><br>RESULTS: Median survival was 6&#x202f;years from symptom onset and 3&#x202f;years from diagnosis. While FTD-ALS phenotype showed significantly shorter survival, no differences were observed among bvFTD, PPAs, and CBS/PSP. Biomarkers were significantly associated with survival. Higher plasma GFAP (HR&#x202f;=&#x202f;1.006, 95%CIs 1.001-1.012; p&#x202f;=&#x202f;0.026) and plasma NfL (HR&#x202f;=&#x202f;1.027, 95%CIs 1.003-1.053; p&#x202f;=&#x202f;0.025) were associated with increased mortality risk in bvFTD, PPAs, and CBS/PSP.<br><br>CONCLUSIONS: These results highlight the potential of NfL and GFAP as valuable biomarkers for assessing prognosis in FTLD and underscore the importance of incorporating biomarker analysis into clinical practice for more accurate patient management. Further studies are needed to refine prognostic models for FTLD.}, }
@article {pmid42069088, year = {2026}, author = {Senerchia, G and Iuzzolino, VV and Spisto, M and Panico, F and Polito, C and Aruta, L and Fiorenza, M and Sirica, R and Terracciano, D and Dubbioso, R}, title = {Elevated plasma sTREM2 reflects microglial activation but lacks diagnostic and clinical relevance in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107430}, doi = {10.1016/j.nbd.2026.107430}, pmid = {42069088}, issn = {1095-953X}, abstract = {Microglial activation contributes to the neuroinflammatory response in amyotrophic lateral sclerosis. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects microglial activity in several neurodegenerative disorders, but its role in amyotrophic lateral sclerosis remains unclear. We evaluated plasma sTREM2 as a marker of microglial activation in amyotrophic lateral sclerosis (ALS) and compared its diagnostic performance with established blood biomarkers of neurodegeneration. Plasma sTREM2, neurofilament light chain (NfL), phosphorylated tau181 (Ptau181), and glial fibrillary acidic protein (GFAP) were measured in 100 patients with ALS, 30 healthy controls, and 30 disease mimics. Group differences were assessed using general linear models adjusted for age and sex. Associations with clinical variables and inflammatory markers were tested using Spearman correlation, and diagnostic performance was evaluated using receiver operating characteristic curves. Plasma sTREM2 differed across groups (p = 0.016), with higher levels in ALS compared with healthy controls (p = 0.013) and in mimics compared with healthy controls (p = 0.007), but no difference between ALS and mimics (p = 0.394). Discrimination between ALS and controls was modest (area under the curve 0.677), with no discrimination between ALS and mimics (area under the curve 0.512). No association was found between sTREM2 and disease severity or inflammatory markers (all p > 0.10). Plasma sTREM2 increases in ALS but lacks diagnostic specificity and clinical associations, supporting its role as a nonspecific marker of neuroimmune activation rather than a biomarker of disease-related neurodegeneration.}, }
@article {pmid42069252, year = {2026}, author = {Zi, X and Li, H and Fan, H}, title = {Considerations on Sayed et al.'s Bimekizumab Trial: Definitions, Bias, and Risk.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.04.1974}, pmid = {42069252}, issn = {1097-6787}, }
@article {pmid42069601, year = {2026}, author = {Robinson, L and Do-Ha, D and Cheng, F and Stevens, CH and Rosa Porto, R and Coles, M and Subachandran, J and Kalajdzic, P and Lui, J and Balez, R and Sanz Muñoz, S and Cabral-da-Silva, MC and Berg, T and Morsch, M and Lisowski, L and Tan, RH and Burgio, G and Karl, T and Lee, A and Chung, RS and Blair, I and Ooi, L}, title = {ALS-FTD-linked CCNF[S621G] drives increased hippocampal astrocyte ramification and mitochondrial dysfunction and impairs motor neuron excitability.}, journal = {Journal of neuroinflammation}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12974-026-03827-x}, pmid = {42069601}, issn = {1742-2094}, support = {APP1107644//National Health and Medical Research Council/ ; APP1135720//National Health and Medical Research Council/ ; CE230100021//Australian Research Council/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both, even within the same family. Most prior studies of CCNF[S621G] have relied on overexpression systems, potentially confounding outcomes through disruption of endogenous Cyclin F. Here, we generated the first knock-in mouse model of endogenous Ccnf[S621G] using CRISPR/Cas9. Heterozygous and homozygous Ccnf[S621G] mice showed no motor decline or neuronal loss after 18 months, however immunohistochemistry revealed increased hippocampal astrocyte ramification, with sex-, age, and subfield-dependent effects. These data indicate that endogenous Ccnf[S621G] may prime early astrocyte alterations in the absence of overt neurodegeneration. Similar astrocyte morphological changes were observed in canonically affected regions of sporadic ALS and FTD-ALS patients post mortem, as well as in CCNF[S621G] iPSC-derived astrocytes following inflammatory stimulation. Proteomics on Ccnf mice identified early dysregulation of pathways related to translation, mitochondrial function, cytoskeletal remodelling, synaptic transmission and neuroinflammation. Correspondingly, CCNF[S621G] iPSC-derived astrocytes displayed impaired mitochondrial membrane potential and altered network morphology under both basal and inflammatory stimuli. As altered neuronal excitability is a hallmark of ALS, we examined astrocyte-driven changes to neuronal excitability. CCNF[S621G] iPSC-derived motor neurons cultured alone were hyperexcitable, firing more action potentials than isogenic controls. Remarkably, co-culture with CCNF[S621G] astrocytes, but not isogenic control astrocytes, abolished repetitive firing, increased the proportion of neurons unable to generate action potentials, and reduced voltage-gated sodium currents in CCNF[S621G] and isogenic control neurons. Together, these findings identify astrocyte alterations as an early feature of CCNF[S621G]-mediated disease, in the absence of neuronal loss. Moreover, the combination of astrocytic mitochondrial dysfunction and the ability of CCNF[S621G] astrocytes to suppress repetitive neuronal firing suggests a critical astrocyte-driven non-cell autonomous mechanism that may contribute to an oligogenic role for CCNF in ALS/FTD pathogenesis.}, }
@article {pmid42070160, year = {2026}, author = {Abdel Mageed, SS and Sayed, GA and Mahdy, A and El-Dakroury, WA and Abdulkader, AO and Moustafa, HAM and Mansour, RM and Mohammed, OA and Elballal, MS and Elesawy, AE and Doghish, AS}, title = {miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42070160}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis/metabolism ; Humans ; *MicroRNAs/genetics/metabolism ; Animals ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.}, }
@article {pmid42070757, year = {2026}, author = {Liu, JY and Liu, SY and Ran, LX and Qiao, WH and Zhang, F and Zhang, KS and Liang, XX and Liu, MY and Yu, ZH and Wei, MJ and Zhong, X}, title = {Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration.}, journal = {Pharmacological research}, volume = {}, number = {}, pages = {108216}, doi = {10.1016/j.phrs.2026.108216}, pmid = {42070757}, issn = {1096-1186}, abstract = {The cGAS-STING signaling pathway serves as a central signalling axis of the innate immune system, and its aberrant activation plays a pivotal role in inflammatory responses. Recent studies have demonstrated that its regulation depends not only on individual organelles but also on a coordinated interorganelle network. This review systematically analyze how mitochondria, centrosomes, the endoplasmic reticulum (ER), membrane contact sites (MCSs), the Golgi apparatus, endosomes, and lysosomes collectively orchestrate cGAS-STING signaling. Mitochondria initiate signaling by releasing mitochondrial DNA; centrosomes serve as platforms for double-stranded DNA accumulation to potentiate cGAS activation; the ER anchors STING in a calcium homeostasis-dependent manner; mitochondrial-associated ER membranes (MAMs) integrate calcium and lipid signaling as regulatory checkpoints governing STING trafficking to the Golgi apparatus; the Golgi amplifies downstream signaling through site-specific post-translational modifications of STING; finally, the endosome-lysosome system, together with ER-lysosome MCSs, acts as a coordinated hub for STING sorting, lysosomal degradation and signal termination. Consequently, disruption of organelle homeostasis leads to persistent STING activation. In neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease, organelle dysfunction resulting from calcium overload, impaired organelle clearance, proteolytic cleavage of tethering proteins or multi-source attacks drives aberrant STING signaling. Sustained STING activity exacerbates pathological cascades such as protein misfolding, chronic neuroinflammation, and progressive neuronal loss. Therefore, therapeutic strategies targeting key regulatory nodes of the STING pathway, from upstream organelle repair to direct pharmacological inhibition, offer significant potential to mitigate disease-associated pathological progression and constitute a promising foundation for precision therapeutics in neurodegenerative disorders.}, }
@article {pmid42071322, year = {2026}, author = {Buttifant, E and Allogmanny, S and Probst, Y}, title = {Investigating Disordered Eating Behaviours Among Individuals Living With Neurodegenerative Disease: A Scoping Review.}, journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association}, volume = {39}, number = {3}, pages = {e70250}, doi = {10.1111/jhn.70250}, pmid = {42071322}, issn = {1365-277X}, mesh = {Humans ; *Feeding and Eating Disorders/etiology/epidemiology/complications ; *Neurodegenerative Diseases/complications/psychology ; *Feeding Behavior/psychology ; Hyperphagia ; Female ; Male ; Alzheimer Disease/complications ; }, abstract = {AIM: Neurodegenerative diseases and disordered eating have become rapidly expanding areas of research. However, research addressing the relationship between the two is lacking.<br><br>METHODS: A scoping review guided by the Joanna Briggs Institute methodological framework was completed to synthesise the evidence related to disordered eating behaviours among individuals living with neurodegenerative disease. A systematic search strategy was applied across four scientific databases. A narrative descriptive analysis was conducted to identify key patterns in the studies categorised by the type of eating behaviour. The types of tools used within studies were explored.<br><br>RESULTS: Thirty-six evidence sources were included in this review. Overeating-related issues such as hyperphagia were identified (n&#x2009;=&#x2009;5, 25%) for dementia and Alzheimer's disease-related studies. Appetite-related changes were prevalent across amyotrophic lateral sclerosis (n&#x2009;=&#x2009;1, 100%) and dementia and Alzheimer's disease-related studies (n&#x2009;=&#x2009;6, 30%). Food addiction and binge eating were reported in all Parkinson's disease studies (n&#x2009;=&#x2009;9, 100%), and in one case report for dementia. Eating disorders such as anorexia, bulimia and binge eating disorder were identified in all multiple sclerosis-related studies (n&#x2009;=&#x2009;6, 100%). Validated and unvalidated tools (53%, n&#x2009;=&#x2009;19) were used to identify eating behaviours.<br><br>CONCLUSIONS: This review revealed reports of disordered eating behaviours among various neurodegenerative disease types. Additional research is required to understand the aetiology and mechanisms behind disordered eating behaviours in these populations. Standardised tools to assess eating behaviours for people living with a neurodegenerative disease are needed. Eating behaviours should be screened upon neurodegenerative disease diagnosis and monitored as part of routine care.}, }
@article {pmid42072614, year = {2026}, author = {Ferreon, JC and Choi, KJ and Quan, MD and Tsoi, PS and Ferreon, CC and Coskun, U and Liao, SJ and Ferreon, ACM}, title = {Modulation of Biomolecular Aggregate Morphology and Condensate Infectivity.}, journal = {Biomolecules}, volume = {16}, number = {4}, pages = {}, doi = {10.3390/biom16040492}, pmid = {42072614}, issn = {2218-273X}, support = {R01 GM122763/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Protein Aggregates ; *Heterogeneous Nuclear Ribonucleoprotein A1/chemistry/metabolism/genetics ; Amyloid/metabolism/chemistry ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Biomolecular Condensates/chemistry/metabolism ; Prions/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism ; }, abstract = {Neurodegenerative diseases feature diverse pathological protein aggregates, including Lewy bodies in Alzheimer's disease (AD) and skein-like filaments in amyotrophic lateral sclerosis (ALS). The physical mechanisms underlying this morphological diversity remain unclear. Here, we demonstrate that aggregation of the prion-like domain of hnRNPA1 (A1PrD), implicated in AD and ALS, is driven by solution composition and phase transition dynamics. Utilizing 3D timelapse and fluorescence lifetime imaging microscopy, we show that solution conditions modulate phase separation, gelation, and fibrillation, resulting in distinct structures such as fibril, gel, and starburst morphologies. Homotypic and heterotypic interactions between A1PrD and RNA were observed to shift the balance between pathological and physiological condensates. Importantly, amyloid-rich starbursts displayed prion-like infection capabilities toward amyloid-poor condensates. Our findings highlight how the interplay between solution composition and kinetic balances of liquid-liquid phase separation, gelation, and fibrillation shapes the diverse pathological aggregate morphologies characteristic of neurodegenerative diseases.}, }
@article {pmid42072687, year = {2026}, author = {Fiorucci, C and Rossi, MN and Santo, RD and Salvatori, I and Scaricamazza, S and Giuliani, S and Carletta, O and Filomena, E and Laurenti, D and Mattioli, R and Mosca, L and Valle, C and Ferri, A and D'Erchia, AM and Cervelli, M}, title = {Transcriptomic Analysis Reveals the Beneficial Effects of Spermidine in an ALS Mouse Model.}, journal = {Biomolecules}, volume = {16}, number = {4}, pages = {}, doi = {10.3390/biom16040566}, pmid = {42072687}, issn = {2218-273X}, support = {LSH-Puglia, T4-AN-01 H93C22000560003//INNOVA - Italian network of excellence for advanced diagnosis/ ; Grant Code IR0000010//ELIXIR-IT/ ; MAE0067342//Protocols of Scientific and Technological Bilateral Cooperation funded by the Ministry of Health/ ; L. 232/2016-art.1 cc. 314-337 awarded to the Department of Science of Roma Tre University (2023-2027)//MIUR-Italy Grants of Departments of Excellence/ ; CUP B83C22002820006//Progetto ECS 0000024 Rome Technopole/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Mice ; Disease Models, Animal ; *Spermidine/pharmacology/therapeutic use ; Muscle, Skeletal/metabolism/drug effects/pathology ; Gene Expression Profiling ; Spinal Cord/metabolism/drug effects ; Mitochondria/metabolism/drug effects/genetics ; Mice, Transgenic ; *Transcriptome/drug effects ; Humans ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of motor neurons and skeletal muscle. Gene expression analysis of the spinal cord and gastrocnemius of the SOD1-G93A ALS mouse model revealed a strong increase in inflammatory pathways and, specifically in the ALS gastrocnemius, a decrease in mitochondrial transcription and an increase in ribosomal protein expression. Treatment of ALS mice with the polyamine spermidine (SPD), a promising molecule in combating neurodegeneration and muscle atrophy, is able to partially restore the expression of more than four thousand genes in gastrocnemius tissue, including the mitochondrial regulator Pgc1α, as well as all the mitochondrial encoded genes and a large class of ribosomal proteins. SPD enhanced mitochondrial bioenergetics, as evidenced by Seahorse experiments, and delayed muscle weakness in vivo, as shown by grip strength records. These findings suggest that SPD can act as a potential supplement in the therapeutic strategy for ALS, offering a foundation for further research to improve patient outcomes.}, }
@article {pmid42073390, year = {2026}, author = {Hossain, R and Surinkaew, S and Sompol, P and Bastaki, NK and Jafrin, R and Sekeroglu, N and Tangpong, J}, title = {Mapping the Polar Neuro-Interactome of Garcinia mangostana Against the AD-PD-ALS Nexus.}, journal = {Life (Basel, Switzerland)}, volume = {16}, number = {4}, pages = {}, doi = {10.3390/life16040580}, pmid = {42073390}, issn = {2075-1729}, support = {WU69203//Walailak University under the New Researcher Development scheme/ ; }, abstract = {Background/Objectives: Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis (ALS) share common molecular pathways, including neuroinflammation and oxidative stress, which complicate the effectiveness of single-target treatments. Garcinia mangostana L. (mangosteen) has shown neuroprotective properties, but previous studies focused on lipophilic xanthones, which have poor bioavailability and uncertain blood-brain barrier permeability. Methods: In the current study, polar metabolites from G. mangostana peel aqueous extract (GMPE) were assessed for potential multi-target interactions via UHPLC-QTOF-MS-based metabolomics, systems pharmacology, and molecular docking analysis. Further, in silico ADMET screening and network-based analyses assessed for overlap between GMPE compounds and genes associated with neurodegeneration (AD, PD, ALS). Results: Analysis of genes linked to AD, PD, and ALS revealed 121 common molecular targets influenced by GMPE metabolites. Network and enrichment analyses indicated that the compounds derived from GMPE may be involved in common pathways related to oxidative stress, neuroinflammation, and neuronal survival. Molecular docking analyses suggest that selected metabolites are likely to exhibit moderate binding affinities to their respective protein targets. Conclusions: The results presented in this study provide evidence that GMPE may possess potential multi-target interactions within common neurodegenerative pathways. However, since the data are based on computational and predictive approaches, these results should be considered hypothesis-generating and warrant further experimental validation.}, }
@article {pmid42073963, year = {2026}, author = {Aokalani, MC and Wisner, KL and Andescavage, NN and Limperopoulos, C and Stuart, BK}, title = {Implementing Outpatient Therapeutic Playgroups for NICU Families: A Quality Improvement Project.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {16}, number = {4}, pages = {}, doi = {10.3390/bs16040600}, pmid = {42073963}, issn = {2076-328X}, support = {(HRSA-GPE)//Health Resources and Services Administration Graduate Psychology Education Program/ ; T32 HD098066/HD/NICHD NIH HHS/United States//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {Therapeutic playgroups have shown promise in enhancing caregiver-infant mental health outcomes, yet tailored approaches for families following neonatal intensive care unit (NICU) admission remain limited. In this brief report on Quality Improvement, we evaluate key strategies and challenges in implementing an adapted therapeutic playgroup intervention designed for caregivers and infants with a history of NICU hospitalization at University of California, San Francisco and Zuckerberg San Francisco (UCSF) Zuckerberg San Francisco General Hospital (ZSFG) We conducted semi-structured interviews with NICU psychologists to assess local feasibility, barriers, and facilitators to implementation. Implementation science frameworks-the Consolidated Framework for Implementation Research (CFIR) and Proctor et al.'s implementation outcomes framework (acceptability, adoption, appropriateness, feasibility, and sustainability)-were used to guide data organization and interpretation. Qualitative reporting guidelines were followed to enhance transparency in describing interviews and analytic procedures. The psychologists emphasized the importance of embedding therapeutic playgroups within existing clinical workflows, providing flexible delivery models, and customizing curricula to meet cultural and family-specific needs. Multidisciplinary collaboration enhanced feasibility and parent engagement. Barriers included organizational constraints and variability in caregiver readiness. These findings inform local program development and highlight considerations for integrating dyadic mental health support into post-NICU care. Future work should incorporate caregiver perspectives and explore effective interventions across diverse settings.}, }
@article {pmid42073997, year = {2026}, author = {Rafique, A and Junaid, A and Bakovic, M}, title = {Impact of Oxidative Stress-Driven Ferroptosis in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, doi = {10.3390/ijms27083353}, pmid = {42073997}, issn = {1422-0067}, support = {APP465536/CAPMC/CIHR/Canada ; }, mesh = {*Ferroptosis ; Humans ; *Oxidative Stress ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Lipid Peroxidation ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease.}, }
@article {pmid42074010, year = {2026}, author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS}, title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, doi = {10.3390/ijms27083368}, pmid = {42074010}, issn = {1422-0067}, support = {FGFU-2025-0004//Russian state contract/ ; }, mesh = {Animals ; Humans ; *Radiation, Ionizing ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Disease Models, Animal ; Disease Progression ; Autophagy/radiation effects ; DNA Repair/radiation effects ; }, abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.}, }
@article {pmid42074053, year = {2026}, author = {Ribeiro, GD and Queiroz, DD and Monteiro-Neto, JR and Gerhardt, E and de Souza, GF and Albino, PCSC and Paranhos, LH and Outeiro, TF and Eleutherio, ECA}, title = {Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, doi = {10.3390/ijms27083409}, pmid = {42074053}, issn = {1422-0067}, support = {CNE 201.174/2022//FAPERJ/ ; PROBRAL 88881.986154/2024-01//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; PQ 309635/2023-3//National Council for Scientific and Technological Development/ ; CNPq Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; 210.034/2026//FAPERJ/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Phosphorylation/drug effects ; Pyruvaldehyde/pharmacology ; Mutation ; Cytosol/metabolism ; Protein Binding ; Glycosylation ; }, abstract = {Glycation of superoxide dismutase 1 (SOD1) has been shown to modulate the cytosolic levels of phosphorylated TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) pathology. In this study, we investigated the interaction between TDP-43 and SOD1 and assessed how methylglyoxal (MGO)-induced glycation and the ALS-associated G93A SOD1 mutation affect this interplay in H4 cells. MGO exposure reduced SOD1 activity and TDP-43 phosphorylation in cells expressing WT SOD1, but not in those expressing G93A SOD1. Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol; however, cytosolic interactions were more prevalent in G93A-expressing cells. Although MGO did not significantly alter the overall interaction between TDP-43 and WT SOD1, it induced cytosolic inclusion formation at 0.4 mM, a concentration associated with reduced cell viability. These inclusions did not colocalize with stress granules, indicating alternative aggregation pathways. Treatment with cyclosporin A, which inhibits the phosphatase calcineurin, decreased both TDP-43-WT SOD1 inclusions and cytosolic interactions between TDP-43 and G93A SOD1. Together, these findings suggest that SOD1 damage, induced by glycation or ALS-linked mutation, may affect TDP-43 phosphorylation status and promote its cytosolic mislocalization and aggregation, providing new insights into ALS-associated proteinopathy.}, }
@article {pmid42074133, year = {2026}, author = {Meltzer, M and Zamir, MS and Tzuri, N and Tan, AM and Geva, M and Hayden, MR and Lichtenstein, RG}, title = {Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, doi = {10.3390/ijms27083489}, pmid = {42074133}, issn = {1422-0067}, mesh = {*Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; *Neural Stem Cells/metabolism/drug effects/pathology ; Endoplasmic Reticulum Stress/drug effects ; *Piperidines/pharmacology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism/drug effects ; Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Tunicamycin/pharmacology ; Transcription Factor CHOP/metabolism ; }, abstract = {The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington's disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 µM), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS.}, }
@article {pmid42074537, year = {2026}, author = {Yesbek Kaymaz, A and Bora-Akoğlu, G and Erdem Yurter, H and Grunseich, C}, title = {Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.}, journal = {Genes}, volume = {17}, number = {4}, pages = {}, doi = {10.3390/genes17040419}, pmid = {42074537}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Genetic Therapy/methods ; *Muscular Atrophy, Spinal/therapy/genetics ; Gene Editing/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Genetic Vectors/genetics ; }, abstract = {Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing highly personalized therapies for other neurodegenerative disorders. As intensive research and efforts to advance gene targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-based gene editing offers the potential for one-time corrective therapies for monogenic disorders like SMA and SOD1-ALS.}, }
@article {pmid42074613, year = {2026}, author = {Quak, ZX and Wang, F and Tay, SKH and Koh, PL and Yap, ES and Ng, KWP}, title = {Thrombosis in Neuromuscular Medicine: Current Evidence, Unmet Needs, and Future Directions.}, journal = {Journal of clinical medicine}, volume = {15}, number = {8}, pages = {}, doi = {10.3390/jcm15082810}, pmid = {42074613}, issn = {2077-0383}, abstract = {Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population.}, }
@article {pmid42074898, year = {2026}, author = {Shovman, Y and Lerner, Y and Gotkine, M}, title = {Slower Progression Rates in Lower Limb-Onset ALS.}, journal = {Journal of clinical medicine}, volume = {15}, number = {8}, pages = {}, doi = {10.3390/jcm15083096}, pmid = {42074898}, issn = {2077-0383}, support = {//Perner Yaacov memorial fund/ ; }, abstract = {Objectives: The aim of this study was to assess the differences in diagnostic delay and disease progression in people with ALS (PALS) based on site of onset. Methods: A retrospective analysis of prospectively collected data was performed, including all PALS seen in the ALS clinic in the Hadassah Medical Center between January 2009 and March 2022. PALS were divided to three groups based on site of onset (upper limb onset-ULO, lower limb onset-LLO, or bulbar onset-BO). A linear mixed-effects model was constructed with the following variables: diagnostic delay, site of onset, age of onset and time since the initial visit. The model was applied to the ALSFRS-R total score and the bulbar and motor subscales. Results: Data from 1255 visits of 281 PALS were included in the study. PALS with LLO had longer diagnostic delays than PALS in the BO group. Slower decline of total ALSFRS-R score was observed in younger PALS, and in PALS with LLO when compared with PALS with BO or ULO. The slower decline of ALSFRS-R in PALS with LLO was due to a slower decline in the motor subscale. Longer diagnostic delays were associated with lower total ALSFRS-R scores at the initial visit and with slower rates of decline. Conclusions: Comparison among PALS with ULO, LLO and BO revealed differences in the diagnostic delay and in the rate of functional decline, suggesting that differentiating between ULO and LLO ALS may be useful in the stratification of PALS in clinical trials.}, }
@article {pmid42076023, year = {2026}, author = {Rodkin, S and Gasanov, M and Tushev, A and Belousova, E and Gordeeva, Y and Nwosu, C and Tolmacheva, A}, title = {The Dual Role of Connexins in Stroke, Neurotrauma, Neurodegenerative and Psychiatric Disorders: A Global Systematic Review.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {8}, pages = {}, doi = {10.3390/molecules31081341}, pmid = {42076023}, issn = {1420-3049}, support = {25-75-10137//Russian Science Foundation/ ; }, mesh = {Humans ; *Connexins/metabolism/genetics ; *Mental Disorders/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism ; *Stroke/metabolism ; Gap Junctions/metabolism ; *Brain Injuries, Traumatic/metabolism ; Spinal Cord Injuries/metabolism ; }, abstract = {Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood-brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries-including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury-as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial-neuronal communication and cognitive-emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood-brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx-particularly Cx43-occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation.}, }
@article {pmid42076656, year = {2026}, author = {Manavalan, G and Arnon, Y and Nithyaa, AN and Arnon, S}, title = {Smart Sensor-Driven Gait Rehabilitation Walker Using Machine Learning for Predictive Home-Based Therapy.}, journal = {Sensors (Basel, Switzerland)}, volume = {26}, number = {8}, pages = {}, doi = {10.3390/s26082547}, pmid = {42076656}, issn = {1424-8220}, mesh = {Humans ; *Machine Learning ; *Gait/physiology ; Electromyography ; Male ; Female ; *Walkers ; Middle Aged ; Aged ; Biomechanical Phenomena ; Pilot Projects ; }, abstract = {Abnormal gait associated with neuromuscular and musculoskeletal disorders represents a growing clinical burden, particularly in aging populations. This study presents a modular, low-cost Smart Rehabilitation Walker (SRW) that integrates multimodal sensing and real-time haptic feedback to enable simultaneous gait monitoring and corrective intervention in both clinical and home environments. The system combines force-sensing resistors for bilateral load symmetry assessment, inertial measurement units for fall detection, and surface electromyography (sEMG) for neuromuscular activity monitoring within a closed-loop assistive feedback architecture. A 15-day pilot study involving ten individuals with rheumatoid arthritis and clinically observed neurological gait abnormalities demonstrated measurable improvements in gait biomechanics. The Force Symmetry Index (FSI), calculated using the Robinson symmetry metric, decreased from an average of 0.9691 to 0.2019, corresponding to a 79.26% average reduction in inter-limb load asymmetry. Concurrently, sEMG measurements showed a substantial increase in neuromuscular activation (ΔEMG = 4.28), with statistical analysis confirming a significant improvement across participants (paired t-test: t(9) = 13.58, p < 0.001). To model rehabilitation trajectories, a nonlinear predictive framework based on Gaussian Process Regression achieved high predictive accuracy (R[2] ≈ 0.9, with a mean RMSE of 0.0385), while providing uncertainty-aware trend estimation. Validation using an independent amyotrophic lateral sclerosis gait dataset further demonstrated the transferability of the analytical pipeline. These results highlight the potential of sensor-enabled assistive walkers as scalable platforms for quantitative gait rehabilitation, adaptive feedback, and long-term mobility monitoring.}, }
@article {pmid42076823, year = {2026}, author = {Petrozziello, T and Mizerak, E and Krishnamoorthy, A and Donahue, RA and Castillo Torres, AL and Monsanto, RZB and Hammerschlag, BL and Webster, HA and Fillingham, B and Kivisäkk, P and Timmons, J and Fox, K and Arnold, SE and Cohen, J and Klee, J and Paganoni, S and Cudkowicz, ME and Chibnik, LB and Berry, JD and Sadri-Vakili, G}, title = {Phosphorylated Tau at Threonine 181 Is Elevated in Amyotrophic Lateral Sclerosis Plasma.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70266}, pmid = {42076823}, issn = {1097-4598}, support = {//Linda and Mike Mussallem Foundation/ ; //Andre Family/ ; P30AG062421//National Institute of Aging (NIA)/ ; }, abstract = {INTRODUCTION/AIMS: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) remain limited. Although previous studies have shown altered cerebrospinal fluid (CSF) tau measures in ALS, the clinical relevance of plasma tau species as biomarkers remains unclear. Here, we sought to determine whether total tau, tau phosphorylated at T181 (pTau-T181), and their ratio are altered in ALS and whether these measures correlate with disease progression.<br><br>METHODS: Plasma samples were obtained from two independent cohorts from the Northeast ALS Consortium (NEALS) Biofluid Repository (cohort 1: n&#x2009;=&#x2009;76 ALS and n&#x2009;=&#x2009;52 healthy controls [HC]; cohort 2: n&#x2009;=&#x2009;98 ALS and n&#x2009;=&#x2009;90 HC). Cohort 1 (mean age ALS 61.8&#x2009;years; 63% male) included longitudinal samples; cohort 2 (mean age ALS 45.8&#x2009;years; 51% male) was cross-sectional. Tau measures were quantified using Quanterix Simoa (cohort 1) and Meso Scale Discovery (MSD) (cohort 2) platforms.<br><br>RESULTS: In cohort 1, total tau was lower in ALS versus HC (0.88 vs. 1.49&#x2009;pg/mL), whereas pTau-T181 (30.29 vs. 12.97&#x2009;pg/mL) and pTau-T181:tau ratio (52.07 vs. 13.18&#x2009;pg/mL) were higher. In cohort 2, total tau (40.07 vs. 25.85&#x2009;pg/mL), pTau-T181 (6.77 vs. 2.18&#x2009;pg/mL), and their ratio (0.37 vs. 0.098&#x2009;pg/mL) were elevated in ALS. Plasma measures in cohort 1 did not correlate with decline on the revised ALS Functional Rating Scale (ALSFRS-R). Brain-derived tau (BD-tau) was elevated in ALS (10.07 vs. 5.65&#x2009;pg/mL) in a subset of samples from cohort 1.<br><br>DISCUSSION: Collectively, plasma pTau-T181 levels are consistently elevated in ALS, supporting future studies to define its potential utility as an ALS biomarker.}, }
@article {pmid42077117, year = {2026}, author = {Chambers, KL}, title = {Enhancement, Autonomy, and the Limits of Beneficence.}, journal = {Bioethics}, volume = {}, number = {}, pages = {}, doi = {10.1111/bioe.70113}, pmid = {42077117}, issn = {1467-8519}, abstract = {Procreative enhancement involves someone making a choice about what genetic trait(s) another person will have. Such control over the body (and mind) of another person, even if done for the recipient's benefit, threatens to overstep the moral boundary between persons. The use of genetic interventions to "enhance" one's offspring without their consent may violate that person's future autonomy. Schaefer, Kahane, and Savulescu argue, however, that the value of autonomy supports at least one class of procreative enhancements: those aimed at enhancing a future person's autonomy by improving their cognitive functioning. I argue that Schaefer et al.'s case for enhancing autonomy rests on a mistaken view about how autonomy bears on our moral obligations. They collapse the value of autonomy into the value of beneficence, or the value of promoting a person's well-being. I will show that while so-called autonomy enhancements may promote a future person's well-being, they cannot make a person more autonomous. Attempts to enhance a future person's autonomy by way of genetic modification instead constitute a violation of that person's autonomy.}, }
@article {pmid42079033, year = {2026}, author = {Tsai, AC}, title = {What breaks when federal commitments break: comment on Beccia et al.}, journal = {SSM. Mental health}, volume = {9}, number = {}, pages = {}, pmid = {42079033}, issn = {2666-5603}, abstract = {In this commentary on Beccia et al.'s mapping of the 2025 first-wave mental health and substance use-related federal grant terminations, I interpret what happened as a stress test of the U.S. postwar research funding compact. The damage was amplified because the U.S. scientific research enterprise is structurally fragile, characterized by debt-financed institutional growth premised on ever-rising federal budgets; heavy reliance on "soft money" salaries; an oversupplied trainee pipeline; and hypercompetitive, winner-take-all funding dynamics. The damage from the grant terminations has radiated, or will radiate, outward in concentric circles of harm: disrupted research studies and abandoned participants; layoffs, fear, and self-censorship among scientists; scarring of early-career trajectories; institutional and regional capacity loss; and future downstream harms to population mental health and public trust. Even if these grant awards are reinstated, political control, administrative delays and payline squeezes, and indirect cost pressures can and likely will operate as durable de facto defunding.}, }
@article {pmid42079104, year = {2026}, author = {Kaye, J and Amirani, N and Chan, &#xda; and Al Bistami, N and Faghihmonzavi, Z and Ahirwar, M and Thomas, R and Robinson, W and Vertudes, E and Raja, K and Barch, M and Linsley, D and Jovicic, A and Finkbeiner, S}, title = {Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.22.719920}, pmid = {42079104}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive, rapid deterioration of motor neurons (MNs). Rare mutations in a handful of genes are sufficient to cause ALS; however, 90% of ALS cases are not linked to these genes and their underlying cause remains unknown. Abnormal subcellular distribution, structure or aggregation of the TDP-43 protein are nearly universal hallmarks of the disease, suggesting a shared molecular mechanism across both genetic and sporadic ALS (sALS). However, the heterogeneity of the ALS clinical syndrome suggests that the underlying mechanisms culminating in ALS and TDP-43 pathology may partly differ among individuals and may need to be understood to develop successful therapies that target subgroups of patients. Here, we harnessed the power of machine learning (ML) to begin to decode, in a systematic and unbiased fashion, the cellular signatures of ALS. We used high-content imaging of live, human iPSC-derived motor neurons (iMNs) from ALS patients or gene-edited and gene-corrected TDP-43 mutant lines to train shallow connected ML algorithms (SMLs) and deep convolutional neural networks (DNNs). Our models identified and distinguished mutant and control iMNs with moderately high accuracy. We then used explainability methods to uncover the discriminating cellular signals and found that the strongest ones mapped to the nuclear area, suggesting underlying alterations within the nucleus. We validated this finding by revealing that TDP-43 mutant iMNs display alterations in nucleocytoplasmic shuttling and cellular integrity. Further, a time-interaction ML model uncovered dynamic morphological transitions preceding degeneration, offering a window into early pathogenic events as well as neurodevelopmental changes. Extending our ML pipeline to iMNs with mutations in the ALS gene C9orf72 or derived from sALS revealed both overlapping and distinguishable signatures, suggesting shared yet distinct mechanistic pathways. Together, these findings establish ML-driven phenotypic profiling as a powerful approach to stratify people with ALS, help disentangle the molecular heterogeneity of ALS and produce a more holistic phenotypic definition in cell-based models, and ultimately find causes and treatments. This strategy offers a scalable and innovative paradigm for uncovering early disease mechanisms not only in ALS but potentially across a spectrum of neurodegenerative and sporadic disorders.}, }
@article {pmid42079349, year = {2026}, author = {Hoshino, A and Nagata, S and Asakura, T and Tamura, H}, title = {Support-receiving networks and the isolation in schizophrenia: A preliminary study toward recovery-oriented occupational therapy.}, journal = {The British journal of occupational therapy}, volume = {89}, number = {5}, pages = {354-363}, pmid = {42079349}, issn = {1477-6006}, abstract = {INTRODUCTION: Social isolation is a major barrier to recovery for individuals with schizophrenia. Although prior studies examined social networks in relation to symptom severity and quality of life, few have integrated structural and relational dimensions of connectedness within a framework relevant to occupational therapy. This study investigated factors associated with social networks among individuals with schizophrenia in Japan, using Wang et al.'s conceptual framework and social network analysis.<br><br>METHOD: A cross-sectional study was conducted with 31 individuals attending a psychiatric day-service center. Social isolation was assessed across four domains: network quantity, network quality, emotional appraisal (mattering and loneliness), and resource appraisal (helping and being helped). Multiple regression analysis identified factors related to network size, with significance set at p&#x2009;<&#x2009;0.05.<br><br>RESULTS: Participants had extremely small networks, averaging fewer than one close contact. Regression analysis showed that only being helped by others was significantly associated with larger network size (&#x3b2;&#x2009;=&#x2009;0.214, p&#x2009;<&#x2009;0.01). Loneliness, helping others, and mattering were not significant predictors.<br><br>CONCLUSION: Individuals with schizophrenia may experience profound social isolation, with networks limited to relationships where they are recipients of help. Occupational therapy should promote opportunities for reciprocal, empowering connections to support recovery and community integration.}, }
@article {pmid42080410, year = {2026}, author = {Kasper, E and Lehto, A and Nordmann, N and Peters, O and Hellmann, J and Priller, J and Spruth, EJ and Petzold, GC and Vogt, I and Weydt, P and Bernsen, S and Dinter, E and Falkenburger, B and Günther, R and Düzel, E and Glanz, W and Synofzik, M and Beichert, L and Spottke, A and Wagner, M and Brosseron, F and Schmid, MC and Schneider, A and Teipel, S and Prudlo, J and Hermann, A}, title = {Impact of Plasma p-tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70423}, pmid = {42080410}, issn = {2328-9503}, abstract = {Phosphorylated tau181 (p-tau181), an Alzheimer's disease biomarker, was recently evaluated in amyotrophic lateral sclerosis (ALS). We investigated plasma p-tau181 in 202 ALS/ALS-FTD patients and 94 healthy controls, assessing cognitive performance, motor function, and longitudinal dynamics. Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable. Neither marker correlated with cognitive performance, and only NfL was associated with disease severity and progression. Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement. The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.}, }
@article {pmid42064053, year = {2026}, author = {Chen, Y and Kang, Q and Nie, D and Zhang, P and Zhou, X and Li, Z and Hu, Y and Xin, T and Gong, H}, title = {Combination of albumin-lymphocyte score and skeletal muscle index predicts prognosis of patients with ovarian cancer after primary debulking surgery.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1781291}, pmid = {42064053}, issn = {1664-3224}, mesh = {Humans ; Female ; Middle Aged ; *Ovarian Neoplasms/surgery/mortality/blood/pathology/diagnosis ; Prognosis ; *Cytoreduction Surgical Procedures ; Retrospective Studies ; *Muscle, Skeletal/pathology ; Aged ; Adult ; *Lymphocytes ; Lymphocyte Count ; }, abstract = {PURPOSE: Accumulating evidence underscores the significance of inflammation and nutrition in tumor progression. Although low albumin-lymphocyte score (ALS) and skeletal muscle index (SMI) are known to be associated with negative outcomes in patients with ovarian cancer (OC) undergoing primary debulking surgery, the usefulness for predicting prognosis remains unclear. We aimed to assess the relevant preoperative prognostic variables and their combined impact on patients with OC.<br><br>METHODS: This retrospective study included 347 patients with primary OC from multiple medical centers. The patients were divided into discovery (237 patients) and validation (110 patients) cohorts. Serological tests and plain computed tomography were performed to quantify the ALS and SMI. We investigated the preoperative prognostic ability of a unique index based on a combination of ALS and SMI, the CAS grade.<br><br>RESULTS: Patients with a lower ALS and a higher SMI showed improved overall survival (OS) and recurrence-free survival (RFS). Upon stratification by CAS grade, grade 1 patients demonstrated the highest body mass index and the most favorable survival prognosis, whereas grade 3 patients demonstrated the poorest OS and RFS. The independent variables for OS and RFS included residual disease and elevated CAS grade. These findings were validated in an independent cohort study.<br><br>CONCLUSION: The CAS grade, a combination of ALS and SMI, is a meaningful and independent predictor of prognosis in patients with OC.}, }
@article {pmid42064717, year = {2026}, author = {Chikamura, K and Yoshida, W and Tsurumi, S and Kawahara, J}, title = {Rightward shift of self-face representation.}, journal = {i-Perception}, volume = {17}, number = {2}, pages = {20416695261444892}, pmid = {42064717}, issn = {2041-6695}, abstract = {Self-face representation refers to an internal image of one's own face that does not necessarily match its physical properties. A previous study showed that remembered facial features located centrally or on the right side, such as the nose and right eye, tend to shift rightward. However, this rightward bias may result from using the right index finger to report locations. The present study examined whether the bias would occur when participants used the left index finger, following Mora et al.'s procedure in which participants, with their eyes closed, pointed to locations on a transparent acrylic board as if the designated facial features were projected in parallel in front of the board. Twenty-eight participants pointed to designated facial features using either their right or left index finger. The reported locations were recorded digitally and compared with the actual feature locations. When using the right finger, a rightward bias appeared for all central and right-side facial features. When using the left finger, all left-side facial features shifted leftward, indicating a leftward bias. Importantly, the rightward bias remained for all right-side facial features. These results suggest that the bias reflects both a general tendency toward rightward shifting and an artifact related to the side of the reporting finger.}, }
@article {pmid42065104, year = {2025}, author = {Doherty, AJ and Howarth, JL}, title = {The Simplified BrainTower and Pipe Cleaners: Model Building as a Learning Tool in Neuroscience.}, journal = {Journal of undergraduate neuroscience education : JUNE : a publication of FUN, Faculty for Undergraduate Neuroscience}, volume = {24}, number = {1}, pages = {27-37}, pmid = {42065104}, issn = {1544-2896}, abstract = {Models have a long history of use in helping students to understand the three-dimensional organisation of biological structures. This is particularly true of neuroanatomical teaching where it is often difficult to distinguish grey and white matter in the fixed prosections often used in dissection rooms. A model system designed to help medical students understand the anatomy of the ascending and descending white matter tracts through the brain and spinal cord had the opposite effect: it made the task of learning these tracts more difficult. The model was complex and difficult for students to engage with. The aim of this study was to introduce a simplified version of this modelling system that was interactive and intuitive, to enable students to build a model in a single workshop session and to assess how the modeling activity impacted on students' learning. Students were asked to build a model of either the anterolateral/spinothalamic tracts (ALS), the dorsal column/medial lemniscus tract (DCML) or the corticospinal tracts (CST) using pipe-cleaners to represent the route of the pathway, including the number of neurons. We found that students were easily able to build a representation of one of these tracts and that they could answer questions on the structure and function of the tract they built significantly better than similar questions related to the other tracts. This enhancement in knowledge was maintained through to end of unit exams eleven weeks after the modelling activity, demonstrating that actively building a model contributes to deep rather than superficial learning.}, }
@article {pmid42067481, year = {2026}, author = {Adhyapak, SU and Mishra, P and Basavaraj, M}, title = {Comment on "Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing".}, journal = {Journal of the neurological sciences}, volume = {}, number = {}, pages = {125886}, doi = {10.1016/j.jns.2026.125886}, pmid = {42067481}, issn = {1878-5883}, }
@article {pmid42067845, year = {2026}, author = {Sawada, J and Nakayama, Y and Shimatani, K and Matsuda, C and Haraguchi, M and Itagaki, Y and Bokuda, K and Hayashi, K and Morishima, R and Shinba, T and Fukui, S and Shimizu, T}, title = {Cluster analysis of heart rate variability reveals subgroups with preserved and early-impaired autonomic regulation in amyotrophic lateral sclerosis.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-04901-w}, pmid = {42067845}, issn = {1471-2377}, support = {Grant-in-Aid for Scientific Research [B] 22H03398 and 23K24656//Japan Society for the Promotion of Science/ ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) occasionally exhibit autonomic nervous system dysregulation. We examined whether autonomic regulation differed across patients with ALS with varying severity and progression.<br><br>METHODS: A total of 45 patients with ALS were enrolled and classified into three subgroups using cluster analysis. Heart rate variability was assessed using the maximum entropy method. The low-frequency (LF) and high-frequency (HF) components, LF/HF ratio (LF/HF), and heart rate (HR) were measured. Temporal changes in each parameter during rest, mental tasks, and post-task rest were evaluated. The values for all patients and subgroups were compared with those of 11 healthy control subjects. Between-group differences were evaluated at rest and using the Task/Rest and After/Task ratios, and within-group changes across the three phases were also analyzed, with non-parametric statistical tests applied.<br><br>RESULTS: Cluster analysis classified the patients into three groups: "Group 1: early-preserved group", "Group 2: late-preserved group", and "Group 3: late-impaired group". Overall, the patients showed lower HF and higher LF/HF at rest than the controls, indicating parasympathetic hypoactivity and sympathetic predominance. Abnormalities were more prominent in Groups 1 and 3 than in Group 2. The former two groups showed blunted HF, LF/HF and HR responses during the tasks. The late-preserved group (Group 2) showed no difference in the Task/Rest ratios of HF, LF/HF and HR compared with the controls.<br><br>CONCLUSION: Autonomic regulatory functions differ depending on the severity and progression of ALS. The presence of HRV abnormalities in early-preserved patients suggests that autonomic dysregulation in ALS may not be limited to a late-stage secondary complication but may also be present earlier stages. Recognizing HRV abnormalities from early stages may help identify patients at risk of faster progression. Future longitudinal studies in larger cohorts are needed to establish the pathophysiological significance of HRV abnormalities.}, }
@article {pmid42068122, year = {2026}, author = {Spataro, E}, title = {Invited Commentary on: Brownlee et al.'s "Effect of an Enhanced Recovery after Surgery (ERAS) Protocol in Post-Operative Pain and Opioid Consumption after Rhinoplasty".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614261447768}, doi = {10.1177/26893614261447768}, pmid = {42068122}, issn = {2689-3622}, }
@article {pmid42068244, year = {2026}, author = {Chevet, E}, title = {Exploring the role of phase separation in TDP-43 pathogenesis with ArtiTDP43.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70577}, pmid = {42068244}, issn = {1742-4658}, abstract = {TDP-43 is a nuclear RNA-binding protein implicated in neurodegenerative diseases such as ALS and FTLD, where it becomes mislocalized to the cytoplasm and forms pathological aggregates. These aggregates are thought to arise through liquid-liquid phase separation, a process by which proteins form dynamic, membrane-less condensates that can mature into solid structures. To better understand this process, the authors developed ArtiTDP43, a chemically controllable system that enables reversible formation of TDP-43 condensates in cells. Using this tool, they showed that TDP-43 forms different structures depending on its concentration: small liquid-like puncta, intermediate condensates associated with stress granules, and large solid aggregates resembling disease pathology. These transitions are reversible at early stages but become irreversible as aggregates solidify. The study by Combe et al. demonstrates that increasing cytoplasmic TDP-43 concentration drives a liquid-to-solid transition, while oxidative stress accelerates this process and promotes pathological features such as phosphorylation and p62 recruitment. Importantly, formation of cytoplasmic aggregates leads to depletion of nuclear TDP-43 and increased cell death, indicating toxicity. Overall, the findings establish a mechanistic link between phase separation, aggregation, and cytotoxicity in TDP-43 proteinopathies. ArtiTDP43 provides a powerful tool to study early disease mechanisms and explore therapeutic strategies aimed at preventing pathological aggregation or maintaining normal TDP-43 dynamics.}, }
@article {pmid42063613, year = {2025}, author = {van der Putten, TAW and Verhees, JJF and Koma, Z and van Hoof, PH and Heijkers, D and de Boer, WF and Esser, HJ and Hoogerwerf, G and Lemmers, P}, title = {Insights into the fine-scale habitat use of Eurasian Water Shrew (Neomys fodiens) using radio tracking and LiDAR.}, journal = {Journal of mammalogy}, volume = {106}, number = {3}, pages = {549-560}, pmid = {42063613}, issn = {0022-2372}, abstract = {The Eurasian Water Shrew (Neomys fodiens) is one of the largest shrew (Soricidae) species in Eurasia. In Western Europe, this semiaquatic species often occurs in riparian and marshland habitats that have a high degree of naturalness, but is being threatened by habitat degradation and other anthropogenic factors. The species mostly occurs in low abundance and is elusive. Therefore, understanding its habitat use is challenging, yet imperative for establishing species-specific conservation measures. Technological developments in radio tracking and high-resolution remote sensing such as Light Detection And Ranging (LiDAR) now enable the quantification of ecological niches and provide insight into habitat requirements for a species. Here, we combined radio tracking and LiDAR to quantify habitat use by Eurasian water shrews. Alongside a lowland brook in the Netherlands, 20 individuals were tracked between September and October 2022, resulting in 332 unique locations of Eurasian water shrews. For each of these locations, 11 LiDAR-derived variables were calculated and subsequently analyzed in a species distribution model (SDM). The SDM yielded a model with a high accuracy (predictive performance AUC = 0.93). The variable of highest importance was dense and relatively short vegetation <1 m, which had a positive effect on Eurasian Water Shrew occurrence. Open areas seem to be avoided. Vegetation of heights between 1 and 15 m were found to be less important for the occurrence. The probability of occurrence decreased with increasing distance to water, indicating that the species occurs in the proximity of water, although vegetation-related variables were more important. The obtained detailed knowledge of fine-scale habitat use can be used to improve habitat conservation, restoration, and management for the species. Combining radiotelemetry data with LiDAR data is a promising approach to identifying species-habitat relationships of elusive species such as the Eurasian Water Shrew.}, }
@article {pmid42060866, year = {2026}, author = {Kiernan, MC and Genge, A and Grosskreutz, J and Kuwabara, S and Lillo, P and Rosenfeld, J and Cummings, C}, title = {The World Federation of Neurology Specialty Group in ALS/MND: toward strategic partnership and new frontiers.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2663915}, pmid = {42060866}, issn = {2167-9223}, abstract = {A memorandum of understanding was recently established between the World Federation of Neurology Specialty Group and the International Alliance of ALS/MND Associations. This new strategic partnership brings together leading clinicians and researchers with national and regional organizations dedicated to supporting ALS patients, their families, and caregivers. The purpose of partnership is to strengthen global coordination in research, education, advocacy, and clinical care for people living with MND. The agreement outlines shared priorities, including promoting equitable access to diagnosis and treatment, supporting capacity building in low- and middle-income regions, and facilitating the exchange of scientific knowledge and best practice. Both parties commit to joint initiatives such as international meetings, guideline development, clinical trials and data-sharing efforts that advance understanding of disease mechanisms and therapeutic approaches. Together, these organizations represent the scientific and human dimensions of the ALS challenge. Through partnership, the WFN Specialty Group and the International Alliance aim to accelerate progress toward improved outcomes and, ultimately, effective treatments for MND worldwide.}, }
@article {pmid42060880, year = {2026}, author = {, }, title = {Retirement of Guidelines: Practice Parameter Update: The Care of the Patient With Amyotrophic Lateral Sclerosis: Drug, Nutritional, and Respiratory Therapies (An Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {106}, number = {10}, pages = {e218083}, doi = {10.1212/WNL.0000000000218083}, pmid = {42060880}, issn = {1526-632X}, }
@article {pmid42060881, year = {2026}, author = {Nolano, M and Provitera, V and Caporaso, G and Areniello, AR and Borreca, I and Stancanelli, A and Senerchia, G and Iuzzolino, VV and Fasolino, I and Vitale, F and Ciccarelli, G and Dell'Aversana, D and Masciarelli, F and Tozza, S and Iodice, R and Santoro, L and Manganelli, F and Dubbioso, R}, title = {Phosphorylated TDP-43 Pathology in Skin and Muscle Tissue of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {106}, number = {10}, pages = {e214940}, doi = {10.1212/WNL.0000000000214940}, pmid = {42060881}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Female ; Middle Aged ; Male ; *DNA-Binding Proteins/metabolism ; Aged ; Cross-Sectional Studies ; *Skin/pathology/metabolism ; Case-Control Studies ; Phosphorylation ; *Tongue/pathology/metabolism ; Biomarkers/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVES: Phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathologic hallmark of amyotrophic lateral sclerosis (ALS), yet no peripheral premortem biomarker is available. We evaluated pTDP-43 distribution in skin and tongue tissues and its association with ALS and clinical stage.<br><br>METHODS: This cross-sectional case-control study included patients with ALS meeting revised El Escorial criteria who underwent skin and tongue biopsies. Control groups included healthy controls (HC), patients with non-ALS neuropathy or neuronopathy (NANN), and patients with burning mouth syndrome (BMS). pTDP-43 was quantified in Meissner corpuscles (MC) and keratinocytes using standardized immunofluorescence. In MC, PGP (%), pTDP-43 (%), and the pTDP-43/PGP ratio were assessed. A subset of skin samples underwent western blot analysis. ALS severity was classified using King's staging system. Diagnostic performance was evaluated using receiver operating characteristic analysis.<br><br>RESULTS: Fifty patients with ALS were included, median age 66.5 years, 36% female. Control groups included 20 HC, median age 60 years, 20% female, and 20 patients with NANN, median age 60 years, 50% female. Tongue biopsy was performed in 10 patients with ALS and 10 patients with BMS. pTDP-43 deposits were detected in ALS across epidermis and dermis structures, whereas they were almost absent in HC and low in NANN. Accordingly, MC pTDP-43% differed across groups (H = 53.30; p < 0.001), with median values of 0.35 (interquartile range [IQR] 0.39) in ALS, 0.04 (IQR 0.03) in NANN, and 0.00 in HC. The pTDP-43/PGP ratio increased with clinical stage at subject level (Z = 2.20, p = 0.028) and single-corpuscle level (H = 21.72, p < 0.001). Western blot showed higher pTDP-43/GAPDH ratio in ALS skin than in HC (median 3.45, IQR 7.23 vs 1.30, IQR 0.80; p = 0.007). Nonphosphorylated TDP-43 did not differ across groups. In keratinocytes, pTDP-43 was higher in ALS than in NANN and HC (median 0.047, IQR 0.023; 0.019, IQR 0.049; and 0.005, IQR 0.047; p < 0.001). Combined cutaneous pTDP-43 measures discriminated ALS from HC (area under the curve [AUC] 0.94, p < 0.001) and from NANN (AUC 0.90, p < 0.001). Tongue biopsies showed pTDP-43 aggregates in intramuscular nerves, denervated endplates, and muscle fibers.<br><br>DISCUSSION: Peripheral pTDP-43 deposition distinguishes ALS from controls and reflects disease stage, supporting its potential role as a biomarker of ALS and disease severity. Larger and longitudinal studies are required for validation.}, }
@article {pmid42061283, year = {2026}, author = {Banerjee, S and Panjwani, D and Singh, S and Singh, TG}, title = {TGR5 and FXR receptors in motor degeneration: Molecular mechanism, crosstalk pathways and therapeutic prospects.}, journal = {Journal of neuroimmunology}, volume = {417}, number = {}, pages = {578942}, doi = {10.1016/j.jneuroim.2026.578942}, pmid = {42061283}, issn = {1872-8421}, abstract = {Motor neuron degeneration in disorders such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Parkinson's disease is increasingly recognized as a consequence of disrupted metabolic, mitochondrial, and inflammatory balance. There is emerging data that bile acid receptors - Takeda G-protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR) are key regulators that combine systemic metabolism with neuronal survival. These receptors modulate the mitochondrial biogenesis, oxidative stress responses, and glial inflammatory signaling and coordinate gut-liver-brain crosstalk. Their malfunction leads to an unaffected energy metabolism, increased reactive oxygen species, and neuroinflammation, thereby accelerating the death of motor neurons. Their dysfunction results in impaired energy metabolism increased reactive oxygen species and neuroinflammation, accelerating motor neuron death. Pharmacological activation of TGR5 and FXR improves mitochondrial integrity reduces cytokines driven toxicity and preserves neuromuscular junction stability in preclinical models. However, translational opportunities are dampened by some factors such as restriction of bioavailability of the central nervous system, receptor variation and metabolic systemic interactions. To clarify, the TGR5 -FXR signaling axis would provide a mechanistic model of how to develop metabolism-based therapeutics that can simultaneously supplement mitochondrial protection, immunologic mangling, and neuro-specific to energetic homeostasis in motor neuron disease.}, }
@article {pmid42061810, year = {2026}, author = {Arasmou-Idrovo, MS and Marín-Rodríguez, B and Gironda-Martínez, A and García, AG and León, R and Pascual-Guerra, J and Torres-Rico, M}, title = {UNEXPECTED MECHANISMS OF REPURPOSED DRUGS IN THE PATHOGENIC PATHWAYS OF NEURODEGENERATIVE DISEASES. DISCOVERING NEW NEUROPROTECTIVE THERAPIES IN CELLULAR MODELS.}, journal = {Neuropharmacology}, volume = {}, number = {}, pages = {110994}, doi = {10.1016/j.neuropharm.2026.110994}, pmid = {42061810}, issn = {1873-7064}, abstract = {Advances in biomedicine have increased life expectancy, leading to a growing prevalence of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease, alongside disorders of genetic or environmental origin including multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Despite their diverse etiologies, these conditions share convergent pathogenic mechanisms-calcium overload, neuroinflammation, and oxidative stress-that drive neuronal apoptosis and progressive neurodegeneration. Developing therapies that effectively target these interconnected pathways remains a major challenge. Here, we applied a drug-repurposing pipeline integrating computational chemistry, calcium channel affinity prediction, and in vitro validation in SH-SY5Y and HEK293 cells. Eight clinically approved CNS drugs were screened for activity against Caᵥ1, Orai1, and P2X7 channels, and subsequently evaluated in neuroprotection assays. Several compounds demonstrated significant efficacy, with chlorpromazine showing broad-spectrum activity (neuroprotection, Caᵥ1.2 and P2X7 antagonism, anti-inflammatory effects), trimipramine emerging as a potent antioxidant, and vilazodone displaying synergistic neuroprotection in combination with procyclidine. These findings reveal multi-target pharmacological profiles in well-tolerated drugs not currently used for neurodegenerative indications. By highlighting both individual and combinatorial strategies, this work provides a foundation for translational studies aimed at repurposing approved agents for complex neurological disorders, with particular relevance to Parkinson's disease.}, }
@article {pmid42062527, year = {2026}, author = {Azzolino, D and Zulueta, A and Piras, R and Mariani, P and Sideri, R and Lucchi, T and Lunetta, C}, title = {Agreement between bioimpedance-measured and calf-derived appendicular skeletal muscle mass in amyotrophic lateral sclerosis patients.}, journal = {European journal of clinical nutrition}, volume = {}, number = {}, pages = {}, pmid = {42062527}, issn = {1476-5640}, support = {Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente//Ministero della Salute (Ministry of Health, Italy)/ ; }, abstract = {BACKGROUND: Over time, amyotrophic lateral sclerosis (ALS) has been considered an accelerated model of sarcopenia. However, muscle mass is rarely assessed in ALS patients. The aim of this study was to explore the agreement between bioelectrical impedance analysis (BIA)-measured and calf circumference (CC)-derived appendicular skeletal muscle mass index (ASMMI) in ALS patients.<br><br>METHODS: Body composition was assessed using anthropometric measures and BIA. Pearson analyses were used to assess correlations and Kappa (&#x3ba;) statistics were used to evaluate agreement between BIA-measured and CC-derived ASMMI. CC predictive ability was assessed through the area under the receiver operating characteristic curve.<br><br>RESULTS: A total of 61 ALS patients were included. The CC-ASMM was highly correlated with the BIA-ASMM (r&#x2009;=&#x2009;0.830, p&#x2009;<&#x2009;0.001) and CC-ASMMI was moderately correlated with BIA-ASMMI (r&#x2009;=&#x2009;0.62, p&#x2009;<&#x2009;0.001). Low CC-derived and BIA-derived ASMMI presented a moderate degree of agreement in the overall sample (k&#x2009;=&#x2009;0.546, 95% CI 0.325-0.767) and in men (k&#x2009;=&#x2009;0.432, 95% CI 0.056-0.809), while a substantial agreement was observed in women (k&#x2009;=&#x2009;0.613, 95% CI 0.344-0.883). The optimal cut-off values for CC in identifying low ASMMI from the ROC analysis, were 34&#x2009;cm for both sexes with an area under the curve (AUC) of 0.818 for men (sensitivity 80%, specificity 78.3%) and of 0.841 (sensitivity 83.3%, specificity 72.7%) for women.<br><br>CONCLUSION: Our preliminary study showed a good predictive ability of the CC, an anthropometric parameter significantly associated with sarcopenia, in reflecting the ASMM. The best performance was found for a CC cut-off point of &#x2264;34&#x2009;cm in both sexes.}, }
@article {pmid42063547, year = {2026}, author = {Demaegd, KC and Kool, L and Baindoor, S and Donovan, PD and Su, J and Westeneng, HJ and van Eijk, RPA and Geoghegan, G and Perez Morrissey, E and Halang, L and Poesen, K and Masrori, P and Gibriel, HAY and Jirström, E and Venø, MT and Kjems, J and Hardiman, O and Veldink, JH and Kenna, K and van den Berg, LH and Van Damme, P and Prehn, JHM and van Es, MA}, title = {Small RNA sequencing identifies serum tDR-1:34-Gly-GCC tiRNA levels as a biomarker for survival in amyotrophic lateral sclerosis.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115636}, pmid = {42063547}, issn = {2589-0042}, abstract = {Survival is highly variable in amyotrophic lateral sclerosis (ALS), complicating prognosis and clinical trial design. Despite advances in biomarker development, accessible prognostic tools are limited. Small non-coding (snc) RNAs are a recently discovered biomarker class showing differential regulation across neurodegenerative diseases, including ALS. Here, we explored changes in sncRNAs over time in ALS. We performed small RNA sequencing in a discovery cohort of 116 longitudinal serum samples from ALS 40 patients collected at 3- to 4-month intervals and identified tRNA-derived stress-induced RNA (tiRNA) tDR-1:34-Gly-GCC as the top sncRNA to increase over time. The finding was validated using TaqMan PCR and replicated in an independent cohort of 35 patients. Both univariate and joint model analyses showed that higher tDR-1:34-Gly-GCC levels correlated with shorter survival. Given that the translation of mRNAs and stress-induced translation inhibition are dysregulated in ALS and linked to familial ALS genes, combined with these findings, serum tDR-1:34-Gly-GCC tiRNA levels hold potential as a prognostic biomarker and outcome measure in clinical trials.}, }
@article {pmid42054734, year = {2026}, author = {Hussein, MA and Saad, H and Eltabaa, A and Abdelnaser, A and Abdelrazek, A}, title = {Can PEEK cage replace bone graft in calcaneal lengthening osteotomy in treatment of pediatric pes planovalgus?.}, journal = {Foot (Edinburgh, Scotland)}, volume = {67}, number = {}, pages = {102226}, doi = {10.1016/j.foot.2026.102226}, pmid = {42054734}, issn = {1532-2963}, abstract = {BACKGROUND: Flatfoot deformity can cause significant functional impairment, often necessitating surgical correction. Calcaneal lengthening osteotomy is a well-established procedure; however, traditional bone grafts have limitations such as donor site morbidity and nonunion risk. Polyether ether ketone (PEEK) cages offer a novel alternative, potentially enhancing surgical outcomes through improved biomechanical properties and bone incorporation.<br><br>PURPOSE: To evaluate the efficacy of PEEK cages in lateral calcaneal lengthening osteotomy in adolescent patients.<br><br>METHODS: This prospective study included 41 adolescent patients with symptomatic flatfoot undergoing lateral calcaneal lengthening osteotomy using PEEK cages. Radiographic parameters, including calcaneal inclination angle (CIA) and talo-first metatarsal angles (TFA), were assessed preoperatively and postoperatively. Functional incorporation was evaluated using Worth et al.'s classification. Patients were followed for at least one year.<br><br>RESULTS: Postoperative radiographic assessments showed significant improvement. The median CIA increased from 3&#xb0; (0&#xb0;-7&#xb0;) to 17&#xb0; (12&#xb0;-20&#xb0;) (P&#x202f;<&#x202f;0.001). TFA lateral decreased from 20&#xb0; (11&#xb0;-26&#xb0;) to 2&#xb0; (0&#xb0;-8&#xb0;) (P&#x202f;<&#x202f;0.001), and TFA anteroposterior reduced from 22&#xb0; (14&#xb0;-28&#xb0;) to 3&#xb0; (0&#xb0;-9&#xb0;) (P&#x202f;<&#x202f;0.001). At one-year follow-up, 92.7% of 41 patients demonstrated satisfactory incorporation (Grades III-IV). Complications included cage subsidence (7.3%) and pseudoarthrosis (2.4%).<br><br>CONCLUSIONS: PEEK cages in calcaneal lengthening osteotomy demonstrated excellent radiographic and clinical outcomes, with high incorporation rates and minimal complications.}, }
@article {pmid42054746, year = {2026}, author = {Biscetti, L and Gambuzza, ME and Princiotto, M and Sabbatinelli, J and Olivieri, F and Fiorillo, M and Chinigò, C and Muglia, L and Cozza, A and Beccacece, A and Gembillo, G and Bruschetta, G and Villalta Savedra, E and Lattanzio, F and Corsonello, A and Soraci, L}, title = {From necroptosis to neuroinflammation: Unraveling mechanisms and therapeutic targets in age-related cognitive decline.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {199}, number = {}, pages = {119326}, doi = {10.1016/j.biopha.2026.119326}, pmid = {42054746}, issn = {1950-6007}, abstract = {Aging is the major risk factor for several chronic conditions, including cognitive decline and dementia. It is accompanied by profound immune alterations characterized by a progressive decline in immune competence, a process known as immunosenescence. The resulting dysregulation of immune function leads to the overproduction of proinflammatory cytokines and fuels a persistent, low-grade inflammatory state termed inflammaging. This chronic inflammation contributes to dysfunction across the central and peripheral nervous systems, promoting neuronal damage and accelerating neurodegenerative processes such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other age-related cognitive disorders. Within this framework, prolonged activation of inflammatory pathways can trigger regulated forms of cell death. Among these, necroptosis has recently emerged as a potential mediator linking inflammaging to neurodegeneration. Its core molecular effectors, including the receptor-interacting protein kinases RIPK1 and RIPK3 and the mixed-lineage kinase domain-like protein (MLKL), are increasingly expressed in aged neural tissues, promoting the release of damage-associated molecular patterns (DAMPs) that amplify glial activation, oxidative stress, and blood-brain barrier disruption. Growing evidence suggests that necroptotic signaling may be upregulated in the aging brain and in neurodegenerative disorders, where it could contribute to neuronal loss and cognitive impairment. This review discusses the potential role of necroptosis in the continuum between inflammation and neurodegeneration, highlighting emerging diagnostic and therapeutic perspectives. Epigenetic and circulating biomarkers, such as phosphorylated MLKL and specific microRNAs, may support early detection, while pharmacological and nutraceutical strategies targeting necroptosis show promising neuroprotective effects in preclinical studies.}, }
@article {pmid42055109, year = {2026}, author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H}, title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.04.024}, pmid = {42055109}, issn = {1873-7544}, abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.}, }
@article {pmid42055290, year = {2026}, author = {Gaillard, SL and Meisenheimer, J and Hou, J and Dellavalle, RP}, title = {Response to Jin et al.'s "Global, regional, and National burden of pruritus: A comprehensive study from the Global Burden of Disease, 1992-2021.".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.116}, pmid = {42055290}, issn = {1097-6787}, }
@article {pmid42055490, year = {2026}, author = {Banerjee, C and Singh, RK and Mehan, S}, title = {Raloxifene Beyond Osteoporosis: Unlocking Neurorestoration Through Remyelination, Inflammatory Regulation, and Neuroimmune Modulation in CNS Pathologies.}, journal = {International immunopharmacology}, volume = {181}, number = {}, pages = {116668}, doi = {10.1016/j.intimp.2026.116668}, pmid = {42055490}, issn = {1878-1705}, abstract = {Raloxifene, a selective estrogen receptor modulator (SERM), has emerged as a promising candidate for repurposing in neurodegenerative and neuropsychiatric disorders. Traditionally approved for osteoporosis and breast cancer prevention, its tissue-selective estrogen receptor modulation underpins its potential therapeutic applications. This review critically examines the pharmacological, preclinical, and clinical evidence supporting raloxifene's neuroprotective and neuropsychiatric effects, as well as its mechanisms of action, safety profile, and clinical limitations. Raloxifene exerts neuroprotective effects by targeting estrogen receptors, including ERα, ERβ, and GPER, modulating genomic and non-genomic pathways. These pathways regulate oxidative stress, mitochondrial stability, neuroinflammation, and apoptosis-core features of neurological disorders such as Alzheimer's (AD), Parkinson's (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Preclinical studies demonstrate raloxifene's ability to reduce amyloid-β aggregation in AD, protect dopaminergic neurons in PD, mitigate demyelination in MS, and decrease protein aggregation in ALS. Additionally, raloxifene exhibits positive effects on memory, attention, and negative symptoms in schizophrenia, alongside antidepressant and anxiolytic properties. Although promising, raloxifene's clinical translation faces challenges. Existing trials are limited by small sample sizes, heterogeneous designs, and a lack of long-term data. Most studies focus on postmenopausal women, leaving gaps regarding effects in men, premenopausal women, and younger populations. Furthermore, discrepancies between preclinical and clinical dosing complicate its therapeutic optimization. Future research should explore sex-specific effects, optimize CNS-targeted dosing strategies, and employ biomarkers for neuroprotection and inflammation. Long-term trials are essential to evaluate its disease-modifying potential. Raloxifene represents a promising repurposing candidate for CNS disorders, however, its therapeutic role remains to be established through robust clinical validation.}, }
@article {pmid42055632, year = {2026}, author = {Alhadidy, MM and Hinton, TV and Ernst, KN and Yang, Y}, title = {Amyloid extraction from neurodegenerative disease tissues for structural studies.}, journal = {Methods in enzymology}, volume = {729}, number = {}, pages = {1-33}, doi = {10.1016/bs.mie.2026.01.032}, pmid = {42055632}, issn = {1557-7988}, mesh = {Humans ; Cryoelectron Microscopy/methods ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Amyloid beta-Peptides/isolation &amp; purification/chemistry/ultrastructure ; alpha-Synuclein/isolation &amp; purification/chemistry ; tau Proteins/isolation &amp; purification/chemistry ; DNA-Binding Proteins/isolation &amp; purification/chemistry ; }, abstract = {Amyloid aggregates are hallmarks of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Yet structural analysis of these brain-extracted filaments requires specialized extraction protocols that minimize structural perturbation while removing tissue matrix components. This chapter focuses on amyloid-β (Aβ) filaments, the primary component of senile plaques in AD, and presents three complementary methods for isolating these filaments from human brain tissues suitable for cryo-electron microscopy analysis. These methods have enabled high-resolution structural studies reaching 2.0-3.5 Å resolution and revealed distinct conformational polymorphs in AD and other neurodegenerative diseases. Method selection depends on tissue type, target filaments, and downstream analysis requirements, with comprehensive guidance provided for optimal protocol choice and implementation. The protocols demonstrate broad applicability beyond Aβ extraction, with successful adaptations provided for tau, α-synuclein, and TDP-43 extraction. Understanding these filamentous structures extracted with minimal perturbation is essential for developing targeted therapeutics and advancing structure-based drug design approaches for AD, PD, ALS, FTD, and other neurodegenerative diseases.}, }
@article {pmid42057546, year = {2026}, author = {Jha, NK and Chauhan, P and Abomughaid, MM and Avinash, D and Almutary, AG and Lakhanpal, S and Singh, A and Sulaimani, GM and Al-Kuraishy, HM and Mohammed, HA and Misra, J and Thakur, K and Kumar, D}, title = {mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {60}, number = {2}, pages = {136-174}, doi = {10.33594/000000858}, pmid = {42057546}, issn = {1421-9778}, mesh = {*TOR Serine-Threonine Kinases/metabolism/antagonists &amp; inhibitors ; Humans ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; AMP-Activated Protein Kinases/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy ; Autophagy ; }, abstract = {Neurodegenerative diseases (NDDs) are defined by the gradual degeneration of neuronal cells, wherein the accumulation of misfolded proteins can lead to memory impairments, motor dysfunctions, and other deteriorations. Despite the widespread impact, there are currently no viable pharmaceuticals to treat these disorders. The mTOR protein is a crucial regulator of cell survival, growth, autophagy, and apoptosis. Targeted modulation of mTOR signaling holds promise for mitigating neurodegeneration in Alzheimer's, Huntington's, ALS, and Parkinson's disease. Understanding its interactions with pathways such as PI3K/Akt, AMPK, and SIRT1 is essential for developing effective therapeutics.}, }
@article {pmid42057560, year = {2026}, author = {Turner, N and Wilson, E and Faull, C and Palmer, J and Davidson, S and Turner, MR}, title = {A qualitative exploration of how people with motor neurone disease who use tracheostomy ventilation understand and experience quality of life.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/09638288.2026.2658439}, pmid = {42057560}, issn = {1464-5165}, abstract = {PURPOSE: This qualitative study aimed to increase awareness of how people with motor neurone disease (pwMND) who use tracheostomy ventilation (TV) understand quality of life.<br><br>METHODS: Semi-structured interviews were conducted with 14 pwMND (age 36-76&#x2009;years) who had used TV for 3&#x2009;months-12&#x2009;years.<br><br>RESULTS: Five themes were identified following thematic analysis. PwMND who use TV associated quality of life with: i) Extending life; ii) Improving symptom management; iii) Adapting to living with MND; iv) Finding purpose; v) Staying positive. TV extended survival and improved management of symptoms such as breathlessness and secretions. Psychological adaptation and acceptance supported pwMND to focus on remaining abilities and sources of enjoyment, whilst the pursuit of meaning and purpose sustained a positive outlook.<br><br>CONCLUSIONS: Quality of life for pwMND who use TV is multidimensional, encompassing physical, psychological, and existential domains. Findings underscore the value of a person-centred approach, recognising that pwMND can maintain a positive outlook despite significant limitations. A holistic assessment of quality of life is recommended, addressing not only physical health but also psychological and social well-being. Effective communication is required to ensure pwMND consider all implications of TV, including costs of adapting the home and demands of living with paid carers.}, }
@article {pmid42058164, year = {2026}, author = {Park, S and Song, Y}, title = {Development and implementation of a student-led, project-based, community health nursing clinical placement focused on health promotion for nursing students in Korea.}, journal = {Journal of research in nursing : JRN}, volume = {}, number = {}, pages = {17449871261427312}, pmid = {42058164}, issn = {1744-988X}, abstract = {PURPOSE: This study aimed to develop and implement a community health nursing clinical placement focused on a health promotion project for nursing students in Korea.<br><br>METHODS: This quantitative descriptive study developed and implemented a community health nursing clinical placement curriculum based on a health promotion project.<br><br>RESULTS: In this study, Jalinus et al's seven steps for project-based learning were applied: formulation of expected learning outcomes through community health promotion projects, understanding the concept of teaching materials, skill training, designing the community health promotion project theme, developing the community health promotion project proposal, executing the community health promotion project, and presenting the community health promotion project outcomes. Nursing students demonstrated positive satisfaction scores with the clinical placement.<br><br>CONCLUSIONS: The community health nursing clinical placement focused on a health promotion project demonstrated a high level of student satisfaction. The nursing students actively engaged in the clinical placement and expressed strong satisfaction with the acquisition of new knowledge and the development of competencies to assess community health issues. Locally co-designed clinical placements that reflect regional characteristics may contribute to improved student satisfaction, and there is a need to include student participation in the future design of learner-driven, problem-solving-oriented curriculum.}, }
@article {pmid42058282, year = {2026}, author = {Kalyani, A and Northall, A and Schreiber, S and Brüggemann, J and Vielhaber, S and Al Dubai, M and Bin Ramadan, A and Mattern, H and Speck, O and Reichert, C and Kuehn, E}, title = {Individualized phenotyping of functional amyotrophic lateral sclerosis pathology in sensorimotor cortex.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag127}, pmid = {42058282}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons in primary motor cortex, leading to muscle weakness, atrophy and death within a median of 3 years. Even though ALS is characterized by different disease subtypes affecting different body parts, individualized phenotyping of functional ALS pathology has so far not been achieved. We recorded 7 Tesla functional MRI data while ALS patients and matched controls moved affected and non-affected body parts in the MR scanner. We applied robust Shared Response Modelling for capturing ALS-specific shared responses for group classification, and Partial Least Squares regression for relating the latent variables to clinical subtypes and the degree of disease progression. We show that disease onset and severity can be best modelled by functional connectivity rather than local activation changes. We also show that functional disease-defining information in primary motor cortex is not the strongest in the area that is behaviourally first-affected, deviating from the behavioural phenotype of the patients. When computing the model's weight distribution of the King stage classification and projecting them back into voxel space, the highest mean weights are present in the foot and tongue/face regions. Our data highlight the importance of 7 Tesla functional MRI task-based functional connectivity measures for classifying ALS patients in addition to structural readouts and provides evidence that a 7 Tesla functional MRI can be used for identifying a disease signature of each individual ALS patient.}, }
@article {pmid42058985, year = {2026}, author = {Balusamy, S and Sivalingam, R and Rooben, S and Helen, S}, title = {RES-MND: Motor neuron disease detection using Res4Net-convolutional block attention module.}, journal = {Turkish journal of medical sciences}, volume = {56}, number = {2}, pages = {426-438}, pmid = {42058985}, issn = {1303-6165}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Magnetic Resonance Imaging/methods ; *Multimodal Imaging/methods ; *Neural Networks, Computer ; Algorithms ; }, abstract = {BACKGROUND/AIM: Motor neuron diseases (MNDs) are progressive neurological disorders that cause muscle weakness and wasting as a result of ongoing neurodegeneration. MNDs require comprehensive diagnostic approaches that integrate clinical symptoms, laboratory findings, and multimodal imaging data.<br><br>MATERIALS AND METHODS: In this study, a novel residual network for motor neuron disease detection (RES-MND) framework is proposed for detecting MNDs using multimodal imaging data. Initially, the input multimodal images, including MRI, CT, PET, and DTI, are preprocessed using adaptive dynamic histogram equalization and the total variation bilateral filter. The preprocessed multimodal images are processed through Res4Net-CBAM for feature extraction to enhance image recognition performance. A dove swarm optimization algorithm is employed to select the most relevant features from the multimodal images. Finally, the deep belief network (DBN) classifies five categories, including one control group (normal) and four MND types: ALS, PLS, PBP, and PMA.<br><br>RESULTS: The performance of the proposed RES-MND method is evaluated using standard metrics such as accuracy, precision, recall, and F1-score. According to the results, the proposed RES-MND method achieved the highest accuracy rate of 99.65%, outperforming existing methods.<br><br>CONCLUSION: The proposed DBN achieved 0.68%, 0.41%, and 0.9% higher accuracy than SNN, DNN, and CNN, respectively. The proposed RES-MND method achieved 1.08%, 2.18%, and 1.7% higher overall accuracy compared to existing methods such as miRNA, vGRF, and SVM-RFE, respectively.}, }
@article {pmid42059647, year = {2026}, author = {Ma, X and Jiang, Z and Yang, T and Zhang, H and Lu, W and Liu, K and Fan, X and Yang, G and Wu, S}, title = {Integrated multi-omics analysis reveals gut dysbiosis and altered energy metabolism in Chinese ALS patients.}, journal = {Microbiology spectrum}, volume = {}, number = {}, pages = {e0060926}, doi = {10.1128/spectrum.00609-26}, pmid = {42059647}, issn = {2165-0497}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a complex etiology. Emerging evidence implicates gut microbiota dysbiosis in ALS pathology via the gut-brain axis, yet the specific integrative profile of the gut microbiome, virome, and metabolome, particularly in Chinese patients, remains incompletely characterized. Although global diversity indices showed no significant differences, taxonomic analysis revealed distinct compositional shifts. The ALS microbiome was characterized by a significant depletion of beneficial anti-inflammatory genera, specifically Akkermansia and Faecalibacterium, and an expansion of opportunistic pathogens such as Escherichia and oral-associated taxa (e.g., Streptococcus). We also observed a specific alteration in the gut virome, with viral genera including Puppervirus and Donellivirus enriched in ALS patients. Functionally, the ALS microbiome exhibited a marked upregulation of pathways involved in L-ascorbate (vitamin C) degradation and fatty acid biosynthesis, suggesting a microbial contribution to systemic oxidative stress. Metabolomic analysis corroborated these findings, identifying 271 differentially expressed metabolites. ALS patients showed elevated levels of inflammatory lipids (e.g., LysoPC) and metabolic intermediates of the tricarboxylic acid (TCA) cycle, alongside a downregulation of antioxidants. Integrative analysis highlighted profound dysregulation in porphyrin metabolism, oxidative phosphorylation, and energy homeostasis. Our findings demonstrate that ALS is associated with a specific dysbiotic gut ecosystem characterized by the loss of protective commensals, unique viral signatures, and functional metabolic reprogramming that exacerbates host oxidative stress and energy deficits. These results provide new insights into gut-brain interactions and highlight microbial antioxidant depletion as a potential therapeutic target.IMPORTANCEAmyotrophic lateral sclerosis (ALS) is a devastating disease with no cure. While gut bacteria are known to influence brain health, we still do not understand exactly how they contribute to ALS progression. In this study, we used advanced DNA sequencing and chemical analysis to deeply examine the gut ecosystem of ALS patients. Beyond just cataloging which bacteria are present, we discovered what they are doing: the ALS microbiome actively breaks down vitamin C (a critical antioxidant) and disrupts energy metabolism. We also found a loss of protective bacteria that maintain the gut barrier. These findings are significant because they suggest that the gut microbiome in ALS patients may be actively fueling the disease by depleting the body's antioxidant reserves. This points to a new potential treatment strategy: targeting these specific bacterial functions or replenishing specific metabolites to protect motor neurons.}, }
@article {pmid42059992, year = {2026}, author = {Ghiyamihoor, F and Asemi Rad, A and Hassanifar, P and Kaur, R and Patel, JH and Kim, I and Marzban, A and Mehdizadeh, M and Levin, DB and Ghavami, S and Toncheva, A and Benali, S and Dubois, P and Balci, F and Habibi, HR and Manto, M and Marzban, H}, title = {Micro- and Nanoplastics in the Human Brain: Mechanistic Plausibility, Translational Challenges, and Links to Neurological Disease Trends.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42059992}, issn = {1559-1182}, mesh = {Humans ; *Brain/pathology/metabolism/drug effects ; *Nervous System Diseases/metabolism/pathology ; *Translational Research, Biomedical/trends ; *Microplastics/adverse effects/toxicity ; Animals ; Blood-Brain Barrier/metabolism ; }, abstract = {The exponential growth in plastic production since the mid-twentieth century has led to the pervasive presence of micro- and nanoplastics (MNPs) across ecosystems and human exposure pathways, coinciding with a rising global burden of neurological disorders. Increasing evidence demonstrates that MNPs are not confined to peripheral tissues but can accumulate even in the human brain, raising concerns about their potential contribution to neurological disease. This structured review synthesizes global trends in plastic production, environmental MNP burden, and human exposure, together with emerging data on brain accumulation, entry pathways, neurotoxic mechanisms, and key translational challenges. We present evidence showing that MNPs may cross brain barriers via multiple routes, including the blood-brain barrier, blood-cerebrospinal fluid barrier, olfactory, and circumventricular pathways, particularly under conditions of barrier vulnerability. Experimental studies reveal that once in neural tissue, MNPs may disrupt synaptic function, mitochondrial homeostasis, autophagy, and redox balance, while activating neuroinflammatory and gut-brain axis-mediated pathways. These mechanisms intersect with disease-relevant processes implicated in multiple neurological disorders whose global prevalence and societal burden have sharply increased over recent decades, including stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, mood disorders, and neurodevelopmental conditions. Despite growing mechanistic plausibility, translational and human epidemiological evidence remains limited by methodological heterogeneity, a lack of standardized detection methods, and the absence of longitudinal clinical data/studies. We highlight critical analytical and translational gaps, public health implications, and priorities for longitudinal, biomarker‑driven studies needed to rigorously test whether MNPs may contribute to population‑level risk of neurological disease.}, }
@article {pmid42043709, year = {2026}, author = {Umar, M and Franjieh, K and White, AL and Ward-Dones, E and Ismael, S and Roskey, RC and Courseault, J and Bix, GJ}, title = {Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.}, journal = {Current nutrition reports}, volume = {15}, number = {1}, pages = {}, pmid = {42043709}, issn = {2161-3311}, abstract = {PURPOSE OF REVIEW: Folate is a key regulator of one-carbon metabolism (OCM), which supports essential physiological processes, including DNA synthesis, repair, methylation, amino acid homeostasis, and redox balance. It is also crucial for brain health throughout life, from neural tube formation during early development to neurotransmitter synthesis, myelination, neuronal development, synaptic plasticity and cognitive function during later stages of life. Disruption of folate-mediated OCM (FOCM) can adversely affect brain health and contribute to neurodegeneration. In this review, we summarize current evidence linking FOCM dysregulation to neurodegenerative diseases, emphasizing disease-specific mechanisms and the therapeutic potential of modulating folate metabolism, as evidenced by experimental and clinical studies.<br><br>RECENT FINDINGS: Disruption of FOCM can lead to oxidative stress, impaired methylation, excitotoxicity, and neuroinflammation, thereby contributing to neurodegenerative diseases. In Alzheimer&#x2019;s disease, impaired FOCM promotes amyloid-&#x3b2; accumulation, tau pathology, cognitive decline, and vascular dysfunction, consistent with low folate and elevated homocysteine observed clinically, though supplementation outcomes remain mixed. In Parkinson&#x2019;s disease, folate deficiency and hyperhomocysteinemia exacerbate motor deficits and dopaminergic neurodegeneration via oxidative stress, mitochondrial dysfunction, and NLRP3-mediated inflammation and combined folate and vitamin B12 supplementation may reduce levodopa-associated risks. Elevated homocysteine and aberrant FOCM have also been reported in Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Huntington&#x2019;s disease and are associated with neuroinflammation, demyelination, neuronal loss, and severe disease phenotypes in these conditions.<br><br>SUMMARY: Overall, maintaining optimal folate levels may be a promising strategy to support brain health and reduce the risk of neurodegenerative disorders.}, }
@article {pmid42048042, year = {2026}, author = {Keha, E and Bugg, JM}, title = {Item-specific control of word reading as evidenced by a novel proportion wordness effect.}, journal = {Memory &amp; cognition}, volume = {}, number = {}, pages = {}, pmid = {42048042}, issn = {1532-5946}, abstract = {Jacoby and colleagues demonstrated that control processes can adapt at the level of individual stimuli, giving rise to the item-specific proportion congruence (ISPC) effect, whereby items that frequently appear as incongruent produce a smaller Stroop effect. Prior research has focused exclusively on informational conflict (competition between word meaning and ink color), leaving open whether item-specific control mechanisms also affect task conflict (competition between the task sets of word reading and color naming). Across two experiments, we addressed this question. In Experiment 1, using an ISPC manipulation, we replicated the classic reduction of informational conflict for mostly incongruent items but found no evidence of item-specific control of task conflict. In Experiment 2, we introduced a novel item-specific proportion wordness (ISPW) manipulation to vary the likelihood of task conflict at the item level, by presenting items mostly with neutral words or neutral nonwords. Results revealed robust item-specific effects on task conflict and informational conflict, with reductions in both types of conflict for items that were mostly neutral words. These findings clarify the scope of item-specific control: while manipulations of reactive informational control selectively influence informational conflict, manipulations of reactive task control can regulate not only task conflict but additionally informational conflict. Our results refine and extend Jacoby et al.'s original insight, providing initial evidence for item-specific control of word reading, and demonstrating the operation of item-specific control at multiple levels of conflict via an ISPW manipulation that modulated the likelihood of word reading.}, }
@article {pmid42049092, year = {2026}, author = {Liu, C and Meng, L and Zhang, Z}, title = {Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.04.066}, pmid = {42049092}, issn = {2090-1224}, abstract = {BACKGROUND: TATA-box binding protein associated factor 15 (TAF15) is a multifunctional DNA/RNA-binding protein that plays pivotal roles in transcription regulation, precursor mRNA splicing, and cellular stress responses. Accumulating evidence demonstrates that TAF15 is strongly implicated in two distinct pathological classes: neurodegenerative diseases and cancers. In neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), TAF15 undergoes abnormal cytoplasmic aggregation and mislocalization in neurons and glia, and TAF15 has been established as a candidate disease gene for ALS. In a wide range of cancers, TAF15 drives oncogenic transcriptional dysregulation either via wild-type protein dysfunction or the formation of oncogenic fusion proteins derived from chromosomal translocations.<br><br>AIM OF REVIEW: A central unresolved question is how TAF15 contributes to two mechanistically distinct disease entities. This review aims to provide a mechanistically integrated analysis of the physiological and pathological functions of TAF15. We use TAF15's intrinsic molecular properties as a unifying framework to connect its roles in neurodegeneration and cancer. We also summarize key pathogenic mechanisms and emerging therapeutic strategies targeting TAF15, with the goal of proposing a novel conceptual perspective to guide future research. Key scientific concepts of review. TAF15 may act as a biologically relevant molecular link between neurodegeneration and cancer through its intrinsic molecular characteristics, such as nucleic acid binding, phase separation, and nucleocytoplasmic shuttling. The "localization determines outcome" hypothesis offers a unifying framework to explain the connection between the two diseases. TAF15 holds promise as a target for novel biomarkers and precision therapeutics across both disease areas. Deepening mechanistic studies of TAF15 will not only advance understanding of its dual pathological roles but also illuminate the largely unexplored molecular link between neurodegenerative diseases and cancers.}, }
@article {pmid42049146, year = {2026}, author = {Senerchia, G and Iuzzolino, VV and Spisto, M and Panico, F and Polito, C and Aruta, L and Fiorenza, M and Sirica, R and Terracciano, D and Dubbioso, R}, title = {Plasma NfL, GFAP and pTau181 define distinct biological axes in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107415}, doi = {10.1016/j.nbd.2026.107415}, pmid = {42049146}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis is biologically heterogeneous, and blood biomarkers may reflect distinct pathological mechanisms. We investigated whether plasma neurofilament light chain (NfL), phosphorylated tau at threonine 181 (pTAU181), and glial fibrillary acidic protein (GFAP) capture non-overlapping biological domains in amyotrophic lateral sclerosis. Plasma biomarkers were measured using a fully automated chemiluminescent immunoassay platform in patients with amyotrophic lateral sclerosis and control groups. Upper motor neuron burden was quantified using transcranial magnetic stimulation and the Penn Upper Motor Neuron Score. Lower motor neuron involvement was assessed by electromyography and Medical Research Council strength scores. Associations were tested using multivariable models adjusted for age, sex, disease progression rate, and phenotype. Latent profile analysis was applied to identify biomarker-defined subgroups. NfL levels increased with greater upper motor neuron burden across both neurophysiological and clinical measures. In contrast, pTAU181 selectively reflected lower motor neuron degeneration, particularly chronic denervation severity. GFAP levels were strongly associated with age and showed no relationship with motor neuron involvement. After adjustment for age and other covariates, higher GFAP levels were independently associated with behavioural lability. Biomarker levels did not differ across cognitive classes. Latent profile analysis identified three biologically distinct clusters characterized by selective pTAU181 elevation, progressive NfL increase, or prominent glial activation. Cluster membership independently predicted disease aggressiveness. These findings demonstrate that plasma NfL, pTAU181, and GFAP capture complementary biological processes in amyotrophic lateral sclerosis and support combined biomarker profiling for mechanistically informed patient stratification.}, }
@article {pmid42049669, year = {2026}, author = {Vrana, KE}, title = {Are Cannabis and/or Cannabinoids a Potential Therapy for ALS?.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70262}, pmid = {42049669}, issn = {1097-4598}, support = {R01 AT012053/GF/NIH HHS/United States ; }, }
@article {pmid42050008, year = {2026}, author = {Gascón, E and Calvo, AC and Zaragoza, P and Osta, R}, title = {Unveiling an ALS Blood Transcriptomic Signature: A Machine Learning Classifier Distinct from Neurodegenerative Controls.}, journal = {Neuroinformatics}, volume = {24}, number = {2}, pages = {}, pmid = {42050008}, issn = {1559-0089}, }
@article {pmid42051098, year = {2026}, author = {Khan, N and Doshi, G}, title = {Zebrafish (Danio rerio) as a Model for Neurodegenerative Disease Research: Mechanisms, Biomarkers, and Translational Promise.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273442688260330060220}, pmid = {42051098}, issn = {1996-3181}, abstract = {Zebrafish (Danio rerio) have gained prominence as a versatile vertebrate model for studying neurodegenerative disorders due to their genetic similarity to humans, rapid development, transparency, and suitability for high-throughput drug screening. The usefulness of zebrafish in modelling human neurological disorders is supported by the similarity of their brains' anatomical and neurochemical characteristics, including comparable divisions of the forebrain, midbrain, and hindbrain, as well as dopaminergic, serotonergic, glutamatergic, and GABAergic pathways. Zebrafish have been used to successfully model several neurodegenerative diseases, including Alzheimer's disease (via tau phosphorylation and amyloid-beta aggregation), Parkinson's disease (via dopaminergic neuronal loss and alpha-synuclein pathology), Huntington's disease (via polyglutamine-expanded huntingtin), and amyotrophic lateral sclerosis (via mutant SOD1 and TDP- 43 transgenes). They have also been used to study multiple sclerosis, spinocerebellar ataxias, and Rett syndrome, enabling mechanistic exploration and preclinical drug discovery. This review crucially depicts how zebrafish models provide an affordable, morally acceptable, and scalable platform for early-stage neurodegeneration research. These models complement, rather than replace, rodent- and human-derived systems. Additionally, we will review how to bridge the gap between therapeutic screening and basic mechanistic findings, highlighting their increasing significance in the neuroscience research continuum.}, }
@article {pmid42051550, year = {2026}, author = {Chakraborty, DK and Roy, T and Ngo, ST and Al-Chalabi, A and Al Khleifat, A}, title = {Gut microbiota and ALS: cause, consequence or correlation? - a systematic review.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1774417}, pmid = {42051550}, issn = {1662-4548}, abstract = {BACKGROUND: Gut microbiome disturbances have been proposed as contributors to amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder characterised by motor neuron loss, extra-motor symptoms, and rapid progression. Mechanistic links between dysbiosis, epithelial and blood-brain barrier dysfunction, metabolic imbalance, and immune activation have been suggested, but causality remains unresolved. We conducted a systematic review to evaluate the evidence supporting microbiome involvement in ALS pathogenesis.<br><br>METHODS: We searched PubMed, Medline, Embase, Scopus, Semantic Scholar, and Google Scholar (Nov 23, 2025) for human and ALS-relevant animal studies assessing bacterial microbiota, gut or blood-brain barrier integrity, microbial metabolites, or immune pathways. No language or date restrictions were applied. Studies were screened according to predefined criteria, and quality was assessed using QUADAS-2. Owing to the heterogeneity of study designs and sequencing approaches, findings were synthesised narratively.<br><br>FINDINGS: 61 of 2,397 studies met inclusion criteria. Across human cohorts, ALS was consistently associated with reduced microbial diversity, shifts in key taxa, and disruption of microbial pathways regulating short-chain fatty acids, nicotinamide metabolism, and inflammatory signalling. Several mechanistic animal studies demonstrated that microbiota manipulation, through antibiotics, faecal microbiota transfer, or supplementation with protective taxa, modulated motor function, microglial activation, gut permeability, and survival, indicating that dysbiosis can influence disease trajectories. Conversely, longitudinal human data showed that dysbiosis often emerged alongside worsening physical function, gastrointestinal dysmotility, weight loss, and changes in dietary intake, suggesting secondary effects of disease progression. Integrative multi-omics studies linked microbial alterations with systemic cytokine profiles, metabolic stress pathways, and CNS immune phenotypes, reinforcing a bidirectional gut-brain axis. However, the predominance of cross-sectional designs and small sample sizes substantially limits causal inference.<br><br>INTERPRETATION: Current evidence supports a model in which gut dysbiosis interacts with ALS via barrier failure, metabolic disruption, and immune dysregulation, but does not establish dysbiosis as a primary cause of disease. Preclinical findings highlight microbiome-derived mechanisms with disease-modifying potential, yet human data largely indicate association rather than initiation. Clarifying temporal relationships will require longitudinal, multi-modal studies, integration with pre-symptomatic cohorts, and controlled interventional trials. Microbiome-targeted therapies remain a promising but unproven avenue for ALS.}, }
@article {pmid42051853, year = {2026}, author = {Eissazade, N and Nazemi, L and Haghi Ashtiani, B and Moradi-Lakeh, M}, title = {Neutrophil-to-lymphocyte ratio in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag132}, pmid = {42051853}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited diagnostic and prognostic biomarkers. The neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been proposed as a potential indicator. This systematic review and meta-analysis assesses the diagnostic and prognostic value of NLR in ALS. We searched PubMed, Scopus, Embase and Web of Science through June 2025 for peer-reviewed studies evaluating NLR in adults with ALS diagnosed by established criteria. Eligible studies reported validated measurements of NLR and diagnostic or prognostic outcomes. Two reviewers independently extracted data and assessed quality. Random-effects meta-analyses were performed, with heterogeneity, publication bias, evidence certainty and sources of heterogeneity evaluated using meta-regression. Sixteen studies from 12 countries including 357 044 participants met inclusion criteria, comprising 8710 ALS patients (mean age 60.3 years; 59.1% male) and 348 334 controls (mean age 57.8 years; 47.6% male). Meta-analysis of 11 studies showed a pooled mean NLR of 2.74 in ALS patients [95% CI (2.42, 3.10); I [2] = 95.4%], while three control studies yielded a pooled mean NLR of 1.94 [95% CI (1.55, 2.43); I [2] = 94.7%]. Comparison of three studies demonstrated a 35% higher NLR in ALS patients than controls [95% CI (1.03, 1.76); I [2] = 88.3%], with low certainty according to GRADE due to observational design and substantial heterogeneity. Elevated NLR was consistently associated with worse clinical outcomes, including faster disease progression, lower ALSFRS-r scores, reduced forced vital capacity, shorter survival and increased mortality. Pooled univariate analyses from four studies showed that higher NLR predicted mortality [HR = 1.16; 95% CI (1.04, 1.29); I [2] = 93.8%]. Multivariable-adjusted analyses from six studies confirmed NLR as an independent predictor of poorer survival (HR = 1.13; 95% CI (1.06, 1.21); I [2] = 86.5%), with heterogeneity modestly reduced after adjustment for age and sample size. Certainty of evidence for prognostic outcomes was rated low to moderate. Associations between higher NLR and age at onset, sex and classical ALS phenotype were inconsistent. NLR correlated with inflammatory markers and gut microbiota features, supporting a potential mechanistic link between systemic inflammation and ALS disease progression. Elevated NLR is associated with ALS diagnosis and poorer prognosis, including faster disease progression and reduced survival. Despite heterogeneity and potential bias, NLR appears to be a readily accessible biomarker for disease monitoring and risk stratification in ALS, warranting validation in large, longitudinal studies.}, }
@article {pmid42051912, year = {2026}, author = {File, C and Price, AM and Ahmad, R and Shanina, E and Sun, RL}, title = {Amyotrophic lateral sclerosis and chronic inflammatory demyelinating polyneuropathy coexistence in a patient with a C9orf72 variant: case report.}, journal = {Frontiers in dementia}, volume = {5}, number = {}, pages = {1785124}, pmid = {42051912}, issn = {2813-3919}, abstract = {BACKGROUND: The C9orf72 variation has been strongly implicated in the inheritance of familial ALS, frontotemporal dementia (FTD), and combined ALS-FTD cases. Increasing evidence implicates immune changes and inflammation in some ALS patients. Several studies demonstrated that ALS coexists with CIDP or polyneuropathy. Mouse models of C9orf72 loss-of-function mutations exhibit fatal immune dysregulation.<br><br>CASE SUMMARY: A 62-year-old Caucasian man developed right foot drop, and he underwent fibular nerve release without significant improvement. At the same time, he developed progressive weakness and numbness in his bilateral hands. MRI revealed cervical canal stenosis and neuroforaminal narrowing that prompted neurosurgical decompression without clinical improvement. Subsequently, he developed left foot drop. At the clinic presentation, he exhibited dysarthria, tongue fasciculations, weakness in all extremities, muscle atrophy, widespread fasciculations, and upper extremity hyperreflexia, meeting clinical criteria for ALS. Genetic testing identified a pathogenic variant in the C9orf72 gene, confirming a C9orf72 variant, commonly linked to familial ALS. Brain MRI demonstrated the motor band sign. Although EMG/NCS findings were consistent with lower motor neuron disease, he also had signs of demyelinating polyneuropathy based on conduction parameters. Neuromuscular ultrasound showed significant multifocal nerve enlargement typical of immune-mediated neuropathy. CSF studies revealed albuminocytologic dissociation (protein: 112&#x202f;mg/dL, with normal cell count) and high albumin quotient and index. He fulfilled the 2021 EAN/PNS criteria for possible typical CIDP. He was treated with intravenous immunoglobulin in addition to riluzole with temporary improvement.<br><br>CONCLUSION: This is the first case of the co-existence of CIDP and ALS in the setting of a pathogenic C9orf72 variant.}, }
@article {pmid42052844, year = {2026}, author = {Chen, W and Wang, J and Li, Q and Zhang, L and Wu, X and Luo, S and Xie, Y and Guo, P}, title = {Keap1-Nrf2 Signaling Pathway-Mediated Antioxidant Defense in Neurodegenerative Diseases: Mechanisms and Traditional Chinese Medicine Therapeutic Strategies.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {31}, number = {4}, pages = {45233}, doi = {10.31083/FBL45233}, pmid = {42052844}, issn = {2768-6698}, support = {81660671//National Natural Science Foundation of China/ ; 202101AZ070001-172//Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Chinese Medicine/ ; 202105AG070014//Yunnan Provincial Key Laboratory of Formula Granules/ ; zyzdxk-2023192//High-level Discipline Construction Project of Dai Medicine, National Administration of Traditional Chinese Medicine/ ; 2024SS24045//Yunnan Key Laboratory for Dai and Yi Medicines/ ; }, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Antioxidants/metabolism/therapeutic use ; Oxidative Stress/drug effects ; Animals ; Drugs, Chinese Herbal/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDs) are incurable, progressively disabling disorders marked by sustained neuronal degeneration and loss. Their molecular basis involves intricate regulatory networks, while current therapeutic strategies remain inadequate. Oxidative stress (OS) constitutes a major driver in the initiation and progression of age-related pathologies. Kelch-like enoyl-CoA hydratase-associated protein-1 (Keap1)-Nuclear factor Erythroid 2-related factor 2 (Nrf2) signaling pathway, an essential antioxidant system, exerts protective effects by limiting OS-mediated cellular injury. Extensive evidence demonstrates a close association between Nrf2 signaling and the pathological processes of NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Traditional Chinese medicine, characterized by multi-target and multi-pathway regulatory actions of its bioactive constituents, offers distinctive therapeutic potential for NDs. This review provides an integrated analysis of current advances of Nrf2 involvement in NDs and evaluates therapeutic strategies based on traditional Chinese medicine and its active components, with the aim of guiding future clinical translation.}, }
@article {pmid42053396, year = {2026}, author = {Russell, C and Walz, T and Manzo, L and Mueller, S and Messina, S and Arana, S and Feng, K and Harner, H}, title = {"It's My Dark Secret": A Qualitative Study on the Abortion Experiences of US Active-Duty Servicewomen.}, journal = {Perspectives on sexual and reproductive health}, volume = {}, number = {}, pages = {}, doi = {10.1111/psrh.70064}, pmid = {42053396}, issn = {1931-2393}, abstract = {INTRODUCTION: The Hyde Amendment limits US military abortion care and coverage for active-duty servicewomen (ADSW). ADSW face numerous barriers to care when seeking an abortion. The purpose of this study was to explore the lived experiences of US servicewomen who had an abortion while serving on active duty.<br><br>METHODS: Researchers conducted a qualitative secondary analysis of free-text response data using thematic analysis. We developed the codebook using a modified version of Coast et&#xa0;al.'s (2018) framework for Trajectories of women's abortion related care. Data were collected between December 2021 to June 2022 and included N&#x2009;=&#x2009;178 participants who self-reported having an abortion while serving on active duty in the US military.<br><br>RESULTS: Most participants (n&#x2009;=&#x2009;122, 62%) cited unplanned pregnancy as their reason for having an abortion. Some participants (n&#x2009;=&#x2009;22, 12%), identified as having a "medically necessary" abortion (i.e., miscarriage, ectopic pregnancy). Emergent themes included lack of understanding about abortion care, financial and logistical barriers to accessing abortion care often exacerbated by military policies, lack of medical privacy, and subpar care received from military treatment facilities during pregnancy options counseling or TRICARE covered abortion care.<br><br>DISCUSSION: ADSW experience systemic barriers to care and often seek care outside of the military medical system to protect their privacy. Military healthcare professionals do not provide adequate pregnancy options counseling or patient education regarding pregnancy loss. The US Department of Defense should enact policies ensuring access to abortion care to maintain the physical well-being and mission readiness of servicewomen.}, }
@article {pmid42053785, year = {2026}, author = {Fernandes, JMA and Dutra Junior, AM and Thomas, FP and Gondim, FAA}, title = {Evolving 10-year epidemiological landscape of amyotrophic lateral sclerosis (ALS) in Ceará, Brazil.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2663916}, pmid = {42053785}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons with variable cognitive impairment. Despite its rarity, ALS has a major social and economic impact and increasing incidence worldwide. There are few population-based studies of ALS in Brazil. Methods: We present a descriptive and quantitative study, with a retrospective and prospective design, of patients with ALS followed at the Walter Cantídio University Hospital (HUWC) from January 2013 to December 2023, with the aim of describing the clinical, epidemiological, and genetic aspects of ALS in this population, as well as the ALS epidemiology within the state of Ceará, Brazil. Results: Two hundred and forty patients had their medical records analyzed. One hundred and thirty-four (55.8%) cases were male, with a male to female ratio of 1.3:1. The mean age of symptom onset was 56.39 ± 13.05 years. 92.1% (221) of cases were sporadic, 7.9% (19) were familial. Spinal onset was most common (72.1%). Genetic mutations were found in 10 patients, with SOD1 mutations (variant: c.358G > C; p.Val120Leu) being the most common. Using riluzole prescription data, the prevalence and incidence of ALS in 2022 were estimated at 2.32 and 0.8/100.000/inhabitants, respectively. Conclusion: The epidemiology of ALS in the state of Ceará is similar to what has been reported in prior studies from Brazil and other developing countries; SOD1 mutations were the most prevalent genetic subtype.}, }
@article {pmid42054542, year = {2026}, author = {Gu, T and Xue, J and Zhang, Z and Cao, J and Song, J and Li, G and Ming, L and Zhu, Z and Wang, H}, title = {Mechanisms of Resistance to ALS Inhibitors and Bentazone in Fimbristylis littoralis and Rapid Identification of the ALS Trp-574-Leu Mutation Using LAMP-CRISPR/Cas12a.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.5c17149}, pmid = {42054542}, issn = {1520-5118}, abstract = {Fimbristylis littoralis Gaudich., a harmful sedge weed in Chinese rice paddy, impairs rice productivity and quality. In this study, we identified a resistant population (FL2) displaying multiple resistance to pyrazosulfuron-ethyl and bentazone, alongside cross-resistance to other acetolactate synthase (ALS)-inhibiting herbicides. The other population (FL6) showed exclusive resistance to bensulfuron-methyl. Sequencing demonstrated that FL2 carried a Trp-to-Leu mutation at codon 574 of ALS, whereas no mutations were detected in the psbA gene of bentazone-resistant FL2 or the ALS gene of bensulfuron-methyl-resistant FL6. Studies on nontarget-site resistance (NTSR) mechanisms indicated that FL2's resistance to pyrazosulfuron-ethyl was associated with neither PBO-inhibited P450s nor NBD-Cl-inhibited GSTs. In contrast, FL6's resistance to bensulfuron-methyl and FL2's resistance to bentazone were linked to P450 activity. A loop-mediated isothermal amplification (LAMP) coupled with CRISPR/FnCas12a assay was established for rapid detection of the Trp-574-Leu mutation, facilitating resistance management. These findings provide insights for managing resistant F. littoralis populations.}, }
@article {pmid42043421, year = {2026}, author = {Cheng, T and Li, M and Yang, Y and Rao, Z and Yang, W}, title = {Glycolysis as a central pathological axis in neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {42043421}, issn = {2191-0200}, abstract = {Glycolysis is increasingly recognized as a pathological backbone in neurodegenerative diseases rather than merely an accompanying epiphenomenon. This article first delineates the division of metabolic labor among neurons, astrocytes, microglia, and oligodendrocytes in the brain, with particular emphasis on cell type-specific glycolytic flux, lactate shuttling, and an integrated brain-periphery framework of energy metabolism. It then systematically compares alterations in glucose uptake, glycolytic intermediates, and lactate metabolism across Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Wilson disease (WD), Huntington's disease (HD), and multiple sclerosis (MS), highlighting pronounced heterogeneity across cell types, disease stages, and brain regions. These metabolic disturbances encompass not only global cerebral hypometabolism and an energy crisis, but also compensatory hyperglycolysis and inflammation-associated metabolic reprogramming in astrocytes and microglia, and extend further to systemic metabolic phenotypes involving peripheral blood cells, muscle, and liver. The article summarizes recent methodological advances for characterizing glycolytic reprogramming, including fluorodeoxyglucose positron emission tomography (FDG-PET), hyperpolarized carbon-13 magnetic resonance spectroscopy(ˆ13C-MRS), metabolomics, single-cell and spatial transcriptomics, genetically encoded metabolic sensors, and Seahorse assays. In addition, potential therapeutic strategies are discussed, focusing on targets such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3), the astrocyte-neuron lactate shuttle (ANLS), microglial glycolysis and lactylation, as well as systemic metabolic modulation and nanodelivery approaches. Finally, key challenges are highlighted, including unclear causal relationships, biphasic and cell type-specific effects, insufficient brain-periphery integration, and the lack of standardized metrics, underscoring the need for longitudinal, multimodal, and stage-specific strategies to reposition glycolysis as a targetable therapeutic dimension in neurodegenerative diseases.}, }
@article {pmid42043769, year = {2026}, author = {Raafat, MA and Al-Hasnaawei, S and Mousa, HM and Hanumanthayya, M and Sahoo, S and Prathiba, S and Singh, G and Sinha, A}, title = {The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {42043769}, issn = {1573-4919}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, remain leading causes of disability and premature death. Although they present with distinct clinical phenotypes, they converge on several pathogenic processes. Among these, mitochondrial dysfunction has emerged as a key driver of neurodegeneration, encompassing impaired bioenergetic capacity, disturbed calcium handling, altered mitochondrial dynamics, insufficient mitophagy, and excessive production of reactive oxygen species (ROS). This review provides a focused synthesis of the ways in which mitochondrial pathology contributes to neurodegeneration across major neurodegenerative disorders and summarizes therapeutic strategies designed to target mitochondria. We outline disease-relevant mitochondrial abnormalities and connect them to neuronal loss, synaptic failure, and neuroinflammatory cascades, with particular attention to mitochondrial ROS and inflammatory signaling linked to mitochondrial DNA. The manuscript further evaluates current and emerging interventions, including mitochondria-targeted antioxidants, mitochondrial transfer/transplantation, exercise, dietary approaches, and nanotechnology-enabled delivery systems. For each strategy, we consider the mechanistic rationale, key preclinical findings, and barriers to translation. Across experimental models, many of these approaches confer measurable neuroprotection-often reflected by lower oxidative burden, stabilization of mitochondrial membrane potential, and partial restoration of ATP production. However, clinical findings have been inconsistent, suggesting that efficacy depends strongly on disease stage, patient heterogeneity, and the specific mitochondrial defect being targeted. By integrating mechanistic insights with therapeutic evidence, this review offers a structured perspective on shared and disease-specific features of mitochondrial dysfunction and highlights priorities for advancing mitochondria-centered interventions toward meaningful clinical benefit.}, }
@article {pmid42044891, year = {2026}, author = {Spons, R}, title = {Reversible Dropped Head Syndrome Due to Olanzapine-Associated Cervical Dystonia in C9orf72-Associated bvFTD Within the FTD-ALS Spectrum.}, journal = {Journal of movement disorders}, volume = {}, number = {}, pages = {}, doi = {10.14802/jmd.26048}, pmid = {42044891}, issn = {2005-940X}, }
@article {pmid42045773, year = {2026}, author = {Rana, R and Mehan, S and Mukherjee, R and Khan, MDN and Das Gupta, G and Narula, AS}, title = {Caffeic Acid Phenethyl Ester Enhanced the Klotho/SIRT1/Nrf2/HO-1 Axis to Protect Against Methylmercury-Induced ALS-Like Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42045773}, issn = {1559-1182}, support = {DST-SERB, Govt. of India (Grant Number: CRG/2021/001009).//Science and Engineering Research Board/ ; }, mesh = {Animals ; *Caffeic Acids/pharmacology/therapeutic use ; *Phenylethyl Alcohol/analogs &amp; derivatives/pharmacology/therapeutic use ; Klotho Proteins ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/chemically induced/pathology ; *NF-E2-Related Factor 2/metabolism ; *Sirtuin 1/metabolism ; Male ; *Heme Oxygenase-1/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Glucuronidase/metabolism ; Oxidative Stress/drug effects ; *Signal Transduction/drug effects ; Apoptosis/drug effects ; Mice ; *Nerve Degeneration/drug therapy/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, and neuroinflammation. This study evaluated the neuroprotective potential of caffeic acid phenethyl ester (CAPE) against MTME + 5-induced neurotoxicity in an ALS-like pathology model. CAPE (50 and 100 mg/kg., p.o.) demonstrated significant therapeutic efficacy by improving motor and cognitive deficits, restoring oxidative balance, and mitigating neuroinflammatory and apoptotic pathways. Behavioral assessments, including the open field, grip strength, forced swim, and Morris water maze, highlighted CAPE's ability to restore neuromuscular coordination and cognitive function in a dose-dependent manner. Cellular and Molecular analyses revealed that MTME[+]5 exposure significantly disrupted Klotho/SIRT-1/Nrf2/HO-1 antioxidant signaling, increased pro-inflammatory cytokines (TNF-α, IL-1β), and elevated apoptotic markers (Bax, caspase-3) while depleting anti-inflammatory cytokines (IL-10) and neuroprotective proteins. Furthermore, CAPE treatment restored these parameters, reduced oxidative stress, and enhanced antioxidant defenses (SOD, CAT, r-GSH). Furthermore, CAPE normalized neurotransmitter imbalances, including acetylcholine, dopamine, GABA, serotonin, and glutamate, alleviating excitotoxicity. Histopathological and gross morphological analyses confirmed CAPE50 and CAPE100 ability to preserve neuronal and myelin integrity across key brain regions, including the cerebral cortex, hippocampus, striatum, midbrain, and cerebellum. CAPE also reduced methylmercury accumulation in the brain and cerebrospinal fluid, indicating detoxifying effects. Co-administration of vitamin B1 (VTB1(200)) further amplified CAPE's therapeutic efficacy. Complete blood count (CBC) analysis demonstrated MTME[+]5-induced hematological abnormalities, including reduced RBCs, hemoglobin, WBCs, and platelets, alongside elevated eosinophils and basophils. CAPE treatment normalized these parameters, indicating systemic recovery. These findings establish CAPE as a promising neuroprotective agent for ALS, capable of targeting neurocomplications.}, }
@article {pmid42046818, year = {2026}, author = {Modi, RD and Rossi, P and Brennan, HB and Ton, LT and Patel, A and Kidd, M and White, SM and Ring, M and Schwartz, ER and Glynn, T and Redwine, LS}, title = {Feasibility of Creating a Teaching and Learning Kitchen for an Interdisciplinary Group of Medical Professional Students While Creating a Bridge With an Inner-City Miami Community.}, journal = {Global advances in integrative medicine and health}, volume = {15}, number = {}, pages = {27536130261442566}, pmid = {42046818}, issn = {2753-6130}, abstract = {OBJECTIVE: While obesity is a public health threat, many providers feel ill-prepared to advise patients on diet and nutrition for disease prevention. Miami, Florida, has a unique mix of ethnicities and cultures, and more than half of its residents are born outside the US, which creates additional barriers to providing adequate dietary advice. This study aimed to develop and refine a "food-as-medicine" and community service program in this culturally diverse region to improve future health care providers' knowledge, skills, and self-care practices.<br><br>METHODS: Feasibility was assessed using Bowen et al.'s framework, examining demand, acceptability, practicality, and implementation. Preliminary efficacy was determined by assessing student learning. A panel of four medical students provided consultation for developing this course. Twenty-four medical and six physical therapy (PT) students attended, and 21 completed both the pre- and post-surveys. The course consisted of four 2.5-hour classes, including lectures on diet/nutrition, social drivers of health, case studies, and chef-led cooking activities. Attendees subsequently provided diet/nutrition workshops to children in the community.<br><br>RESULTS: Most students (87%) attended at least three class sessions and the community service activity. Nutrition subscales, knowledge (P = 0.018), health equity awareness (P < 0.05), and dietary advice confidence (P < 0.05) improved. PT and medical students did not differ in attitudes toward the importance of nutrition for disease prevention or the survey subscales.<br><br>CONCLUSIONS: Strong participation, improved understanding, and confidence in dietary advice confirmed the feasibility and preliminary effectiveness of integrating a "food-as-medicine" program into medical and PT curricula, enhancing nutrition awareness and developing referral competencies for obesity-related chronic disease prevention.}, }
@article {pmid42046889, year = {2026}, author = {Martinez-Gonzalez, L and Sanchez-Santos, C and Huang, CS and Gil, C and Martinez, A}, title = {Innovative therapies under clinical development for ALS treatment: Small molecules.}, journal = {Expert opinion on investigational drugs}, volume = {}, number = {}, pages = {}, doi = {10.1080/13543784.2026.2667249}, pmid = {42046889}, issn = {1744-7658}, abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is a rapidly evolving field, characterized by significant obstacles but also by an increasing volume of novel therapeutics entering clinical research. Expanding on our 2022 work, this review examines the current state of the ALS clinical pipeline. Given the high volume of ongoing trials, the diversity of their biological targets and the nature of their therapeutic approaches, we focus this comprehensive update in providing a comprehensive overview of the current state of small-molecule development, focusing on agents that have entered or progressed through clinical evaluation since 2022 to the end of 2025.<br><br>AREAS COVERED: Clinical trials for ALS registered within the United States (ClinicalTrials.gov) and European Union (EU Clinical Trials Register/CTIS) databases have been systematically reviewed and are detailed in this report.<br><br>EXPERT OPINION: The implementation of advanced clinical trial platforms has introduced more efficient, adaptive strategies, leading to a significant increase in the breadth of explored therapies for ALS. Furthermore, the advent of precision medicine, powered by Artificial Intelligence (AI) for enhanced patient selection and stratification, offers a critical pathway toward overcoming the challenges posed by this severe and heterogeneous disease.}, }
@article {pmid42047551, year = {2026}, author = {Zeng, Y and Qian, H and Zhao, H and Fu, M and Pan, L and Liu, M}, title = {LrGSTU181 Contributes to Glufosinate Resistance in the Multiple Resistant Lolium rigidum Populations.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.5c17635}, pmid = {42047551}, issn = {1520-5118}, abstract = {Glufosinate is increasingly applied alongside glyphosate to control glyphosate-resistant weeds, a practice that has led to emerging resistance issues. Here, glufosinate resistance was confirmed in two multiple-resistant Lolium rigidum (glyphosate, ALS- and ACCase inhibitors) populations, NLR70 and WALR70 (RIs of 4.47 and 2.17, respectively), with no target-site GS resistance mutations. GST and P450 inhibitor studies identified distinct mechanisms: NBD-Cl reversed glufosinate resistance in both populations, while malathion reversed resistance only in population NLR70. Resistance in population NLR70 involved both the overexpression of LrGS1-2 and LrGS2 and the upregulation of LrGSTU181, CYP94B3, and possibly other GSTs and P450s. Whereas in population WALR70, resistance likely involved LrGSTU181 and possibly other GSTs. Transgenic validation demonstrated that LrGSTU181 contributes to glufosinate resistance and clodinafop-propargyl. These findings suggest a possible preadaptation scenario wherein detoxification genes selected under long-term herbicide pressure contribute to the evolution of resistance to chemically distinct herbicides.}, }
@article {pmid42047858, year = {2026}, author = {Hu, N and Liu, M and Cui, L}, title = {Slowly progressive amyotrophic lateral sclerosis associated with a rare SOD1 Pro67Arg mutation: a case report.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {5}, pages = {}, pmid = {42047858}, issn = {1590-3478}, }
@article {pmid42036021, year = {2026}, author = {Kim, YH and Jing, FZ and Brewer, JD and Demer, AM}, title = {Response to O'Neill et al.'s "Disparities in melanoma survival in Asian American and Pacific Islander patients: A Surveillance, Epidemiology, and End Results (SEER) program-based analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.112}, pmid = {42036021}, issn = {1097-6787}, }
@article {pmid42036022, year = {2026}, author = {Chen, B and Yang, L and Wang, J and Hu, T}, title = {Response to Bar et al.'s "Cancer progression, recurrence, and infection outcomes in psoriasis patients with active or recent malignancy treated with biologic therapy: A cohort study showing comparable safety to conventional agents".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.02.133}, pmid = {42036022}, issn = {1097-6787}, }
@article {pmid42036024, year = {2026}, author = {Xiao, Y and Li, S and Cao, X}, title = {Comments on Chiu et al.'s " Comparative risk of reactivation of hepatitis B and C after treatment with biologics and targeted synthetic DMARDs in psoriasis and psoriatic arthritis: A 15-year multicenter cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.113}, pmid = {42036024}, issn = {1097-6787}, }
@article {pmid42036719, year = {2026}, author = {Lin, CY and Hsieh, WC and Wang, SM}, title = {Poly-GR promotes ferroptosis-associated vulnerability in C9orf72-ALS.}, journal = {Cell &amp; bioscience}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13578-026-01574-3}, pmid = {42036719}, issn = {2045-3701}, support = {MOST 111-2628-B-039- 006-MY3//National Science and Technology Council/ ; CMU114-MF-04//China Medical University, Taiwan/ ; }, abstract = {Ferroptosis, an iron-dependent form of oxidative cell death driven by uncontrolled lipid peroxidation, has been increasingly implicated in neurodegeneration. However, its involvement and the underlying regulatory mechanism in C9orf72-linked amyotrophic lateral sclerosis (ALS), the most common genetic form of the disease, remain incompletely understood. Here, we show that the arginine-rich dipeptide repeat protein poly-GR promotes ferroptosis-associated molecular and biochemical features in motor neuron-like NSC34 cells. Poly-GR expression significantly increased lipid peroxidation, intracellular ferrous iron, and reactive oxygen species, indicating a cellular environment permissive for ferroptotic vulnerability. Mechanistically, poly-GR suppresses the Nrf2/Slc7a11 antioxidant defense axis by reducing Nrf2 nuclear localization and its occupancy at the Slc7a11 promoter, resulting in decreased Slc7a11 transcription. Restoration of Nrf2 or Slc7a11 expression attenuated lipid peroxidation and oxidative stress, while the iron chelator deferiprone effectively reduced Fe[2+] accumulation and ferroptosis-associated injury. Functionally, poly-GR sensitized neuronal cells to erastin-induced ferroptotic stress-associated cell death, an effect reversed by Nrf2 or Slc7a11 overexpression and iron chelation. Together, these findings indicate that poly-GR disrupts redox homeostasis and iron metabolism to increase susceptibility to ferroptosis, highlighting the Nrf2/Slc7a11 pathway and labile iron regulation as potential therapeutic targets in C9orf72-associated ALS.}, }
@article {pmid42037134, year = {2026}, author = {Classen, S and Del Mundo, J and Kulkarni, D and Prabhakar, S and Hicks, A and Hammel, M}, title = {BilboMD: a web-accessible SAXS and AlphaFold-guided modeling pipeline.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkag377}, pmid = {42037134}, issn = {1362-4962}, support = {//Office of Biological and Environmental Research/ ; P30 GM124169/NH/NIH HHS/United States ; CA92584/CA/NCI NIH HHS/United States ; //Advanced Research Projects Agency for Health/ ; //National Energy Research Scientific Computing Center/ ; DDR-ERCAP0031203//Department of Energy User Facility/ ; }, abstract = {BilboMD is a web-accessible platform that facilitates integrative modeling of flexible macromolecules using experimental small-angle X-ray and neutron scattering data. BilboMD combines a browser-based interface with high-performance back-end services hosted locally at the SIBYLS beamline and at the National Energy Research Scientific Computing Center (NERSC). BilboMD guides users through a workflow that includes preparing compatible input files, conformational sampling through molecular dynamics (MD) simulations, small-angle X-ray scattering (SAXS) fitting with FoXS, and establishing multi-state models with MultiFoXS. Input assistants (Inp Jiffy and PAE Jiffy) streamline the process of defining rigid and flexible regions for conformational sampling, including automatic inference from AlphaFold PAE matrices. All analyses are containerized to ensure reproducibility, with job metadata and provenance stored in a central database. By leveraging GPU-enabled MD engines, such as OpenMM (on NERSC resources), BilboMD significantly accelerates conformational sampling and expands the set of models used for SAXS fitting. The platform reduces technical barriers for non-specialists while providing API access for advanced users to automate and integrate with custom workflows. Thus, BilboMD democratizes ensemble-based SAXS modeling, accelerates high-throughput SAXS/small-angle neutron scattering analysis, and lays the groundwork for future integration of AI-driven structure prediction with experimental scattering data. It is freely available without a login requirement at https://bilbomd.bl1231.als.lbl.gov.}, }
@article {pmid42037681, year = {2026}, author = {Wölk, SA and Prudlo, J and Walter, U and Patejdl, R}, title = {Augmented and prematurely occurring H-reflex recovery curve shows enhanced spinal network excitability in ALS patients when employing the double stimulation paradigm.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1790581}, pmid = {42037681}, issn = {1664-2295}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder in which motoneuron loss in the brain and spinal cord induces complex neuroplastic changes. Although these alterations hold considerable potential for clinical diagnosis and disease monitoring, they remain underutilized due to the lack of sensitive and non-invasive assessment methods. The H-reflex is a monosynaptic spinal reflex arc and represents the neurophysiological analog of the Achilles tendon reflex. A modified H-reflex double-stimulation paradigm enables differentiation of the temporal dynamics of spinal inhibitory and excitatory mechanisms. In ALS, this approach may provide clinically relevant insights into motor system dysfunction. Furthermore, this approach may contribute to a better understanding of the pathophysiology of spinal network plasticity associated with this disease, reflecting the complex interplay between spinal and supraspinal pathways. We assessed H-reflex recovery in 15 ALS patients and 82 non-ALS subjects, including 12 age-matched healthy controls (HC). The protocol included 14 interstimulus intervals (ISI) within a timeframe of up to one second. In contrast to the HCs, ALS patients exhibited recovery at ISIs of 30 or 50 ms. At interstimulus intervals ranging from 50 to 200 ms, the extent of recovery was significantly elevated in the ALS group compared to the age-matched HCs. ALS patients thus demonstrate heightened spinal network excitability as evidenced by an augmented and prematurely occurring H-reflex recovery measurement. These alterations likely reflect changes in neuronal network activity and can be attributed to modifications in both segmental spinal circuits and supraspinal regulatory pathways.}, }
@article {pmid42037767, year = {2026}, author = {McGee, SB and Stanisheuski, S and Mehl, RA and Cooley, RB}, title = {Efficient and Site-Specific Incorporation of 3-Nitro-Tyrosine Into Recombinant Proteins in Escherichia coli.}, journal = {Bio-protocol}, volume = {16}, number = {8}, pages = {e5674}, pmid = {42037767}, issn = {2331-8325}, abstract = {3-nitro-tyrosine (nitroTyr) is one of numerous oxidative protein modifications implicated in diseases such as cardiovascular disease, cancer, and amyotrophic lateral sclerosis (ALS). Because of this, the ability to site-specifically encode nitroTyr into recombinant proteins is a powerful approach for studying these disease pathways. However, producing proteins with defined nitration sites is technically challenging due to the limitations of traditional chemical nitration via peroxynitrite, which lacks residue and site-specificity. Genetic code expansion (GCE) offers a solution by enabling precise incorporation of nitroTyr at designated TAG codons using engineered aminoacyl-tRNA synthetase/tRNA pairs from Methanocaldococcus jannaschii and Methanomethylophilus alvus. This protocol provides a reliable, optimized workflow for incorporating nitroTyr into proteins in E. coli using GCE. It guides users through key considerations in selecting cell lines, media conditions, and GCE systems to minimize off-target effects such as release factor 1 competition, near-cognate suppression, and chemical reduction of nitroTyr. The method is demonstrated using wild-type and TAG-containing superfolder GFP but is broadly applicable to other proteins of interest. Key features • This protocol offers a practical guide for the recombinant expression of proteins containing site-specific 3-nitro-tyrosine in E. coli. • These methods should be used to characterize the functional and structural consequences of site-specific tyrosine nitration on proteins without having to modify any other residues. • This protocol avoids the use of peroxynitrite as a method to nitrate proteins, which modifies all solvent accessible tyrosine residues to different extents. • Users are guided through the advantages and disadvantages of using different expression strains and genetic code expansion systems depending on specific needs.}, }
@article {pmid42038083, year = {2026}, author = {MacMillan, C and Gogtay, N and Gibson, D and Qian, JJ and Sauve, WM and Shih, E}, title = {Psychometric evaluation of the DSM-5-TR-Level 1 Cross-Cutting Symptom Measure: transdiagnostic factor analysis in a real-world psychiatric outpatient sample.}, journal = {Frontiers in psychiatry}, volume = {17}, number = {}, pages = {1680352}, pmid = {42038083}, issn = {1664-0640}, abstract = {BACKGROUND: Dimensional approaches to psychiatric assessment are increasingly used to complement categorical diagnoses. The DSM-TR Level 1 Cross-Cutting Symptom Measure (DSM-XC) assesses symptoms across psychopathology domains, but its latent structure remains unexplored in large, real-world psychiatric outpatient populations, limiting guidance on how clinicians interpret and apply results.<br><br>METHODS: We analyzed real-world data from patients (N =&#xa0;3,101) using the Osmind platform who completed the DSM-XC as part of measurement-based care (the systematic collection of patient-reported outcomes to guide clinical decision-making). Exploratory factor analysis was conducted in half of the sample, and confirmatory factor analysis tested two models in the remaining half: a 6-factor general model, a 5-factor bifactor model with a general psychopathology factor. A third confirmatory model based on Caspi et&#xa0;al's framework was also evaluated using the full sample.<br><br>RESULTS: The 6-factor general model identified domains of 'Mood', 'Anxiety', 'Depression', 'Psychosis', 'Substance Use', and 'Distress and Disconnection'. The 5-factor bifactor model demonstrated a strong general psychopathology factor. The Caspi-inspired model showed acceptable fit but weaker support for the specific dimensions. These results underscore the DSM-XC's capacity to capture both shared and domain-specific dimensions of psychopathology, highlighting its relevance for dimensional assessment.<br><br>CONCLUSION: By clarifying its latent structure, this study identified clinically meaningful symptom dimensions which helps facilitate interpretation and application of the DSM-XC in the real-world. As dimensional and measurement-based approaches continue to expand in psychiatry, clearer understanding of tools such as the DSM-XC may support their integration into clinical practice and future research.}, }
@article {pmid42038869, year = {2025}, author = {Behroozinia, M and Khosrawi, S}, title = {Rehabilitation Interventions in Adults with Amyotrophic Lateral Sclerosis: A Review :.}, journal = {Galen medical journal}, volume = {14}, number = {}, pages = {e3708}, pmid = {42038869}, issn = {2322-2379}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common and rapidly devastating neurodegenerative disease, which causes impairment of motor neurons in the upper and lower limbs, as well as in the bulbar muscles among adults. This leads to progressive weakness of voluntary muscles. The median survival after the emergence of initial symptoms is typically three years. During this period, due to the worsening of general well-being and independence, patients and their caregivers experience significant emotional stress. Furthermore, there is currently no definitive treatment for ALS. Consequently, patients face various challenges associated with motor impairment, including mobility disturbances, respiratory dysfunction, speech difficulties, and limitations in activities of daily living. Therefore, rehabilitation plays a vital role as a component of multidisciplinary care for managing these issues and reducing the impact of the disease on patients and their families. It is considered the optimal choice for alleviating the discomfort of ALS patients until a curative treatment is discovered.This narrative review aims to provide an overview of different aspects of rehabilitation, including physical therapy, occupational therapy, speech therapy, and respiratory strategies focused on enhancing independence, functional abilities, and overall quality of life while minimizing disabilities and complications in patients coping with this debilitating condition.}, }
@article {pmid42039076, year = {2026}, author = {Tao, Y and Xiao, M and Mofreh, SAM and Salem, S}, title = {The effect of EFL learners' identity on English speaking proficiency and autonomous learning skills among university students: the mediating role of speaking anxiety.}, journal = {Frontiers in psychology}, volume = {17}, number = {}, pages = {1773756}, pmid = {42039076}, issn = {1664-1078}, abstract = {INTRODUCTION: As a Foreign Language (EFL) learner identity constitutes a pivotal sociopsychological factor in higher education; however, empirical research on how learner identity relates to speaking proficiency (SP) and autonomous learning skills (ALS) remains limited, particularly regarding the affective mechanism through speaking anxiety (SA).<br><br>METHODS: Drawing on Identity Theory and the Affective Filter Hypothesis, the present study examined the effect of EFL learner identity, modeled as a second order latent construct indicated by identity belongingness (IDB) and identity expectations (IDE), on SP and ALS among 392 Chinese non-English major sophomores, and tested speaking anxiety (SA) as a mediator using structural equation modeling (SEM).<br><br>RESULTS: The results showed that overall learner identity significantly predicted both SP and ALS, and that SA served as a meaningful affective pathway, accounting for approximately 36% of the total effects on learning outcomes.<br><br>DISCUSSION: These findings highlight the importance of fostering an identity-supportive learning environment that reduces the "affective filter" and strengthens university students' oral communication and learner autonomy in EFL contexts.}, }
@article {pmid42039423, year = {2026}, author = {Rout, SR and Kulke, M and Droemer, MA and Wendel, M and Cheng, TC and Mauck, TA and Asgari, S and Nemec, AA and Shein, M and Sato, Y and Fukai, S and Witte, G and Tomko, RJ and Stengel, F and Zacharias, M and Schuetz, AK and Sakata, E}, title = {The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.16.718620}, pmid = {42039423}, issn = {2692-8205}, abstract = {The multifunctional AAA+ ATPase p97/VCP is a pivotal regulator of cellular proteostasis, extracting polyubiquitinated substrates from protein complexes or organelle membranes for proteasomal degradation. Mutations in p97 are linked to a broad spectrum of neurodegenerative disorders, including multisystem proteinopathy and amyotrophic lateral sclerosis. Here, we provide insights into the basis of dysfunction in p97 [D] [395] [G] , implicated in vacuolar tauopathy, using an integrated structural approach. The mutation destabilizes the interaction network in the transient ADP.P i state previously identified in p97 [WT] and alters the dynamics of the linker between the tandem ATPase domains, resulting in decreased ATPase activity. We further demonstrate that the D395G mutation sensitizes p97 to oxidative stress by enhancing C522 oxidation, thereby perturbing nucleotide binding in D2, and define the functional basis of this oxidative inactivation of p97. These findings reveal redox control as a key regulatory layer of the p97 ATPase cycle and provide a mechanistic framework for how oxidative stress contributes to p97-associated neurodegeneration.}, }
@article {pmid42039583, year = {2026}, author = {Sowoidnich, L and Norman, AL and Gerstner, F and Siemund, JK and Buettner, JM and Pagiazitis, JG and Dreilich, V and Pilz, K and Tian, D and Sumner, CJ and Paradis, A and Mentis, GZ and Simon, CM}, title = {A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.15.718647}, pmid = {42039583}, issn = {2692-8205}, abstract = {UNLABELLED: Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.<br><br>HIGHLIGHTS: Spinal cord segment-specific analysis reduces variability and allows accurate MN quantificationChAT is the most reliable MN marker in murine and human spinal cordsDeep learning-based segmentation enables unbiased MN quantification in intact spinal cordsMN degeneration is widespread in ALS but restricted to pools innervating proximal muscles in severe SMA.}, }
@article {pmid42040341, year = {2026}, author = {Rong, P and Heidrick, L and Pattee, G}, title = {Translation of surface electromyography into a clinically applicable objective bulbar assessment tool to improve measurement-based care in amyotrophic laterals sclerosis.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1784520}, pmid = {42040341}, issn = {1662-4548}, abstract = {OBJECTIVE: This study aims to translate surface electromyography (sEMG) into a clinically applicable, objective tool for assessing bulbar involvement in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A clinically grounded sEMG framework was developed, integrating a standardized, repeatable protocol with a novel analytic pipeline, to automatically extract 60 features from six craniofacial muscle groups during a set of motorically demanding but cognitively and linguistically less challenging oral diadochokinetic (DDK) tasks. Using this framework, 104 oral DDK recordings were acquired from 16 individuals with ALS-nine with overt bulbar symptoms (ALS+B) and seven without (ALS-B)-and 10 healthy controls (HCs). The sEMG features were clustered into 10 interpretable composite measures and validated by evaluating their (1) internal consistency using Cronbach's &#x3b1; ; (2) associations with standardized functional outcomes and a biomechanical metric-stiffness-via mediation analysis; (3) discriminatory efficacy in distinguishing ALS+B and ALS-B from HC, as well as from each other, using machine learning classifications; and (4) robustness to common nonmotor confounders, including age, sex, and cognitive-linguistic impairments, through a comparison of discriminatory performance before and after adjustment for these factors.<br><br>RESULTS: All composite measures exhibited (1) high internal consistency (Cronbach's &#x3b1; = 0.89 &#xb1; 0.071), (2) significant (or marginally significant) direct or stiffness-mediated indirect associations with the functional outcomes, and (3) consistently high discriminatory accuracy (0.82-0.85), both before and after adjustment for confounders.<br><br>CONCLUSION: The sEMG framework demonstrates strong potential as a reliable, valid, and robust objective tool to detect subclinical neuromuscular changes throughout the prodromal and symptomatic phases of bulbar involvement in ALS, while remaining resistant against disease-related cognitive-linguistic impairments and disease-unrelated confounders. This tool may augment standard clinical evaluations, enabling earlier detection of bulbar involvement and measurement-based care in ALS.}, }
@article {pmid42040397, year = {2026}, author = {Maia, ME and Carvalho, M and Sousa Gomes, C and Arruda, M and Antunes de Magalhães, AJ and Farias, D}, title = {Plant-Derived Peptides with Neuroprotective Activity: Advances and Perspectives in the Prevention of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {11}, number = {15}, pages = {22458-22478}, pmid = {42040397}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, represent an increasing global public health challenge, driven by population aging and the lack of effective curative therapies. In this context, plant-derived peptides have emerged as promising bioactive compounds due to their multitarget neuroprotective properties and favorable safety profiles. This review provides a comprehensive overview of plant peptides with reported activity against neurodegeneration, highlighting their natural sources, biological activities, and mechanisms of action. Evidence from in vitro and in vivo models indicates that these peptides act through multiple complementary pathways, including attenuation of oxidative stress, modulation of neuroinflammation, regulation of apoptosis, preservation of mitochondrial function, and inhibition of toxic protein aggregation. Additionally, several peptides have been shown to enhance synaptic plasticity, modulate neurotransmission, and regulate ion channel activity, suggesting beneficial effects on neuronal communication and cognitive function. Some studies explored structural modifications, such as the introduction of specific residues or glycosylation, which have resulted in greater stability and enhanced efficacy against oxidative insults. Overall, plant-derived peptides demonstrate consistent neuroprotective effects and low toxicity; however, challenges related to the blood-brain barrier, bioavailability, and the understanding of molecular mechanisms must still be overcome to enable their clinical application.}, }
@article {pmid42041525, year = {2026}, author = {Bertoni, G and Ristori, S and Monti, D}, title = {Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.}, journal = {Cells}, volume = {15}, number = {8}, pages = {}, doi = {10.3390/cells15080657}, pmid = {42041525}, issn = {2073-4409}, support = {DM 1557 11.10.2022//Next Generation EU/ ; }, mesh = {Humans ; *Immunosenescence/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *Inflammation/immunology/pathology ; Animals ; *Aging/immunology ; *Neuroimmunomodulation ; }, abstract = {Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.}, }
@article {pmid42041567, year = {2026}, author = {Auburger, G and Kandi, AR and Vutukuri, R and Almaguer-Mederos, LE and Gispert, S and Sen, NE and Key, J}, title = {Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies.}, journal = {Cells}, volume = {15}, number = {8}, pages = {}, doi = {10.3390/cells15080699}, pmid = {42041567}, issn = {2073-4409}, support = {AU96/21-1//Deutsche Forschungsgemeinschaft/ ; SFB1039//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; *Microglia/metabolism/pathology ; *Ataxin-2/genetics/metabolism ; Mice ; *Transcriptome/genetics ; *Ribosomes/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; *Astrocytes/metabolism/pathology ; *RNA Processing, Post-Transcriptional/genetics ; Gene Knock-In Techniques ; *Aging/genetics ; Spinocerebellar Ataxias/genetics/pathology ; }, abstract = {Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis type 13 (ALS13) are triggered by polyglutamine expansion in Ataxin-2 (ATXN2). To understand these neurodegenerative disorders at the molecular level, the brains of 10-month-old Atxn2-CAG100-knockin mice were analyzed as microglial, astroglial and neuronal fractions via global RNA sequencing. Data were validated by comparison with the spinal cord oligonucleotide microarray profile or filtered by RNA-seq consistency. Here, we show that the mutation causes a massive inflammatory response in microglia and a reciprocal loss of neuronal transcripts in glial fractions, suggesting severe synapse loss. Beyond these general neurodegenerative signs, we identify pathognomonic changes in the machinery for protein translation and RNA splicing. Glial fractions showed upregulation of Gpnmb (to 2082%), Cst7, Clec7a, Axl, Csf1, Lgals3, Lgals3bp, Slc11a1, and Usp18 as an unspecific neuroinflammatory signature, versus downregulation of axonal Nefh (to <19%), and synaptic Scn4b, Camk2b, Rab15, and Grin1 mRNAs correlating with circuit disconnection. In all fractions, reductions in Kif5a, Rph3a, and Cplx1 were noted versus disease-specific inductions of ribosomal subunits, presumably mirroring the partial loss-of-function of ATXN2 as RNA translation modulator. Selective accumulations of embryonic factors Rnu1b2 and Eef1a1 versus downregulation of adult Eef1a2 specify the mutation impact on splicing and translation elongation. As a potential underpinning of toxic gain-of-function, the proteostasis transcript Rnf213 appeared increased in astroglial and microglial fractions. These transcriptome data suggest altered ribosomal and spliceosome machinery, with massive microgliosis versus mild astrogliosis, at the core of SCA2 and ALS13.}, }
@article {pmid42041816, year = {2026}, author = {Kleinerova, J and Tully, J and Lope, J and Tan, EL and Toomey, A and Siah, WF and Bede, P}, title = {Driving with Motor Neuron Disease: Disease-Specific Considerations, Multi-Domain Assessments and Support Strategies.}, journal = {Brain sciences}, volume = {16}, number = {4}, pages = {}, doi = {10.3390/brainsci16040408}, pmid = {42041816}, issn = {2076-3425}, support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND - 2025 "Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, abstract = {Motor neuron diseases (MNDs) encompass a clinically heterogeneous group of neurodegenerative conditions with varying impact on dexterity, mobility, decision making, respiratory and bulbar dysfunction. While consensus best-practice recommendations exist for genetic screening, diagnostic work-up, pharmacological and respiratory management, disease-specific facets of driving safety, assessment approaches and intervention strategies to support patients for safe driving have not been comprehensively reviewed. MNDs have unique, phenotype-specific clinical features, which are distinct form other neuromuscular conditions which necessitate a careful and systematic approach to evaluate driving safety. While MNDs are primarily associated with progressive motor impairment, extrapyramidal, cerebellar, cognitive, behavioural, and respiratory manifestations of the disease also affect driving safety and necessitate comprehensive driving assessments and individualised strategies to enable patients to continue to drive. The majority of existing papers focus on amyotrophic lateral sclerosis, and low-incidence MND phenotypes, such as PLS, SBMA, PPS, are glaringly understudied from a driving safety perspective despite the relatively slower progression of these conditions. Beyond the review of specific aspects of driving in MNDs, the main objective of this review paper is to raise awareness of non-motor aspects of MNDs with regard to driving safety and to explore viable strategies to support patients to maintain their independence. Despite the considerable differences in driving regulations around the globe, there are core, disease-specific aspects of MND which are universal. The careful consideration of these clinical factors, comprehensive domain-by-domain assessments, and the implementation of practical, individualised adaptations may enable patients to continue driving safely, maintain their independence and enhance their quality of life.}, }
@article {pmid42042751, year = {2026}, author = {Aguilera-Méndez, A and Aguilera-Manuel, K and Saavedra-Molina, A and Ríos-Chávez, P and Villafaña, S and Nieto-Aguilar, R and Godínez-Hernández, D and Ortega-Cuellar, D and Palomera-Sanchez, Z and Gauthereau-Torres, M}, title = {Alpha-Lipoic Acid and Biotin in Neurodegenerative Diseases: Convergent Mechanistic Insights from Preclinical Models to Clinical Perspectives.}, journal = {Neurology international}, volume = {18}, number = {4}, pages = {}, doi = {10.3390/neurolint18040064}, pmid = {42042751}, issn = {2035-8385}, support = {CIC-19443//CIC-UMSNH/ ; }, abstract = {BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, represent a major global health burden and share convergent pathogenic mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, calcium imbalance, and neuronal loss. Despite advances in symptomatic management, effective disease-modifying therapies remain limited.<br><br>OBJECTIVES: This review aims to critically synthesize mechanistic, preclinical, and clinical evidence on &#x3b1;-lipoic acid and biotin as candidate neuroprotective agents in neurodegenerative diseases, with emphasis on shared signaling pathways, therapeutic potential, generally favorable safety profiles, and translational limitations.<br><br>METHODS: A narrative and integrative review was conducted, encompassing mechanistic studies, preclinical experimental models, and clinical trials and observational studies evaluating ALA and biotin in neurodegenerative diseases. The evidence was qualitatively analyzed with attention to biological plausibility, consistency across models, and clinical relevance.<br><br>RESULTS: ALA and biotin modulate key cellular pathways implicated in neurodegeneration, including mitochondrial metabolism, redox homeostasis, inflammatory signaling, and neurovascular function. Preclinical studies consistently report beneficial effects on mitochondrial efficiency, oxidative stress, and neuroinflammatory markers. In contrast, clinical evidence remains heterogeneous, with more extensive evaluation of biotin in progressive multiple sclerosis and more limited or exploratory findings for ALA across neurodegenerative disorders.<br><br>CONCLUSIONS: ALA and biotin exhibit mechanistic convergence across pathways relevant to neurodegeneration and generally favorable safety profiles. Although current evidence supports their biological plausibility as adjunctive or exploratory therapeutic strategies, clinical outcomes remain inconsistent and appear to be influenced by dosing regimens, disease stage at intervention, and endpoint selection. Well-designed clinical studies are required to define their efficacy, optimal dosing, and disease-specific applicability.}, }
@article {pmid42031063, year = {2026}, author = {Shi, C and Jia, K and Guo, Y and Qian, S and Wang, B and Qiu, Y and Dan, L and Dang, Z and Xue, K and Gao, F and Zhao, L}, title = {Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.}, journal = {Behavioural brain research}, volume = {}, number = {}, pages = {116242}, doi = {10.1016/j.bbr.2026.116242}, pmid = {42031063}, issn = {1872-7549}, abstract = {Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.}, }
@article {pmid42031611, year = {2026}, author = {Etik, D&#xd6; and Dişibeyaz, S and Özmert, EH}, title = {Pancreatitis due to afferent loop syndrome: A case report and a brief review of the literature.}, journal = {Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajg.2026.02.003}, pmid = {42031611}, issn = {2090-2387}, abstract = {Afferent loop syndrome (ALS) should be a part of the differential diagnosis in a patient with acute pancreatitis with a history of gastric surgery. Although it is a rare clinical entity, association of ALS with acute pancreatitis can lead to poor clinical outcomes. Herein, we report the case of a 41-year-old man with a history of subtotal gastrectomy and Roux-en-Y gastric bypass who presented with abdominal pain and tenderness. Treatment of choice in this case was purely medical. A brief review of similar cases in the literature highlights the wide array of etiologies of acute pancreatitis due to ALS and reveals a broad spectrum of treatment options from medical to surgical.}, }
@article {pmid42032949, year = {2026}, author = {Sipilä, J and Solje, E and Ahola, S and Surakka, L and Jokela, M}, title = {Death certificate data of patients with amyotrophic lateral sclerosis in easternmost Finland.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2662015}, pmid = {42032949}, issn = {2167-9223}, abstract = {Objective: Topical data on causes of death and death certificate (DC) accuracy in patients with amyotrophic lateral sclerosis (ALS) are constantly needed. Methods: Data on a previously published ALS cohort from North Karelia in easternmost Finland was updated by extracting DC information from the electronic health records. Results: Death certificate data were available for 91% of the deceased. In all cases, ALS had been coded as a cause of death. In four cases, it had been inserted as a contributory cause of death. In three cases, ALS was indicated but incorrect coding was used. Three of the four cases in which ALS had not been deemed the underlying or immediate cause of death were cardiovascular deaths. One or more contributory causes of death had been recorded in 28% of DCs (54% of these were cardiovascular disorders), although comorbidities had not always been coded in the DC. In individual cases, the death had been sudden and unexpected, resembling a cardiovascular death, but this had not been coded. Conclusion: Finnish DC data remain a very reliable data source for ALS epidemiology, albeit with the caveat that data need to be obtained rigorously. Comorbidities are incompletely recorded as may be some immediate causes of death.}, }
@article {pmid42033202, year = {2026}, author = {Yusuf, S and Allen, MD and Kang, H and Phillips, DE and Genge, A}, title = {Opportunities and challenges related to participant stratification and cohort enrichment in ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2659128}, pmid = {42033202}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is marked by substantial clinical heterogeneity. This heterogeneity has impacted clinical trials by obscuring treatment effects and causing inefficiency. In this review, we summarize potential approaches for addressing heterogeneity in ALS via patient stratification and cohort enrichment methods and highlight potential challenges and limitations. These categories include stratification based on genetics, clinical characteristics (e.g. pattern of weakness, ALS Functional Rating Scale rates of progression), wet biomarkers (e.g. neurofilament light chain), neuroimaging, and novel methods employing statistical modeling or machine learning. These stratification methods have yet to be fully leveraged in clinical trial design. But these strategies must be employed thoughtfully and judiciously due to potential issues stratification can introduce. Future clinical trials should explore how participant stratification and cohort enrichment strategies may improve our ability to identify treatment effects, which may ultimately aid in the quest to establish more personalized medicine for persons with ALS.}, }
@article {pmid42033225, year = {2026}, author = {Barber, HM and Parasrampuria, MA and Jurado-Arjona, J and Gamir-Morralla, A and Berninger, B and González, C and Gagnon, KT and Damha, MJ and Garavís, M}, title = {Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.}, journal = {Nucleic acids research}, volume = {54}, number = {8}, pages = {}, doi = {10.1093/nar/gkag343}, pmid = {42033225}, issn = {1362-4962}, support = {MSCA-IF-799693//European Union Marie Sk&#x142;odowska-Curie Actions/ ; MSCA-IF-841260//European Union Marie Sk&#x142;odowska-Curie Actions/ ; MSCA-IF-750624//European Union Marie Sk&#x142;odowska-Curie Actions/ ; RYC2023-043599-I//CSIC/ ; 1R01GM135646-01/NH/NIH HHS/United States ; #2022-03372//Natural Sciences and Engineering Research Council of Canada/ ; PID2023-146366NB-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; P2024-02-015//ERA-NET Neuron/ ; //Fonds de Recherche du Qu&#xe9;bec/ ; }, mesh = {*C9orf72 Protein/genetics/antagonists &amp; inhibitors ; *Oligonucleotides, Antisense/chemistry/genetics/pharmacology ; Humans ; *DNA Repeat Expansion ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Frontotemporal Dementia/genetics ; Nucleic Acid Conformation ; Halogenation ; Fluorine/chemistry ; Protein Biosynthesis ; RNA/genetics/chemistry ; }, abstract = {Hexanucleotide repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. These expansions give rise to pathogenic sense and antisense repeat RNAs that form nuclear foci and undergo repeat-associated non-AUG translation, producing dipeptide repeat proteins with cellular toxicity. Directly targeting the causative repeat RNAs with antisense oligonucleotides represents a promising therapeutic strategy. One barrier to further development is the propensity of this G-rich repeat-containing RNA target to form stable secondary structures, which may hinder efficient hybridization. In this study, we designed a panel of fluorine-modified ASOs that target the sense repeat expansions. We identified C-rich F-ASO gapmers that reduced translation from sense repeat RNAs in a cell-based reporter assay and lowered the RNA foci burden in patient-derived cells. Structural analyses in vitro revealed that the 2'F-RNA gapmer formed a stable hairpin structure. Our results demonstrate that structural properties of fluorine modifications can be leveraged for effective binding of repeat RNA and highlight the potential for F-ASOs to serve as therapeutic tools when targeting toxic repeat RNAs in C9ORF72-mediated FTD/ALS and other repeat expansion diseases.}, }
@article {pmid42033865, year = {2026}, author = {Wang, F}, title = {Polyphenols and physical activity stimulate gut microbiota mediated Nrf2 signaling to combat neurodegeneration.}, journal = {Pathology, research and practice}, volume = {283}, number = {}, pages = {156478}, doi = {10.1016/j.prp.2026.156478}, pmid = {42033865}, issn = {1618-0631}, abstract = {Polyphenols and regular physical activity are increasingly recognized as complementary lifestyle interventions that influence the gut-brain axis and contribute to neuroprotection. Emerging evidence highlights the central role of the gut microbiota in mediating these effects by transforming dietary and host-derived substrates into bioactive metabolites. These metabolites can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a key regulator of cellular antioxidant defenses, mitochondrial function, and anti-inflammatory responses processes that are critically impaired in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review synthesizes current mechanistic insights into how polyphenol-derived metabolites and exercise-induced alterations in gut microbial composition converge to modulate Nrf2 signaling. We discuss the roles of key microbiota-derived metabolites, including short-chain fatty acids, urolithins, and indole derivatives, in regulating oxidative stress, neuroinflammation, and synaptic function. Furthermore, we examine evidence from preclinical models supporting the synergistic effects of dietary polyphenols and physical activity on gut microbiota-mediated neuroprotection. Finally, we address translational challenges and highlight the potential of integrating dietary and exercise-based strategies to harness microbiota-dependent Nrf2 activation. This integrative framework provides a basis for developing personalized, microbiome-informed interventions aimed at delaying or mitigating neurodegeneration.}, }
@article {pmid42034127, year = {2026}, author = {Ghaderi, S and Mohammadi, S and Kalra, S and Batouli, SAH}, title = {Functional Adaptive Longitudinal Reorganization of Superior Parietal Lobule Networks in Amyotrophic Lateral Sclerosis: Evidence Suggesting Compensatory Mechanisms.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {111900}, doi = {10.1016/j.brainresbull.2026.111900}, pmid = {42034127}, issn = {1873-2747}, abstract = {PURPOSE: To investigate longitudinal changes in resting-state functional connectivity (rs-FC) of the superior parietal lobule (SPL) in limb-onset amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Resting-state fMRI was used to compare SPL connectivity between 14 ALS patients and 14 healthy controls (HCs) at baseline and during a 5-month follow-up (n=10 ALS patients). Imaging sequences were acquired using a 3-Tesla scanner equipped with a 64-channel head coil. The data were preprocessed and analyzed using CONN and SPM12, employing FDR correction (p<0.05) to identify significant resting-state functional connectivity (rs-FC) alterations.<br><br>RESULTS: ALS patients showed significant FC alterations in both right and left SPL compared to HCs. At baseline, the right SPL exhibited increased FC with the right Lateral Visual Network, Medial Visual Network (MVN), right Occipital Fusiform Gyrus (OFG), and left Lingual Gyrus (LG). At follow-up, these increases persisted and expanded, notably to the Occipital Visual Network and left LVN. For several connections, including the right OFG and MVN, the corresponding beta values were descriptively larger at follow-up than at baseline. Conversely, at follow-up, the right SPL showed decreased FC with the left Salience Network (SN). The left SPL showed no baseline changes but, at follow-up, exhibited increased FC with visual networks and the Default Mode Network, alongside decreased FC with the SN.<br><br>CONCLUSION: These findings may be suggestive of adaptive reorganization of SPL-related brain networks in response to neurodegeneration in ALS.}, }
@article {pmid42035155, year = {2026}, author = {Pedde, M and Adar, SD and Jang, DG and Feldman, EL and Goutman, SA}, title = {Air pollution and mortality in a University of Michigan amyotrophic lateral sclerosis cohort: a survival analysis.}, journal = {Environmental health : a global access science source}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12940-026-01295-7}, pmid = {42035155}, issn = {1476-069X}, support = {R01TS000327/TS/ATSDR CDC HHS/United States ; R01TS000327/TS/ATSDR CDC HHS/United States ; }, }
@article {pmid42035914, year = {2026}, author = {Li, F and Tao, S and Wang, S and Ren, T and Qiu, M and Xu, X}, title = {New Perspectives on oligodendrocytes: Guardians of iron homeostasis and defenders against ferroptosis.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.04.052}, pmid = {42035914}, issn = {2090-1224}, abstract = {BACKGROUND: Oligodendrocytes (OLs) play a pivotal role in preserving iron homeostasis within the central nervous system (CNS), as they harbor the largest cellular iron reservoir essential for myelination. However, this indispensable function places OLs at heightened risk of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. The susceptibility of OLs to ferroptosis has significant implications for CNS health, particularly in the context of neurodegenerative diseases where OL dysfunction exacerbates demyelination and accelerates disease progression.<br><br>AIM OF REVIEW: This review aims to systematically elucidate the mechanisms by which mature OLs balance their dual roles as guardians of iron homeostasis and defenders against ferroptosis. Furthermore, it aims to underscore the ramifications of impaired OL iron regulation in prominent neurodegenerative conditions and to investigate potential therapeutic interventions aimed at bolstering OL resilience.<br><br>Mature OLs employ a sophisticated, multi-layered defense system to maintain iron homeostasis and prevent ferroptosis, encompassing precise metabolic regulation of iron uptake and storage, alongside a specialized antioxidant network centered on selenoprotein synthesis. Disruption of this delicate balance renders OLs vulnerable in diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), leading to a vicious cycle of OL death, iron dysregulation, and demyelination. Targeting OL iron homeostasis and anti-ferroptotic pathways through iron modulation, antioxidant reinforcement, or direct ferroptosis inhibition represents a promising strategy to promote remyelination and mitigating neurodegeneration.}, }
@article {pmid42035928, year = {2026}, author = {Codron, P and Desquiret, V and Prunier, D and Amati-Bonneau, P and Nguefackngoune, V and Rapenne, C and Legoff, L and Cassereau, J and Procaccio, V}, title = {Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107412}, doi = {10.1016/j.nbd.2026.107412}, pmid = {42035928}, issn = {1095-953X}, abstract = {Mitochondrial DNA (mtDNA) has received increasing attention in amyotrophic lateral sclerosis (ALS) following the recent report of recurrent low-heteroplasmy mtDNA variants in patients. Here, we performed mtDNA analysis on an independent cohort of 20 sporadic ALS patients using an in-house next-generation sequencing pipeline designed for diagnostics. Using standard filters, none of the previously reported low-heteroplasmy mtDNA variants were detected. These variants only appeared in the low-quality data and were present at similar rates in a large reference population without ALS, localizing to homopolymeric regions that are prone to sequencing errors. Our findings suggest that these low-level mtDNA variants are a result of the technical limitations of short-read next-generation sequencing rather than being associated with the disease.}, }
@article {pmid42030003, year = {2026}, author = {Arslan, HN and Bozkul, G and Çelik, S&#x15e;}, title = {Emotional, Ethical and Cultural Challenges in Percutaneous Endoscopic Gastrostomy (PEG) Decision-Making: A Systematic Review and Meta-Synthesis.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {29}, number = {2}, pages = {e70294}, doi = {10.1111/hex.70294}, pmid = {42030003}, issn = {1369-7625}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Humans ; *Gastrostomy/ethics/psychology/methods ; *Decision Making/ethics ; *Emotions ; Qualitative Research ; Caregivers/psychology ; }, abstract = {BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a critical intervention for patients with neurological and gastrointestinal conditions affecting oral intake. While clinical guidelines emphasise medical indications, they often overlook the intricate emotional, ethical and cultural concerns that shape decision-making. This gap in understanding leads to variability in clinical recommendations and uncertainty among patients and their families. A deeper exploration of these factors is necessary to support informed, patient-centred decision-making.<br><br>AIM: This systematic review and meta-synthesis aimed to explore the emotional, ethical and cultural challenges influencing PEG decision-making, while also considering the broader context of shared decision-making.<br><br>DESIGN: A systematic review and meta-synthesis of qualitative studies.<br><br>METHODS: The review was conducted by systematically searching six databases, including CINAHL, Scopus, Web of Science, MEDLINE, PubMed and TRDizin. Only qualitative studies published between 2004 and 2024 were included to capture subjective experiences related to PEG decision-making. Studies focusing only on clinical outcomes or utilising quantitative methodologies were excluded. The review considered perspectives from adult patients, family members, caregivers and healthcare professionals while paediatric studies were excluded due to differences in decision-making dynamics. Data were synthesised using thematic analysis to organise findings into main themes and sub-themes.<br><br>RESULTS: A total of 15 studies representing a variety of clinical settings and patient conditions, such as amyotrophic lateral sclerosis, advanced dementia and stroke, were included. These studies involved 141 patients (41.1%), 62 caregivers (18.1%) and 140 healthcare professionals (40.8%), ensuring a comprehensive analysis of perspectives on PEG decision-making. Seven major themes were identified: (1) emotional and psychological impact of decision-making, (2) ethical and moral considerations both patients and caregivers, (3) communication challenges and information gaps, (4) impact of healthcare professionals on decision-making, (5) ethical and emotional challenges in decision-making, (6) communication barriers and conflicting advice and (7) professional responsibility and advocacy. Family members and caregivers reported feelings of anxiety, guilt and regret, often due to uncertainty and inadequate communication. Healthcare professionals also faced challenges, including conflicting messages and a lack of comprehensive information.<br><br>CONCLUSION: Emotional, ethical and cultural factors significantly impact the PEG decision-making process involving patients, caregivers and healthcare professionals. Improving healthcare professionals' communication skills, developing decision aids and encouraging interdisciplinary collaboration are crucial for supporting informed and shared decision-making.<br><br>IMPLICATIONS FOR NURSING: Nurses play a central role in the PEG decision-making process, as they are the healthcare professionals with the most frequent and direct contact with patients and their family support networks. Addressing the gaps in communication and emotional support can help improve the quality of care provided to patients undergoing PEG. Implementing structured emotional support programmes, integrating psychological counselling into routine care and training healthcare professionals in empathetic communication strategies can significantly reduce patient and caregiver distress. Beyond providing clinical care, nurses act as essential advocates, educators and emotional support providers, ensuring that patients and families receive clear, consistent and compassionate guidance throughout the decision-making process. Their involvement in interdisciplinary collaboration and shared decision-making frameworks is crucial for aligning PEG decisions with patient values and preferences.<br><br>This review synthesised findings from studies capturing the experiences of patients, families, caregivers and healthcare professionals involved in PEG decision-making, ensuring their perspectives were represented.}, }
@article {pmid42030149, year = {2026}, author = {Varela, V and Garcimartín, S and Trias, E and Zeida, A and Richter, M and de León, A and Miquel, E and King, PH and Vulliez-Le Normand, B and Martinez, M and Alzari, PM and Bartesaghi, S and Radi, R and Barbeito, L}, title = {Monoclonal antibodies against nitrated nerve growth factor reveal an oxidation-dependent pathogenic hallmark in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {17}, pages = {e2536562123}, doi = {10.1073/pnas.2536562123}, pmid = {42030149}, issn = {1091-6490}, support = {EI_2020//Universidad de la Rep&#xfa;blica Uruguay (UdelaR)/ ; CSIC I + D _ 2022//UdelaR | Comisi&#xf3;n Sectorial de Investigaci&#xf3;n Cient&#xed;fica (CSIC)/ ; CSIC I _ 2023//UdelaR | Comisi&#xf3;n Sectorial de Investigaci&#xf3;n Cient&#xed;fica (CSIC)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology ; *Antibodies, Monoclonal/immunology ; Humans ; *Nerve Growth Factor/immunology/metabolism/chemistry ; Animals ; Oxidation-Reduction ; Mice ; Rats ; Motor Neurons/metabolism/pathology ; Tyrosine/metabolism ; Epitope Mapping ; Female ; *Nitrates/metabolism ; Male ; }, abstract = {Nerve growth factor (NGF) is a member of the neurotrophin family, essential for neuronal survival and phenotypic maintenance. However, in vitro, its function can be disrupted by oxidative posttranslational modifications such as tyrosine nitration. Nitrated NGF (NO2NGF) has been shown to have a gain-of-toxic, pro-apoptotic, activity in motoneuron cultures. Herein, we report the generation and characterization of monoclonal antibodies (mAbs) that specifically recognize NO2NGF to unravel its formation in vivo. Using hybridoma technology, we produced mAbs with high affinity and selectivity for NO2NGF, as demonstrated immunochemically and by surface plasmon resonance. The antibodies elicit neutralizing capacity to NO2NGF in neuronal cells. Nitrated Tyr52 within the NGF48-58 sequence was identified as the primary antigenic determinant by crystallographic analysis of antibody:peptide complexes at atomic resolution, peptide-based epitope mapping and molecular dynamics simulations, whereas local sequence NGF motifs around the nitrated tyrosine are important for protein specificity. The antibodies revealed NO2NGF accumulation in amyotrophic lateral sclerosis (ALS) rodent models and human subjects. Indeed, immunofluorescence showed selective accumulation of NO2NGF in spinal cord regions undergoing motor neuron degeneration, as well as in sciatic nerves and neuromuscular junctions. Our findings establish NGF nitration as an oxidative hallmark in ALS and demonstrate that monoclonal antibodies targeting this chemical modification are powerful tools for both mechanistic studies and biomarkers development. This work proposes a link between neurotrophin nitration and neurodegenerative disease progression and opens avenues for therapeutic exploration along the peroxynitrite-tyrosine nitration pathway.}, }
@article {pmid42025938, year = {2026}, author = {McColgan, L and Evans, TV and Marku, RN and Perim, RR and Xu, G and Amorim, IP and Urdaneta, M and Mitchell, GS}, title = {Physiological Predictors of Respiratory Motor Plasticity: A Machine-Learning Reappraisal of Phrenic Motor Facilitation.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {}, number = {}, pages = {104574}, doi = {10.1016/j.resp.2026.104574}, pmid = {42025938}, issn = {1878-1519}, abstract = {Acute intermittent hypoxia (AIH)-induced phrenic long-term facilitation (pLTF) is a well-established form of respiratory motor plasticity and a subtype of phrenic motor facilitation (pMF), which also includes pharmacologically induced plasticity. Understanding the mechanisms of pLTF and pMF represents opportunities for therapeutic targets for spinal cord injury, amyotrophic lateral sclerosis and other neurological disorders. Here, we performed a secondary analysis of previously generated experimental datasets to reassess physiological predictors of pLTF and pMF. Given the limitations of expressing pMF as a percent, and to systematically evaluate complex and potentially nonlinear relationships among physiological variables, we employed a supervised machine learning approach using Gradient Boosted Decision Trees and Shapley Additive Explanations (SHAP) analysis to identify and rank both established and novel determinants of respiratory plasticity via percent-based (%) and absolute (Δ) changes in pLTF and pMF. Gradient Boosted Decision Trees models were trained to predict Δ and % outcomes using baseline physiological variables and AIH- or drug-evoked responses as input features, and model interpretability was achieved using SHAP to quantify the contribution of each predictor. The pooled datasets included experiments in which pLTF was induced via AIH (n=75) and pMF via pharmacologic intervention (n=39) using established experimental protocols. All animals underwent standardized measurement of phrenic nerve activity, respiratory frequency, arterial blood pressure, and evoked hypoxic responses, which were incorporated into the predictive models. Hypoxia-induced phrenic nerve response (ΔHypoxicPNA) was the primary predictor of ΔpLTF, while ΔMaximalPNA exerted a lesser influence in our analysis. Similarly, %pLTF was most strongly influenced by %HypoxicPNA but was also influenced by baseline phrenic nerve activity (BL PNA) and the hypoxia-evoked blood pressure response (ΔHypoxicBP). Notably, calculating percent change in pLTF versus absolute change in pLTF presents certain limitations. Each animal has a unique level of baseline phrenic nerve activity, so calculation via percent change can conceal or misrepresent the overall magnitude of respiratory motor plasticity. For ΔpMF, BL PNA was the strongest positive correlate, while body mass, which strongly correlates with age in laboratory rats, was inversely correlated to ΔpMF. Rat body mass was strongly inversely correlated with %pMF, while BL PNA and BL respiratory frequency (RF) exerted some influence. Similarities in determinant variables for pMF and pLTF indicate the two phenomena exhibit overlapping mechanisms of action, while the differing variables in each measure of respiratory motor plasticity demonstrate the unique sensitivities of pLTF and pMF. This study provides a comprehensive evaluation of respiratory motor plasticity, discovering new determinants while validating previous research regarding pLTF. Better understanding its mechanism could further research into new therapies for increasing respiratory drive.}, }
@article {pmid42026110, year = {2026}, author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Pradat, PF and Hogrel, JY}, title = {Exploring the interplay between quantitative muscle strength, functional performance, and patient-reported outcomes in amyotrophic lateral sclerosis: a cross-sectional pilot study.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-45898-z}, pmid = {42026110}, issn = {2045-2322}, support = {ANR-23-BIOC-0003//Agence Nationale de la Recherche/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) shows marked clinical heterogeneity, while standard clinical assessments may fail to capture its multidimensional burden. Integrating quantitative muscle strength, functional tests and patient-reported outcomes (PROs) may improve disease characterization. Ten ambulant adults with ALS were enrolled in a cross-sectional pilot study. Functional performance was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R), Six-Minute Walk Test (6MWT), Ten-Meter Walk Test, Timed Up and Go, Berg Balance Scale and a fatigability index, lower-limb strength with dynamometry, and PROs with ALS Assessment Questionnaire-40 (ALSAQ-40), Hospital Anxiety and Depression Scale, Fatigue Severity Scale and Modified Fatigue Impact Scale (MFIS). Despite relatively preserved ALSFRS-R scores (40.6 ± 2.8), participants showed reduced 6MWT (61.3 ± 21.7% predicted), marked fatigability (- 47.3 ± 112.3%) and a lower-limb strength index of 58.2 ± 13.8% predicted. The ALSAQ-40 score averaged 183.1 ± 59.5. Fatigue was prominent, while anxiety and depression remained mild. Muscle strength correlated positively with ALSFRS-R gross motor score and inversely with anxiety. ALSAQ-40 and MFIS components showed significant associations with both functional and walking performance. Even at ambulant stages, measurable muscle weakness and fatigability co-occur with functional and PROs changes in ALS, supporting the use of multidomain, sensitive clinical assessment. The trial was registered at ClinicalTrials.gov (NCT06199284) on 29/12/2023.}, }
@article {pmid42026661, year = {2026}, author = {Kuppens, A and Rogister, B and Neirinckx, V}, title = {Pharmacological modulation of CXCL12/CXCR4/ACKR3 for brain disorders - an overview.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-02877-1}, pmid = {42026661}, issn = {1478-811X}, support = {7.6518.24//Fonds De La Recherche Scientifique - FNRS/ ; }, }
@article {pmid42026720, year = {2026}, author = {Kamal, S and Kennel, N and Li, AM and Gale, S and Hennessey, EL and Rodriguez, BN and Feany, MB and Stern, AM and Ganesh, VS and Schildkrout, B and Daffner, K and Silbersweig, DA and Singhal, T and Kletenik, I and Miller, MB}, title = {Case Study 11: A 67-Year-Old Man With Behavioral Disturbances and Frequent Falls.}, journal = {The Journal of neuropsychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {appineuropsych20250213}, doi = {10.1176/appi.neuropsych.20250213}, pmid = {42026720}, issn = {1545-7222}, }
@article {pmid42027094, year = {2026}, author = {McElvaney, R and Starrs, B}, title = {Adolescents' Positive Experiences of Psychotherapy Following Sexual Abuse: A Systematic Review.}, journal = {Trauma, violence &amp; abuse}, volume = {}, number = {}, pages = {15248380261437090}, doi = {10.1177/15248380261437090}, pmid = {42027094}, issn = {1552-8324}, abstract = {While a small body of work focuses directly on young people's experiences of psychotherapy following sexual abuse, to our knowledge, there are no existing reviews of this literature. This systematic review was conducted using Siddaway et al.'s guidelines. Inclusion criteria were: published between 2000 and 2022; used qualitative methodologies; and captured adolescents' perspectives. Eleven studies were identified, representing an aggregated sample size of 72 young people aged 12 to 18. Methodologies used included thematic analysis, content analysis, conversation analysis, and narrative analysis. A total of 9 of the 11 studies addressed experiences of individual therapy using semi-structured interviews; 2 studies explored experiences of group therapy through focus groups. The review identified three key processes that reflect adolescents' experiences: engagement, ambivalence to trust; painful processing: exercising agency; and integrating: taking responsibility. Young people struggled to engage in therapy, and it took time to build trust; they experienced improvements in mood and general well-being, facilitated by psychoeducation, talking about the abuse, experiencing difficult emotions, and learning coping skills. They described integrating their abuse experience into their life story, discovering their inner strength and resilience. The therapeutic experience was underpinned by two key support processes: the therapeutic relationship and a supportive environment outside of therapy. This review supports the components of trauma-focused therapy alongside personalizing psychotherapy to the needs of adolescents for agency and autonomy.}, }
@article {pmid42027125, year = {2026}, author = {Aiello, EN and De Luca, G and Curti, B and Torre, S and Gendarini, C and Cocuzza, A and Colombo, E and De Sandi, A and Mellace, D and Ferrucci, R and Barbieri, S and Maranzano, A and Verde, F and Messina, S and Doretti, A and Morelli, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Prevalence and determinants of anxiety in amyotrophic lateral sclerosis.}, journal = {BJPsych open}, volume = {12}, number = {3}, pages = {e114}, doi = {10.1192/bjo.2026.11025}, pmid = {42027125}, issn = {2056-4724}, abstract = {BACKGROUND: Clinically relevant anxiety can be detected in patients with amyotrophic lateral sclerosis (ALS), but its prevalence and determinants have not yet been fully assessed.<br><br>AIMS: This study aimed at assessing the prevalence and clinical underpinnings of anxiety in ALS.<br><br>METHOD: Non-demented ALS patients (N = 433) and healthy controls (N = 313) were administered the State- and Trait-Anxiety Inventory - Form Y (STAI-Y1 for state-anxiety and STAI-Y2 for trait-anxiety) and the Beck Depression Inventory (BDI). Patients were further assessed for cognition (Edinburgh Cognitive and Behavioural ALS Screen), behaviour (Frontal Behavioural Inventory) and motor status (disease duration, ALS Functional Rating Scale-Revised and progression rate). The prevalence of clinically significant state- and trait-anxiety were estimated by applying age-stratified cut-offs to STAI-Y1/-Y2 t-scores. Linear and logistic regressions were run to test the determinants of STAI-Y1/-Y2 scores.<br><br>RESULTS: STAI-Y1 and -Y2 scores above cut-off were detected in 18.2 and 13.9% of patients, respectively - with proportions being higher in cases versus controls (ps < 0.001). BDI, but neither cognitive/behavioural nor motor variables, was identified as a significant predictor of STAI-Y1/-Y2 scores (ps < 0.003). The cognitive-affective subscale of BDI was the sole predictor of scores above cut-off on both STAI-Y1 and STAI-Y2 (ps < 0.001).<br><br>CONCLUSIONS: Clinically significant levels of state- and trait-anxiety occur in &#x223c;18 and &#x223c;14% of non-demented ALS patients, respectively, mostly driven by cognitive and affective facets of depression, and are independent of motor and cognitive/behavioural features.}, }
@article {pmid42029573, year = {2026}, author = {Kuroiwa, N and Sakaue, F and Miura, M and Go, A and Iwase, R and Iwata Hara, R and Sanjo, N and Ui-Tei, K and Yokota, T}, title = {Rational Design of a Multivalent RNA Combining Structural Motifs Tailored to Multiple Domains of Fused in Sarcoma for Potent Inhibition of Aggregation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {27}, number = {8}, pages = {e202500568}, doi = {10.1002/cbic.202500568}, pmid = {42029573}, issn = {1439-7633}, support = {KKCS20220502009//Kyowa Hakko Kirin/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/chemistry/antagonists &amp; inhibitors ; Humans ; *RNA/chemistry/pharmacology/metabolism ; G-Quadruplexes ; Protein Aggregates/drug effects ; Drug Design ; Protein Domains ; }, abstract = {Fused in sarcoma (FUS) is an RNA-binding protein whose pathological aggregation, driven by aberrant phase separation, is implicated in amyotrophic lateral sclerosis (ALS). Although RNA molecules can modulate the FUS phase behavior, identifying highly effective sequences remains challenging because of FUS's multiple low-specificity RNA-binding domains. In this study, we rationally designed a 65-mer RNA, U1'+TERRA, by combining a stem-loop-GGU motif and a G-quadruplex (G4) structure, each known to interact with distinct FUS domains. U1'+TERRA exhibited strong binding affinity and effectively inhibited FUS aggregation in vitro. We introduced 2'-O-methyl modifications, generating (U1'+TERRA)-2'-OMe, which retained structural integrity and demonstrated resistance to nuclease degradation to enhance biological stability. Notably, (U1'+TERRA)-2'-OMe suppressed FUS aggregation even at a low concentration. These findings suggested that multivalent RNA constructs with rationally arranged motifs can serve as potent inhibitors of FUS aggregation. Our approach highlights the potential of structure-guided RNA engineering for the development of nucleic acid therapeutics targeting RNA-binding proteins involved in neurodegenerative diseases, such as ALS.}, }
@article {pmid42029829, year = {2026}, author = {Bordoni, M and Scarian, E and Messa, L and Garofalo, M and Jacchetti, E and Raimondi, MT and Diamanti, L and Gagliardi, S and Carelli, S and Cereda, C and Pansarasa, O}, title = {Development and characterization of 3D spinal cord organoids to advance the study of amyotrophic lateral sclerosis.}, journal = {Molecular biomedicine}, volume = {7}, number = {1}, pages = {}, pmid = {42029829}, issn = {2662-8651}, support = {Starting Grant//BraYn Association/ ; RC2025-2027//Ministero della Salute/ ; }, }
@article {pmid42029890, year = {2026}, author = {Aktan, R and Yakıt Yeşilyurt, S and Özalevli, S and Sonbahar, AE}, title = {Response to Letter to the Editor: "Concerns Regarding Baseline Balance, Blinding Validity, and Clinical Relevance in Aktan et al.'s Study on Home-Based Inspiratory Muscle Training for Stress Urinary Incontinence".}, journal = {International urogynecology journal}, volume = {}, number = {}, pages = {}, pmid = {42029890}, issn = {1433-3023}, }
@article {pmid42018749, year = {2026}, author = {Niu, RZ and Zhang, MY and Yang, HH and Zeng, XF and Liu, J and Bao, TH}, title = {Single-cell multiregion dissection of central nervous system aging.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glag103}, pmid = {42018749}, issn = {1758-535X}, abstract = {Central nervous system (CNS) aging is a major risk factor for many disorders, including cerebrovascular disease, neurodegeneration and amyotrophic lateral sclerosis, yet the cellular pathways driving its progression across CNS regions remain poorly defined. Here we present a single-nucleus transcriptomic atlas spanning seven human CNS regions, comprising ∼1.0 million nuclei from 235 post-mortem samples derived from 200 neurologically and psychiatrically normal donors aged 19-101 years. Across regions, we delineate both shared and region-specific features of CNS aging, integrating analyses of transcriptional noise, programmed cell-death signatures, disease associations, metabolic reprogramming and transcriptomic remodeling. We identify cross-regional vulnerability of astroglia, oligodendrocytes, and excitatory and inhibitory neurons, and show that microglial and astrocytic activation represents a broadly conserved aging response across the CNS, highlighting potential targets for intervention. Finally, we present within-dataset proof-of-concept predictive modeling use cases based on aging-associated gene signatures, providing a resource for within-atlas prioritization and hypothesis generation of candidate biomarkers of CNS aging. Together, this work offers a region-by-region map of the aging human CNS and informs the selection of specific cell types and/or regions for future anti-aging strategies.}, }
@article {pmid42020605, year = {2026}, author = {}, title = {Somatic mutations link focal onset to widespread neurodegeneration in ALS and FTD.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {42020605}, issn = {1546-1718}, }
@article {pmid42020791, year = {2026}, author = {Tsagkas, C and Donadieu, M and Sun, R and Bujak, B and Hu, K and Rood, C and Cameron, K and Dodd, S and Reich, DS and Nair, G}, title = {A pipeline to characterize spinal cord pathology in neurological disorders combining magnetic resonance microscopy and histopathology.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01577-8}, pmid = {42020791}, issn = {2730-664X}, abstract = {BACKGROUND: The length, shape, and size of the spinal cord (SC) present unique challenges for MRI, including the need for high resolution to distinguish anatomical and pathological features along its span. Postmortem MRI offers an opportunity to map SC tissue abnormalities and investigate their histological correlates.<br><br>METHODS: We developed a pipeline combining postmortem microscopic resolution MRI (MR microscopy; MRM) of whole formalin-fixed SC specimens with targeted histopathological analysis. A gadolinium-based tissue preparation protocol was optimized using SC tissue from common marmosets with experimental autoimmune encephalomyelitis. A custom tissue holder and container were designed to enable postmortem MRI of the entire human SC. Human SC samples from individuals with multiple sclerosis, amyotrophic lateral sclerosis, and intracranial hemorrhage were scanned at 75 &#x3bc;m isotropic resolution on a 9.4&#x2009;T Bruker system after gadolinium preparation.<br><br>RESULTS: MRM after gadolinium-based tissue preparation yields images with high signal- and contrast-to-noise ratio while minimizing acquisition times. MRI demonstrates fine anatomical detail and pathological features, including demyelination and neurodegeneration throughout the SC. A complementary custom-made cutting rack enables targeted histological sectioning of MRI-identified regions. This approach provides precise spatial correspondence between imaging and histological findings, demonstrating strong agreement across modalities.<br><br>CONCLUSIONS: In summary, this pipeline facilitates comprehensive SC assessment by integrating MRM with histology. It enables accurate localization of both subtle and widespread SC pathology and enhances interpretation of MRI signals in the context of neurodegenerative and inflammatory diseases.}, }
@article {pmid42021292, year = {2026}, author = {Yang, T and Wang, Y and Dong, N and Ding, J and Yan, X and Luo, J and Chen, P and Qiu, Y and Lin, T and Tong, J and Mao, J and Dai, Y and Shentu, H and Tang, S and Sheng, L and Zhao, M and Yang, G}, title = {Predicting amyotrophic lateral sclerosis stage based on multi-parameter ultrasound: development and validation of an interpretable machine learning model.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04871-3}, pmid = {42021292}, issn = {1741-7015}, support = {2025HZZD09//The Construction Fund of Key Medical Disciplines of Hangzhou - Rare Disease (Motor Neuron Disease)/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks sensitive, objective staging tools to guide clinical management and trials. Existing methods have limited granularity and rely on subjective assessment, while biomarker and imaging approaches can be invasive or impractical for serial use. Ultrasound is a safe, portable imaging modality that can detect neuromuscular changes, but it has not yet been applied to ALS staging. We developed and validated an interpretable ultrasound model for clinical staging and risk stratification in ALS.<br><br>METHODS: We enrolled 300 ALS patients, classified as early-stage (King's stages 1-2; n&#x2009;=&#x2009;148) or late-stage (3-4; n&#x2009;=&#x2009;152). Each patient underwent ultrasound of key muscle groups, including the diaphragm (excursion and thickening), geniohyoid (shear-wave velocity), and peripheral skeletal muscles (thickness and cross-sectional area). Six machine learning models were trained to predict early vs late stage from these ultrasound metrics combined with clinical factors. Performance was evaluated on a test set using area under the curve (AUC), F1 score and Brier score. Feature importance was analyzed with SHapley Additive exPlanation (SHAP) values.<br><br>RESULTS: In the test set, the random forest achieved an AUC of 0.843, an F1 score of 0.727, and a Brier score of 0.177, with sensitivity 0.80 and specificity 0.68. SHAP analysis identified diaphragm excursion during deep breathing (DEDB) as the top predictor, followed by masseter muscle thickness (MMT) and geniohyoid shear-wave velocity (GHSWVmean). Higher DEDB, MMT and GHSWVmean values predicted earlier stage, whereas lower peripheral muscle thickness and older age indicated late-stage disease.<br><br>CONCLUSIONS: Multiparameter ultrasound combined with machine learning offers a non-invasive, bedside tool for ALS staging. The model's accuracy and interpretability enable objective tracking of disease progression and may support timely interventions and patient stratification in clinical practice and trials. Leveraging widely accessible ultrasound technology, this approach is feasible for routine ALS care and research.}, }
@article {pmid42021677, year = {2026}, author = {Mukhija, S and Lehner, F and Jung, HH}, title = {[Amyotrophic lateral sclerosis (ALS): current perspectives and the Swiss ALS Registry].}, journal = {Praxis}, volume = {115}, number = {4}, pages = {100-106}, doi = {10.23785/PRAXIS.2026.04.003}, pmid = {42021677}, issn = {1661-8157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/epidemiology ; *Registries ; Switzerland ; Disease Progression ; Risk Factors ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to muscle weakness, atrophy, and ultimately death. In addition to mutations in ALS-related genes, environmental and lifestyle factors may increase disease risk. Diagnosis is based on clinical evaluation, supplemented by electroneuromyography, imaging, and molecular genetic testing. No curative therapy exists, but Riluzole and Edaravone can slow progression, and genetic therapies offer promising perspectives in certain genetically determined forms. In practice, diagnosis is often delayed. The Swiss ALS Registry collects comprehensive data on environmental, lifestyle, clinical, genetic, and biomarker factors, aiming to improve understanding of risk, disease progression, and therapeutic approaches.}, }
@article {pmid42021792, year = {2025}, author = {Iztleuov, M and Abugaliyeva, N and Ryzhkin, S and Iztleuov, Y and Saparbaev, S and Smagulova, G}, title = {Current Insights into Plausible Mechanisms of Chromium (VI) Neurotoxicity in the Brain and Future Perspectives.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {39}, number = {}, pages = {157}, pmid = {42021792}, issn = {1016-1430}, abstract = {BACKGROUND: Hexavalent chromium (Cr (VI)) is a known neurotoxin and environmental contaminant. Despite its recognition, the underlying mechanisms by which Cr (VI) induces neurological damage remain insufficiently explored. The complexities of the Central Nervous System (CNS), including the Blood Brain Barrier (BBB) and supporting brain cells, contribute to regions-specific susceptibility within the brain. Understanding Cr (VI) neurotoxicity is crucial for its potential role in neurodegenerative diseases.<br><br>METHODS: A Systematic Review was conducted using international databases (PubMed, Medline, Scopus, and Web of Science) and Google Scholar. Only open-access, free full-text articles published in English between 2010 and 2025 were included. Following PRISMA 2020 guidelines, a total of 19 relevant studies were selected, comprising 12 animal-based and 7 human cohort studies.<br><br>RESULTS: Animal studies investigated the effects of Cr (VI) via various administration methods and doses, revealed evidence of oxidative stress, inflammatory markers, and apoptotic changes in the brain. Interventional studies showed delayed toxicity when antioxidant agents were used prior to Cr (VI) exposure, including PDC (Potassium Dichromate), SA (Sodium Alginate), and TNG (Tangeretin). Human studies, including autopsies and cell culture analyses, demonstrated neurotoxic effects in conditions such as ALS (Amyotrophic Lateral Sclerosis), nAMD (Neovascular Age-Related Macular Degeneration).<br><br>CONCLUSION: Animal studies have clarified the role of oxidative stress in Cr (VI)-induced neurotoxicity. Human cohort studies have identified Cr (VI) as an environmental risk factor for both neurodegenerative and neurobehavioral disorders. Future research should focus on defining harmful levels of Cr (VI) and exploring potential antioxidant therapies.}, }
@article {pmid42022335, year = {2026}, author = {Cutti, L and Turra, GM and Machado, FM and Sulzbach, E and Angonese, PS and Markus, C and Gaines, TA and Merotto, A}, title = {Subgenomic Distribution and Herbicide Cross-Resistance of ALS Gene Mutations in Allohexaploid Echinochloa crus-galli.}, journal = {Plant direct}, volume = {10}, number = {}, pages = {e70168}, pmid = {42022335}, issn = {2475-4455}, abstract = {Herbicide target site resistance in polyploid species is more complex than in diploids due to potential subgenome interactions. This study characterized mutations in the ALS gene across distinct subgenomes of hexaploid Echinochloa crus-galli and evaluated the cross-resistance patterns conferred by each mutation to various ALS-inhibiting herbicides. E. crus-galli populations were screened, and dose-response curves were performed with ALS inhibitors from different chemical groups. The ALS gene copies of each subgenome (A, B, and C) were sequenced. Copy number variation, global relative expression, and the specific relative expression of ALS gene from each subgenome were performed. The mutations Ala122Thr, Ala205Asn, and Ser653Asn conferred resistance only to imazethapyr, whereas Trp574Leu to imazethapyr, penoxsulam, bispyribac-sodium, and nicosulfuron, when considered the label rate. ALS mutations were more frequent in subgenome A, but ALS from subgenome C had the highest expression. Biotypes with the same mutation showed different resistance level to herbicides. The biotype SAOJER-01 had Trp574Leu mutation in subgenome C and was 22 times more resistant to imazethapyr and penoxsulam than CAMAQ-01, which had the same Trp574Leu mutation in subgenome A. Both SAOJER-01 and CAMAQ-01 biotypes showed CYP450 metabolism mediating penoxsulam resistance in addition to the target site mutation. In conclusion, the mutations Ala122Thr, Ala205Asn, Trp574Leu, and Ser653Asn confer resistance to imazethapyr, but only Trp574Leu confers resistance to the other chemical groups. The herbicides penoxsulam, bispyribac-sodium, and nicosulfuron are effective in controlling three out of four mutations. CYP450-mediated metabolism coexists in biotypes carrying the Trp574Leu mutation. The subgenome location of the ALS mutation may result in variable levels of resistance.}, }
@article {pmid42023099, year = {2026}, author = {Galluzzi, G and Ruocco, G and Fornetti, E and Genovese, I}, title = {Modeling ALS in a dish: how organoids are transforming research.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1792336}, pmid = {42023099}, issn = {2296-858X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. The multifactorial etiology of ALS, encompassing genetic mutations, protein aggregation, oxidative stress, excitotoxicity, and dysregulated RNA metabolism, has hindered the development of effective therapies. Traditional animal and 2D cell models have provided important mechanistic insights but often fail to fully capture the human-specific and multicellular aspects of disease pathophysiology. Recent advances in induced pluripotent stem cell (iPSC)-derived organoids offer a promising human-based platform for ALS research, enabling the generation of disease-relevant neural and neuromuscular subtypes in three-dimensional architectures. These models recapitulate key pathological features, including protein mis-localization, neuromuscular junction defects, synaptic impairments, and glial contributions to motor neuron degeneration, while also serving as platforms for drug screening and mechanistic studies. Importantly, spinal and neuromuscular organoids bridge the gap between simplified in vitro systems and the complex human nervous system, providing a unique framework to study ALS pathogenesis. This review provides a comprehensive overview of the various differentiation protocols, experimental strategies and key results obtained to date, with a primary focus on validating and benchmarking organoid models, while also highlighting their limitations, emerging clinical applications, translational potential, and opportunities for personalized therapeutic discovery.}, }
@article {pmid42024796, year = {2026}, author = {Mei, J and Xia, M and Peng, L and Li, X}, title = {Alcohol and neurodegenerative diseases: a review of mechanistic insights and disease specific effects.}, journal = {The American journal of drug and alcohol abuse}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/00952990.2026.2645215}, pmid = {42024796}, issn = {1097-9891}, abstract = {Background: Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) represent a significant global public health problem. Alcohol consumption is a common lifestyle factor that has been implicated as both a risk factor and potential modifier of disease progression.Objectives: This review integrates evidence from human and experimental studies to characterize the effects of alcohol consumption on the onset and progression of major neurodegenerative diseases.Methods: A narrative review was undertaken examining the pathophysiological effects of alcohol on the brain and its disease-specific effects on neurodegenerative disorders, integrating findings from human cohort studies and mechanistic investigations in preclinical models.Results: Experimental evidence indicates that chronic alcohol consumption exacerbates neurodegeneration through multiple converging mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, inflammatory signaling, disruption of neurotrophic pathways, impairment of dopaminergic neurotransmission, and alcohol-induced gut microbiota dysbiosis with blood-brain barrier compromise. Epidemiological data suggest dose-dependent and disease-specific associations, with heavy and sustained consumption more consistently linked to increased risk or accelerated progression of AD and PD, while evidence in ALS and HD remains inconsistent.Conclusion: Alcohol exerts a multifaceted and context-dependent influence on neurodegenerative diseases. Accumulating evidence supports that long-term heavy alcohol consumption is associated with enhanced neurodegeneration. Minimizing alcohol consumption may present a pragmatic opportunity to reduce neurodegenerative risk.}, }
@article {pmid42025804, year = {2026}, author = {Woodard, GE}, title = {C3 and C5 Complement Cascade Activation in Brain Injury and Disease: Molecular Mechanisms, Pathological Roles, and Therapeutic Implications.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {106161}, doi = {10.1016/j.neuint.2026.106161}, pmid = {42025804}, issn = {1872-9754}, abstract = {The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular hubs in the complement cascade, orchestrating inflammatory responses, synaptic pruning, and neuronal injury across diverse neurological conditions. This comprehensive review examines the molecular mechanisms underlying C3 and C5 activation in the brain, their pathological contributions to acute brain injuries including traumatic brain injury and ischemic stroke, and their complex involvement in chronic neurodegenerative diseases such as Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Emerging evidence demonstrates that complement activation in the central nervous system extends beyond traditional immune functions to encompass critical roles in neurodevelopment, synaptic plasticity, and neural circuit refinement. The dual nature of complement function in the brain, exhibiting both neuroprotective and neurodegenerative properties depending on context and activation levels, presents unique therapeutic challenges and opportunities. This review synthesizes current understanding of complement-mediated neuroinflammation, discusses validated and emerging therapeutic strategies targeting C3 and C5, evaluates complement biomarkers for disease diagnosis and monitoring, and identifies critical knowledge gaps requiring future investigation. Understanding the nuanced roles of C3 and C5 in neurological disease provides essential foundations for developing targeted immunomodulatory therapies that preserve beneficial complement functions while mitigating pathological activation.}, }
@article {pmid42013845, year = {2026}, author = {Xu, Y and He, J and Wang, S and Ge, Y and Jia, Y and Guo, W and Lv, C and Yao, X and Mao, Y and Mei, F and Fan, D and Yuan, P and Lu, B}, title = {BDNF insufficiency exacerbates ALS progression.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {102758}, doi = {10.1016/j.xcrm.2026.102758}, pmid = {42013845}, issn = {2666-3791}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUS[R521C], we demonstrate that BDNF haploinsufficiency leads to shortened lifespan, accelerated motor dysfunctions, and exacerbated motor neuron death. Importantly, activation of the BDNF receptor TrkB by an agonistic antibody effectively rescues these ALS-associated phenotypes. In additional ALS mouse models, TrkB activation antibody also shows superior therapeutic effects compared to current ALS medication riluzole. Our data indicate that insufficient BDNF could be a crucial contributing factor for ALS progression, and activation of BDNF-TrkB pathway may represent a promising therapeutic strategy against ALS.}, }
@article {pmid42014727, year = {2026}, author = {Guo, X and Hu, J and Kanwal, S and Yuan, J and Tariq, M and Zheng, J and Sun, M and Lu, Y and Wang, J and Jiang, M and Wang, A and Castells-Garcia, A and Zheng, X and Peng, B and Wang, D and Wei, X and Yang, T and Volpe, G and Wu, L and Mazid, MA and Li, W and Lai, Y and Qin, D and Aguilo, F and Zhou, Y and Liu, C and Cosma, MP and Xu, X and Lundberg, E and Mulder, J and Hutchins, AP and Maxwell, PH and Di Croce, L and Zhang, X and Esteban, MA and Lv, Y}, title = {A framework for the exploration of subcellular compartmentalization of RNA-binding proteins.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71511-y}, pmid = {42014727}, issn = {2041-1723}, abstract = {The ability of RNA-binding proteins to form complexes with other biomolecules underpins a broad range of structural properties and functions. Understanding the subcellular distribution of RNA-binding proteins and their interacting partners in the steady state and upon perturbation can therefore shed light on these aspects. Here, we present the compartmentalized RNA-Binding Protein (or coRBP) map, an experimental resource and analytical pipeline to study subcellular RNA-binding proteins through multimodal dataset integration and machine learning. Using this approach, we generate a dataset of 1,768 known and putative RNA-binding proteins distributed in a broad panel of subcellular compartments and delineate their intermolecular and intercompartmental relationships. We also establish a hierarchy of RNA-binding protein-containing complexes at multiple scales across the cell, which suggests additional functions for multiple RNA-binding proteins. Furthermore, we investigate changes in RNA-binding protein complex composition and subcellular distribution in response to C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia dipeptide repeats and DNA damage stress. The coRBP map provides a resource to study the roles of RNA-binding proteins in homeostasis and disease.}, }
@article {pmid42014913, year = {2026}, author = {Cai, F and Xu, D and Yang, D and Huang, F and Song, X and Jiang, Q and Wan, S and Zhao, Y and Zhou, J}, title = {Correction: Multidimensional predictors of fatigue in amyotrophic lateral sclerosis: a cross-sectional study in China.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, doi = {10.1038/s41598-026-49397-z}, pmid = {42014913}, issn = {2045-2322}, }
@article {pmid42015728, year = {2026}, author = {Wang, H and Li, G and Liang, F and Xia, X and Zhang, W and Fan, Z}, title = {A nomogram for estimating baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {58}, number = {1}, pages = {2654938}, doi = {10.1080/07853890.2026.2654938}, pmid = {42015728}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; *Nomograms ; Middle Aged ; Retrospective Studies ; *Respiratory Insufficiency/etiology/diagnosis/physiopathology/epidemiology ; Aged ; Respiratory Function Tests/methods ; Muscle Strength/physiology ; Vital Capacity ; Adult ; ROC Curve ; }, abstract = {OBJECTIVES: To develop and validate a nomogram for estimating the risk of baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis (ALS). This also aims to analyze the association between readily available clinical predictors and pulmonary function.<br><br>MATERIALS AND METHODS: This retrospective study assessed 142 ALS patients treated at the First Hospital of Shanxi Medical University from August 2020 to June 2023. ALS was diagnosed based on revised El Escorial criteria with Awaji modifications. Clinical data and pulmonary function tests (PFTs) were performed during a single hospital stay. Respiratory insufficiency was marked as forced vital capacity (FVC) < 80% of predicted. Muscle strength of neck and limbs was measured with the Medical Research Council (MRC) scale. Multivariable logistic regression evaluated independent predictors of respiratory insufficiency. A nomogram was created and internally validated using bootstrap resampling (1,000 iterations). Model performance was assessed with ROC curve analysis, calibration curve analysis, and decision curve analysis (DCA).<br><br>RESULTS: Of the 142 patients, 30 (21.1%) presented with baseline respiratory insufficiency. In the multivariable analysis, neck flexor muscle strength (OR = 0.497, 95% CI: 0.321-0.769; p&#x2009;=&#x2009;0.002) and bulbar onset (OR = 4.392, 95% CI: 1.674-11.521; p&#x2009;=&#x2009;0.003) were independent predictors in the multivariable analysis. The nomogram showed good discrimination and calibration (AUC = 0.823, 95% CI: 0.739-0.907).<br><br>CONCLUSIONS: Weakness of neck flexors and bulbar onset are independently associated with baseline respiratory insufficiency in ALS patients. The proposed nomogram may serve as a useful tool for baseline screening and risk stratification. External validation in larger multicenter cohorts is warranted before clinical application.}, }
@article {pmid42016758, year = {2026}, author = {Liu, Y and Xia, X and Chen, Y and Yang, H and Chen, X and Cai, L and Shi, B}, title = {When Rare Is Not Small: Amyotrophic Lateral Sclerosis Initiatives and Therapy.}, journal = {Exploration (Beijing, China)}, volume = {6}, number = {2}, pages = {70114}, pmid = {42016758}, issn = {2766-2098}, abstract = {In the precision-medicine era, rare diseases must not be sidelined in translational infrastructure. The Mr. Cai Lei-led "Ice-Breaking Team" turns an amyotrophic lateral sclerosis patient community into a sustainable ecosystem, realigning philanthropy, data, and research and development to reshape rare-disease pipelines and guide precision therapies, offering a replicable blueprint for rare-disease strategies.}, }
@article {pmid42016770, year = {2026}, author = {Cao, L and Chen, G and Zhou, J and Huang, H and Xu, A and Zhan, T and Zhao, Y and Liu, H}, title = {Subtype-specific associations between serum lipid profiles and disease severity in patients with amyotrophic lateral sclerosis.}, journal = {Biomedical reports}, volume = {24}, number = {6}, pages = {68}, pmid = {42016770}, issn = {2049-9442}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder. Notably, the differences in lipid metabolism between bulbar- and limb-onset subtypes of ALS remain unclear, particularly in non-Western populations. The present study investigated serum lipid profiles in a Chinese cohort of patients with ALS to explore their associations with disease severity and clinical subtypes. A retrospective, cross-sectional study was conducted, involving 158 patients with ALS and 62 matched healthy controls. Serum lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), small dense LDL cholesterol (sdLDL-c), apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB) and the TG/HDL ratio, were compared between the groups. Correlation analyses and multivariable linear regression models incorporating phenotype x lipid interaction terms were conducted after adjusting for age, sex, body mass index and disease duration. Patients with ALS exhibited significantly higher TC, TG, LDL, sdLDL-c, ApoA1, ApoB and TG/HDL ratios than controls. Subtype-specific analyses revealed different associations; in bulbar-onset ALS, higher sdLDL-c and TG/HDL ratios were associated with better functional status, whereas higher HDL and ApoA1 levels were negatively correlated with functional status. By contrast, in limb-onset ALS, higher sdLDL-c and ApoB levels were associated with worse function. Interaction analyses confirmed significant phenotype modification for sdLDL-c, TG/HDL ratio, HDL and ApoA1. These results suggest that lipid-severity relationships in ALS vary by subtype, indicating metabolic heterogeneity across phenotypes and supporting the potential of specific lipid parameters as exploratory markers for disease monitoring.}, }
@article {pmid42004396, year = {2026}, author = {Kallavus, K and Laisaar, T and Laisaar, KT}, title = {Lung cancer screening knowledge, opinions and attitudes among healthcare professionals in Estonia prior to national program initiation.}, journal = {Journal of public health research}, volume = {15}, number = {2}, pages = {22799036261439973}, pmid = {42004396}, issn = {2279-9028}, abstract = {BACKGROUND: This study aimed to gain insight into the opinions and attitudes about, and potential barriers and facilitators to lung cancer screening (LCS) among healthcare professionals in Estonia. It also aimed to determine knowledge gaps that could be addressed when planning next steps toward a national LCS program.<br><br>METHODS: A cross-sectional, web-based survey was conducted in June to August 2023 among primary care providers (PCPs), pulmonologists, radiologists, oncologists, and thoracic surgeons in Estonia. Differences between PCPs and other specialists were analyzed with regard to their knowledge, beliefs and attitudes toward LCS.<br><br>RESULTS: About 146 healthcare professionals responded, 57% were family physicians. Less than half of all respondents considered existing evidence or international recommendations sufficient to support national LCS implementation, with uncertainty higher among PCPs. Adjusted analyses revealed that the PCPs had substantially higher odds of responding "Do not know" concerning international recommendations (aOR 5.06; 95% CI 1.97-13.85), and were far less likely to agree to assigning main responsibility for LCS participation to family physicians (aOR 0.10; 95% CI 0.02-0.40). PCPs also demonstrated greater uncertainty about the costs and labor intensity in LCS.<br><br>CONCLUSION: This study reveals substantial variation in LCS knowledge, attitudes, and certainty across healthcare profession(al)s, highlighting the need for targeted training. Although for most professionals the benefits of LCS outweigh potential harms, structural constraints and uncertainty should still be carefully considered. Despite limited generalizability, study findings support evidence-informed planning and have already been considered in the Estonian LCS pilot study, the first step toward a national LCS program.}, }
@article {pmid42006515, year = {2026}, author = {Cheung, N}, title = {Synaptic Plasticity Fragility Underlies a Microglial Pruning Continuum in Major Depressive Disorder and Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e107259}, pmid = {42006515}, issn = {2168-8184}, abstract = {Background Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are clinically distinct yet show intriguing comorbidity, often early in the disease course. We hypothesized a shared microglia-mediated synaptic pruning vulnerability, amplified differently by disorder-specific pathways, autophagy collapse in ALS versus RNA processing and immune dysregulation in MDD, thereby creating a biological continuum. Methods Using large-scale genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC) (MDD, N=829,249) and Project MinE (ALS, effective N=87,381), we applied Multi-marker Analysis of GenoMic Annotation (MAGMA) for gene- and set-level associations, Gene Set Enrichment Analysis (GSEA)/Differential Gene Set Enrichment Analysis (DGSEA) for pathway enrichment and differential enrichment, S-PrediXcan transcriptome-wide association study (TWAS) across 14 GTEx tissues, and linkage disequilibrium score regression (LDSC) for partitioned heritability and cross-trait genetic correlation. Eight gene sets (housekeeping controls, monoaminergic, neurosteroid, glutamatergic, synaptic pruning, autophagy/protein quality, RNA processing, and immune/neuroinflammation) were tested for convergence and divergence. Results Synaptic pruning emerged as the sole consistent cross-disorder signal, with robust enrichment in MDD (LDSC 1.32×, GSEA NES=1.415, p=0.0001) and nominal but consistent signals in ALS (GSEA NES=1.40, p=0.011; TWAS HLA-B). Autophagy dominated ALS (LDSC 2.20×, TWAS C9orf72 Z=13.43, GSEA NES=1.94) but was depleted in MDD. RNA processing and immune pathways were prominent in MDD (LDSC 1.48× and 1.89×, respectively), with only nominal signals in ALS. Overall genetic correlation was near zero (rg=-0.044, p=0.196). Conclusions These findings support a microglial pruning continuum model: shared pruning liability as the foundation, with autophagy failure driving ALS neurodegeneration and RNA/immune dysregulation shaping MDD stress sensitivity. The low rg explains the modest overlap, while pathway specificity accounts for comorbidity and divergent progression. This framework offers testable predictions for polygenic risk score (PRS) stratification, complement modulators in ALS mood subsets, and microglial therapies in treatment-resistant MDD.}, }
@article {pmid42006781, year = {2026}, author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD}, title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.07.26350339}, pmid = {42006781}, abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A [2] ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A [2] ND glucose dysregulation spatial signature remains undescribed.<br><br>OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A [2] ND.<br><br>DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).<br><br>STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.<br><br>DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.<br><br>MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t-or Z-values, and annotations indicating the disease of interest, whether the outcome was for hyper-(disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.<br><br>RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A [2] ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A [2] ND which included both hypo-and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A [2] ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.<br><br>CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A [2] ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A [2] ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.}, }
@article {pmid42007068, year = {2026}, author = {Li, Z and Catelli, E and Stergar, J and Milanič, M and Sáez-Hernández, R and Prati, S and Oliveri, P and Sciutto, G}, title = {Expanding the Capabilities of Portable Mapping in Macroscopic External Reflection FT-IR through a Targeted Data-Driven Spectral Enhancement and Denoising Strategy.}, journal = {ACS measurement science au}, volume = {6}, number = {2}, pages = {361-373}, pmid = {42007068}, issn = {2694-250X}, abstract = {Reliable spectral quality is essential for extracting meaningful information from infrared reflectance data, particularly when using portable systems with limited scan numbers. This study presents a data-driven spectral enhancement workflow designed to improve the interpretability of portable macroscopic external reflection Fourier Transform Infrared (MA-rFT-IR) mapping systems developed by the Authors, operating in the near- and mid-infrared (NIR-MIR) ranges. Despite the growing use of reflectance imaging spectroscopy, limited attention has been devoted to the development of robust denoising strategies capable of minimizing noise and unwanted variability while preserving spectral quality and enabling more reliable and accurate data analysis. This study proposes a broadly applicable processing framework aimed at enhancing the efficiency and performance of reflectance-based spectral analysis. Denoising methods including Savitzky-Golay filtering and wavelet- and PCA-based denoising were tested and evaluated individually and in combination. Quantitative performance was assessed using arccosine similarity (ACOS) and derivative-based root-mean-square error (dRMSE) metrics across selected spectral regions of interest, with a derivative ACOS (dACOS) index applied to monitor band-shape variations. The evaluation results were integrated through Pareto analysis to identify the optimal trade-off between noise reduction and spectral-feature preservation. Application of the proposed approach to a multilayered painting mock-up demonstrated that the enhancing spectral data workflow preserves key diagnostic features revealing subtle spectral bands. Furthermore, applying multivariate curve resolution-alternating least-squares (MCR-ALS) to the denoised data enabled chemically meaningful separation of complex overlapping signals, improving the interpretability of compositional information compared with traditional denoising methods and data processing. The workflow strengthens the analytical reliability of low-scan reflection-mode data and provides a transferable framework for optimizing denoising strategies in portable infrared applications.}, }
@article {pmid42008451, year = {2026}, author = {Pena, C and Sinar, MK and Koza, LA and Boehler, N and Buechler, E and Smith, AC and McGarr, A and Baybayon-Grandgeorge, AN and Herda, MS and Jaques, S and Linseman, DA}, title = {Preclinical study of red dragon fruit (Hylocereus polyrhizus) betacyanins in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/1028415X.2026.2661760}, pmid = {42008451}, issn = {1476-8305}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of cortical and spinal motor neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Betacyanins, betalain pigments found in red dragon fruit and beetroot, display powerful anti-inflammatory and free-radical scavenging properties which may help ameliorate ALS pathology and slow disease progression. The present study characterized the therapeutic effects of a betacyanin-rich red dragon fruit extract (DFE) in the G93A mutant hSOD1 transgenic mouse model of ALS. Mice were treated orally with 5% (v/v) DFE in drinking water ad libitum, from disease onset until end-stage. DFE treatment had a statistically significant effect on survival, with an approximate 13-day extension of median lifespan in the treated G93A mutant hSOD1 group. Treatment with DFE also significantly preserved muscle strength and endurance, as assessed by grip strength and rotarod behavioral testing. This was associated with a modest but statistically significant preservation of gastrocnemius muscle weight in the DFE-treated group. Histopathological analyses demonstrated improvements in NMJ size and complexity, an increase in surviving spinal cord motor neurons, and a reduction in spinal cord astrogliosis in G93A mutant hSOD1 mice treated with DFE, when compared to their untreated mutant littermates. Overall, these findings indicate that DFE, or purified betacyanin compounds, should be investigated further as potential therapeutic agents for patients with SOD1-related ALS. Additional preclinical studies in non-SOD1 models of ALS will need to be completed to determine the potential benefit of betacyanin compounds in sporadic ALS.}, }
@article {pmid42008552, year = {2026}, author = {Sidibe, DK and Smith, EM and Spivey, ML and Vogel, MC and Maday, S}, title = {Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0345890}, doi = {10.1371/journal.pone.0345890}, pmid = {42008552}, issn = {1932-6203}, mesh = {*Astrocytes/metabolism/cytology ; *Neurons/metabolism/cytology ; *Sequestosome-1 Protein/metabolism ; *Ubiquitin/metabolism ; Animals ; *Stress, Physiological ; Lysosomes/metabolism ; Humans ; Mice ; Autophagy ; Cells, Cultured ; }, abstract = {Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.}, }
@article {pmid42008764, year = {2026}, author = {Stone, AK and Veinot, TC}, title = {Access to Technology-Mediated Community Mental Health Care Among Low-Socioeconomic Status Consumers With Serious Mental Illness: Qualitative Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e79608}, doi = {10.2196/79608}, pmid = {42008764}, issn = {2561-326X}, mesh = {Humans ; *Mental Disorders/therapy/psychology ; *Health Services Accessibility/statistics &amp; numerical data ; Qualitative Research ; Female ; Male ; Adult ; Middle Aged ; *Community Mental Health Services/statistics &amp; numerical data/methods ; Telemedicine ; Social Class ; Poverty ; }, abstract = {BACKGROUND: Access to mental health care is critical for the effective management of serious mental illness (SMI), but consumers with low socioeconomic status (SES) have lower rates of service usage and worse retention in care. Digital technologies are often lauded as a way to bridge access gaps; however, little is known about how technology-mediated care may influence care access among low-SES consumers and how consumers use technology in care access.<br><br>OBJECTIVE: This study aimed to examine the applicability of Levesque et al's access framework to technology-mediated care for SMI and analyze how low-SES consumers use technology to facilitate care access. Furthermore, the study assesses whether and how technologies are involved in care access at multiple points within the process of accessing care.<br><br>METHODS: This study used 2 qualitative methods: ethnographic observations at a mental health treatment court and interviews with low-SES consumers with SMI using community mental health care (n=14) and key informant interviews with health and service providers working with this population (n=14). Observations occurred from July 2022 through September 2023, and interviews occurred between January 2022 and May 2024. Data analysis involved both inductive and deductive coding approaches. Data from both the interviews and observations were analyzed in NVivo and further triangulated through analytic memos.<br><br>RESULTS: Levesque et al's framework required several extensions to accommodate technology-mediated care related to SMI for low-SES consumers: (1) a cyclical rather than linear trajectory; (2) simultaneous care acquisition from multiple health and service providers; (3) staying in care long-term; (4) identification of both one-time and ongoing health needs; and (5) an emergency pathway for entering care. Consumers often faced challenges related to the varied digital requirements of each provider and a dearth of integrative, patient-facing tools like portals. Within this context, some consumers use mobile apps, communication, and telehealth technologies across various care access stages. Consumers used technology by figuring out how to navigate technology-mediated care, especially by leaning on others, such as case managers, for support. These others provided consumers with temporary technologies, showed them how to use technologies, and accompanied them through the process of using technology for accessing care.<br><br>CONCLUSIONS: This study highlights that accessing care is iterative and ongoing, involving multiple forms of co-occurring service provision. A theoretical contribution of this work is its extension of Levesque et al's care access framework to better reflect technology-mediated care for SMI among low-SES consumers. This work also underscores ongoing challenges for accessing technology-mediated care and the importance of human support in addressing access difficulties. Clinical implications include incorporating digital readiness assessments and providing comprehensive guidance on how consumers can effectively use technologies for care. Future work should investigate how technology-mediated care can make care access easier rather than harder.}, }
@article {pmid42009215, year = {2026}, author = {Nassar, JE and Knebel, A and Ammar, LA and Singh, M and Kuris, EO and Diebo, BG and Daniels, AH}, title = {Differentiating Neurologic Disorders from Spinal Conditions: Evidenced-Based History and Physical Examination Clues for the Orthopedic Clinic.}, journal = {The American journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.amjmed.2026.04.017}, pmid = {42009215}, issn = {1555-7162}, abstract = {This narrative review highlights neurologic disorders that mimic or worsen degenerative spine disease and provides key clinical clues for recognition in spine surgery practice. A focused review examined amyotrophic lateral sclerosis, normal pressure hydrocephalus, multiple sclerosis, Parkinson's disease, Guillain-Barré syndrome, peripheral neuropathies, and transverse myelitis. These conditions frequently overlap with structural spinal pathology through motor, sensory, and gait disturbances. Amyotrophic lateral sclerosis presents with combined upper and lower motor neuron signs. Normal pressure hydrocephalus is characterized by gait impairment, urinary incontinence, and cognitive decline. Multiple sclerosis often causes relapsing multifocal deficits that do not localize to a single spinal level. Parkinson's disease is identified by bradykinesia, rigidity, tremor, and progressive postural deformity. Other mimics including Guillain-Barré syndrome, small and large fiber neuropathies, and transverse myelitis further complicate evaluation. Careful history and neurologic examination remain central, while disease-specific tools such as the 2017 McDonald criteria and the Dubousset Functional Test improve recognition. Early identification is essential to avoid unnecessary surgery, guide multidisciplinary referral, improve risk stratification, and optimize patient outcomes.}, }
@article {pmid42011674, year = {2026}, author = {Doyle, L and Galvin, M and Tague, AM and Meldrum, D and Murphy, D and Hardiman, O and Murray, D}, title = {Speech and swallow outcome measures for ALS and perspectives on remote monitoring: an international survey of speech &amp; language therapists.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2026.2655735}, pmid = {42011674}, issn = {2167-9223}, abstract = {OBJECTIVE: Dysarthria and dysphagia occur frequently in Amyotrophic Lateral Sclerosis (ALS). To manage these symptoms, speech &amp; language therapists (SLTs) must identify relevant speech and swallow outcomes and select suitable outcome measurement instruments. Remote monitoring is an evolving mode of health status tracking. This survey aimed to establish SLT perspectives on ALS assessment regarding 1) the clinical meaningfulness of existing outcome measurement instruments 2) remote monitoring 3) usefulness of assessment devices for patient care and 4) bulbar function outcomes and measurement instruments useful for research studies.<br><br>METHODS: An online English-language survey was distributed internationally through gatekeepers and social media.<br><br>RESULTS: Sixty-six SLTs responded from 13 countries. Current outcome measurement instruments were regarded as clinically meaningful in ALS by 35% for speech and 41% for swallow. Only 12% had access to remote monitoring, but 77% would like to avail of it, with 58% perceiving its potential to enhance care. Eighty-two percent deemed remote monitoring using digital patient-reported outcome measures (PROMs) useful. Speech intelligibility measurement was selected as the most useful communication outcome for remote monitoring (92%) and research (94%). SLTs agreed that speech intelligibility test software (72%), smart device apps (70%) and tongue pressure measurement devices (54%) are useful assessment equipment.<br><br>CONCLUSIONS: SLTs want better measurement instruments for speech and swallow in ALS. They regarded technologies including remote monitoring incorporating digital PROMs as useful. Outcomes reflecting communication and swallow functional success level were deemed most useful. These survey findings can inform the selection of digital speech and swallow outcomes for ALS.}, }
@article {pmid42011986, year = {2026}, author = {Palma, A and Stefanelli, R and Trenta, F and Projetti, C and Massa, G and Canterini, S and Fiorenza, MT}, title = {A Cross-Disease Microglial Transcriptional Program Characterizes Neurodegeneration and Highlights SPP1 as a Biomarker.}, journal = {Glia}, volume = {74}, number = {6}, pages = {e70163}, doi = {10.1002/glia.70163}, pmid = {42011986}, issn = {1098-1136}, support = {RM123188F700A7B2//Sapienza Universit&#xe0; di Roma/ ; RG1221816B9646F5//Sapienza Universit&#xe0; di Roma/ ; GSP20006_Covid050//Fondazione Telethon/ ; }, mesh = {*Microglia/metabolism/pathology ; Animals ; Humans ; Mice ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Osteopontin/genetics/metabolism ; Biomarkers/metabolism ; Transcriptome ; Cells, Cultured ; }, abstract = {Microglial cells are key players in maintaining brain homeostasis and responding to pathological conditions. Their multifaceted roles in health and disease have garnered significant attention in the context of neurodegeneration. In recent years, single-cell transcriptomic techniques have provided unprecedented insights into microglial heterogeneity, revealing distinct subpopulations and gene expression patterns associated with neuroprotection or neurotoxicity. Here, we dissect the transcriptomic landscape of microglia by leveraging human single-nuclei RNA sequencing datasets from multiple neurodegenerative conditions, including Amyotrophic Lateral Sclerosis, frontotemporal dementia, Alzheimer's disease, aging, and Parkinson's disease. This integrative analysis identifies distinct microglial subpopulations, reflecting functional heterogeneity across diseases and reveals a shared cross-disease microglial transcriptional program associated with inflammatory and neurodegenerative processes. Using a machine learning framework, we further demonstrate that this transcriptional program enables robust discrimination between neurodegenerative and control samples. Experimental validation in primary microglia isolated from a mouse model of Niemann-Pick disease type C, also known as juvenile Alzheimer's disease, supports the conservation of key components of this program and highlights Spp1 as a biomarker of disease-associated microglia states. Overall, this study provides an improved portrait of microglia transcriptional remodeling across neurodegenerative disorders and offers a framework for identifying conserved molecular features that may inform therapeutic strategies aimed at modulating microglial activity to mitigate disease progression and foster neuroprotection.}, }
@article {pmid42012311, year = {2026}, author = {Erol, ZY and Quintanilla, C and Ozdinler, PH}, title = {Bringing cellular clarity to the cortical component of ALS with a high-density multi-electrode array system.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70552}, pmid = {42012311}, issn = {1742-4658}, support = {R01AG061708//NIH-NIA/ ; }, abstract = {There is selective vulnerability in diseases, requiring the understanding of cell-type specific aspects of neurodegeneration with cellular resolution. Single-cell electrophysiology enables direct investigation of neuronal excitability, ion-channel dynamics, and synaptic transmission with high temporal precision, which is crucial in understanding neuronal circuitries and how they are affected in diseases. Microelectrode arrays (MEAs) have emerged as powerful platforms enabling long-term, parallel, and non-invasive extracellular measurements. The advent of complementary-metal-oxide-semiconductor (CMOS)-based and high-density microelectrode arrays (HD-MEAs) has expanded the spatial and temporal resolution attainable both in vitro and ex vivo. Combined with acute slices, novel cell-culture approaches and three-dimensional (3D) brain organoids, these tools now expedite translational research in disease modeling, neurotoxicity, and pharmacology. Here, we summarise the significance of single-cell electrophysiology, the advantages of the MEA systems, and the latest biomedical and technological advances in this area of research.}, }
@article {pmid42013251, year = {2026}, author = {Wu, ZC and Deng, LJ and Huang, TZ and Dou, HX and Vivone, G and Liu, Y}, title = {Tensor Wheel Decomposition: Theory and Application to Tensor Completion.}, journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TIP.2026.3684420}, pmid = {42013251}, issn = {1941-0042}, abstract = {Recently, tensor network (TN) decompositions have gained prominence in computer vision and contributed promising results to tensor recovery for their capability of compactly and efficiently representing high-order tensors. However, current TN topologies are rather being developed towards more intricate structures to pursue incremental improvements, resulting in a drastically increased number of TN ranks, which requires laborious hyper-parameter selection, especially for higher-order cases. In this paper, we propose a novel TN decomposition, dubbed tensor wheel (TW) decomposition, in which a high-order tensor is represented by a set of latent factors mapped into a specific wheel topology. Such a decomposition is constructed starting from analyzing the graph structure, aiming to more accurately characterize the complex interactions inside objectives while maintaining a lower hyper-parameter scale, theoretically alleviating the above deficiencies. The comprehensive analysis of the mathematical properties fully demonstrates that TW decomposition can be more potential in representation capabilities and more flexible in controlling both parameter storage and computational costs. To compute the TW-format decomposition, the sequential singular value decomposition (SVD)-based and the alternating least squares (ALS)-based learning algorithms are developed. Furthermore, to investigate the validity of TW decomposition, we provide its one numerical application, i.e., tensor completion (TC), yet develop an efficient proximal alternating minimization-based solving algorithm with guaranteed convergence. Experimental results on both synthetic and real-world data reveal that TW decomposition significantly outperforms other state-of-the-art tensor decompositions for incomplete-tensor inference, especially under solely few observations, thus substantiating the superiority and reliability of TW decomposition.}, }
@article {pmid42013353, year = {2026}, author = {Szabo, A}, title = {When treatment becomes the problem: A qualitative analysis of addiction components in rhinitis medicamentosa.}, journal = {Journal of behavioral addictions}, volume = {}, number = {}, pages = {}, doi = {10.1556/2006.2025.00461}, pmid = {42013353}, issn = {2063-5303}, abstract = {Prolonged use of topical nasal decongestants such as xylometazoline or oxymetazoline can lead to rhinitis medicamentosa (RM). This medication-induced condition is characterized by rebound congestion and compulsive reuse. A debated question is whether RM signifies physiological dependence, addiction, or simply a habit. This commentary aimed to evaluate Lakatos et al.'s (2025) work, which investigated this issue through qualitative interviews with 20 affected individuals. Using directed content analysis based on Griffiths' (2005) components model of addiction, Lakatos et al., identified all six elements (salience, mood modification, tolerance, withdrawal, conflict, and relapse) in patient histories. Lakatos et al. (2025) performed a timely and conceptually sophisticated study that connects addiction theory to a common otorhinolaryngological condition. Their qualitative approach captures the everyday lived experience of patients with RM with robust ecological validity and clinical relevance. However, the theory-driven analysis risks confirmation bias by fitting data to Griffiths' addiction model, and the small, convenience-based sample limits generalizability. Despite these constraints, the paper offers valuable insight into how negative reinforcement and conditioned anxiety sustain compulsive nasal spray use. Overall, it successfully bridges clinical observation and theoretical debate, advancing understanding of iatrogenic dependence within everyday medical practice.}, }
@article {pmid42013406, year = {2026}, author = {Weemering, DN and van Unnik, JWJ and Genge, A and van den Berg, LH and van Eijk, RPA}, title = {Heterogeneity in the Analysis of the ALSFRS-R in ALS Clinical Trials and its Effect on the Validity and Precision of Trial Conclusions.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e214937}, doi = {10.1212/WNL.0000000000214937}, pmid = {42013406}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/therapy ; *Randomized Controlled Trials as Topic/standards ; Reproducibility of Results ; *Disability Evaluation ; Severity of Illness Index ; }, abstract = {BACKGROUND AND OBJECTIVES: Disability rating scales play a pivotal role in clinical trials, but there is a notable lack of guidance on how to analyze these scales. Using amyotrophic lateral sclerosis as a case study, our aim was to explore how disability rating scales have been analyzed in completed clinical trials and to assess how these different approaches influence both the risk of false-positive findings and the statistical power to detect true treatment effects.<br><br>METHODS: We searched PubMed and Embase to systematically identify randomized, placebo-controlled clinical trials using the revised ALS functional rating scale (ALSFRS-R) as primary end point, with &#x2265;20 randomly assigned patients and &#x2265;12-weeks of follow-up. Data were extracted on the statistical analysis approaches and strategies for handling missing data. Variability in statistical methods was mapped to the various research questions that the trials aimed to address. A simulation study assessed how each statistical method influenced validity (false-positive rate) and precision (statistical power), using the Ceftriaxone trial data set to model a realistic trial scenario.<br><br>RESULTS: Our analysis included 45 randomized clinical trials, comprising a total sample size of 7,338 patients, and identified 39 distinct statistical methods using a mixture of longitudinal and cross-sectional techniques. Most trials (55.6%) did not use all available (longitudinal) ALSFRS-R measurements, resulting in suboptimal utilization of patient data and reduced statistical precision. Applying the different statistical methods to the same trial data set resulted in large differences in the estimated treatment effect size, ranging from a negative 1.33 to a positive 2.33 SD difference. Among the methods used, 38.9% (95% CI 24.8%-55.1%) were at risk of increasing false-positive rates, potentially contributing to the erroneous advancement of ineffective treatments. Statistical power of valid strategies varied widely, ranging from 17.9% to 78.2%.<br><br>DISCUSSION: Our results demonstrate considerable variability in statistical methods, with the choice of method able to influence the estimated treatment effects, potentially resulting in misleading conclusions and uncertainty about treatment effects. This limits the interpretability and comparability of clinical trials and influences clinical decision-making and drug development. Establishing statistical consensus recommendations could improve the utility of disability scales in clinical trials and accelerate progress toward effective therapies for neurodegenerative diseases.}, }
@article {pmid42013408, year = {2026}, author = {de Carvalho, M}, title = {The Cat is Out of the Bag: Confronting False-Positive Risks in Amyotrophic Lateral Sclerosis Clinical Trials.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e218029}, doi = {10.1212/WNL.0000000000218029}, pmid = {42013408}, issn = {1526-632X}, }
@article {pmid42013466, year = {2026}, author = {Darke, A and Orsulak, C}, title = {How effective does a new drug for Amyotrophic Lateral Sclerosis need to be - the patient perspective: a letter in response to "Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND" published in vol. 26, pp. 249-258.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {485-486}, doi = {10.1080/21678421.2025.2589781}, pmid = {42013466}, issn = {2167-9223}, }
@article {pmid42013476, year = {2026}, author = {El-Agamy, SE and Mattedi, F and Fratta, P}, title = {Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics.}, journal = {Annual review of genomics and human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-genom-022024-011307}, pmid = {42013476}, issn = {1545-293X}, abstract = {TDP-43 is an RNA-binding protein that regulates multiple aspects of RNA processing, and its mislocalization from the nucleus to the cytoplasm is a defining feature of amyotrophic lateral sclerosis (ALS). While both loss- and gain-of-function mechanisms contribute to disease, the discovery of cryptic splicing has shed light on the downstream consequences of TDP-43 nuclear clearance for neuronal health. Here, we highlight how loss of nuclear TDP-43 can drive a cascade of events that lead to the impairment of cellular proteostasis and result in a positive feedback loop that perpetuates neuronal dysfunction. This sustains the appearance of cryptic splicing events in genes that are involved in key pathways for the maintenance of axonal homeostasis and synaptic transmission. In contrast to their detrimental effects on neuronal health, cryptic splicing mechanisms may be harnessed to develop novel therapeutic strategies, unprecedentedly expanding the availability of therapeutic avenues for TDP-43 proteinopathies.}, }
@article {pmid42013513, year = {2026}, author = {Saldanha-Castro, P and Vyas, MV and Jain, D and Santos-Neto, D and Mirian, A and ,  and Zinman, L and Abrahao, A}, title = {Association between statin use and survival in patients with ALS: A propensity score-matched analysis.}, journal = {Journal of the neurological sciences}, volume = {486}, number = {}, pages = {125916}, doi = {10.1016/j.jns.2026.125916}, pmid = {42013513}, issn = {1878-5883}, abstract = {OBJECTIVE: To evaluate the association between statin use, disease progression, and survival in patients with amyotrophic lateral sclerosis (ALS) using data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.<br><br>METHODS: We conducted a retrospective cohort study of adults (&#x2265;18&#xa0;years) diagnosed with ALS and included in the PRO-ACT database. Statin exposure was defined as any statin use at cohort entry. Statin users were matched 1:1 to non-users using propensity score matching based on age, baseline ALS Functional Rating Scale (ALSFRS), disease duration, ethnicity, bulbar onset, riluzole use, and cardiovascular or metabolic comorbidities. Participants were followed from cohort entry or statin initiation until death, end of follow-up (36&#xa0;months), or loss to follow-up. The primary outcome was all-cause mortality at three years. The secondary outcome was disease progression, defined as time to a four-point decline in ALSFRS score. Cox proportional hazards models were used to estimate hazard ratios (HRs).<br><br>RESULTS: Among 3439 eligible participants, 131 statin users (mean age 63.1&#xa0;years; 34% female) were identified and matched to 131 non-users. Statin use was not associated with all-cause mortality at three years (HR 0.97; 95% CI 0.66-1.44; P&#xa0;=&#xa0;0.89). Disease progression was also similar between statin users and non-users (HR 1.02; 95% CI 0.80-1.31; P&#xa0;=&#xa0;0.90).<br><br>CONCLUSIONS: In this large observational cohort, statin use was not associated with survival or disease progression in ALS. These findings do not support statin initiation or discontinuation based solely on ALS diagnosis or disease course.}, }
@article {pmid42013739, year = {2026}, author = {Mirveis, Z and Patil, N and Byrne, HJ}, title = {Evaluating data-mining strategies for label-free Raman microspectroscopic analysis of cellular processes in vitro: dynamic dimensionality reduction.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {359}, number = {}, pages = {127923}, doi = {10.1016/j.saa.2026.127923}, pmid = {42013739}, issn = {1873-3557}, abstract = {Understanding dynamic intracellular metabolism is essential for elucidating cellular function and disease mechanisms. However, analysing time-resolved spectral data is challenging due to overlapping signals, high dimensionality, and biological variability. This study evaluates the applicability of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) for resolving complex cellular spectral data and introduces a framework that integrates Principal Component Analysis (PCA) of sequential time points as a preprocessing step. PCA was used to extract dominant spectral variance associated with biological kinetics (PC1), and MCR-ALS was subsequently applied to the sequential PC1 loadings to enhance the recovery of kinetic trends. To validate the approach, simulated Raman datasets were generated by combining predefined component spectra with known kinetic profiles, representing sequential (glycolysis-like) and parallel (glycolysis + glutaminolysis) models. These signals were superimposed onto real cellular spectra ("Sim-Cell" data) to include intercellular variability and background interference. Standard MCR-ALS was first assessed to determine the optimal number of components and, when applied to cell-free datasets, resolved up to three components. It was then applied to Sim-Cell datasets to evaluate performance under simulated biological conditions. MCR-ALS resolved the sequential model up to a cellular background weight of 2 but failed for the parallel model, highlighting limitations in complex, overlapping systems. In contrast, PCA-MCR-ALS substantially improved performance under strong cellular background, maintaining accurate resolution up to weight = 5 for sequential and weight = 8 for parallel models. Overall, this study benchmarks chemometric performance in label-free Raman microspectroscopy and highlights PCA-assisted MCR-ALS for analysing time-resolved intracellular spectral data.}, }
@article {pmid42013766, year = {2026}, author = {Kravitz, D and Saker, TS and Odess, N and Drory, VE and Abraham, A}, title = {Quantitative sonographic assessment of relaxed and contracted muscle thickness predicts survival in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {187}, number = {}, pages = {2111845}, doi = {10.1016/j.clinph.2026.2111845}, pmid = {42013766}, issn = {1872-8952}, abstract = {OBJECTIVES: To explore the ability of quantitative sonographic assessment of muscle thickness to predict mortality in amyotrophic lateral sclerosis (ALS) patients compared with manual muscle testing (MMT) and the ALS functional rating scale-revised (ALSFRS-R).<br><br>METHODS: 86 prospectively recruited ALS patients underwent clinical assessment and quantitative sonographic assessment of muscle thickness in 8 relaxed and 4 contracted limb muscles. Average monthly decline rates of MMT and ALSFRS-R scores and measured relaxed and contracted muscle thickness were calculated at study entry. The area under the curve (AUC), optimal cutoff points, and hazard ratio (HR) for 1 to 3-year mortality were calculated and adjusted for covariates.<br><br>RESULTS: Significant increased 1-year mortality was associated only with lower contracted muscle thickness (HR-8.1), while increased 3-year mortality was in greater correlation with a reduced contracted muscle thickness (HR-4.85) than with a decline in MMT (HR-3.31) and ALSFRS-R (HR-2.12) or a reduced relaxed muscle thickness (HR-2.65).<br><br>CONCLUSION: Reduced limb muscle thickness, especially in a contracted state, is associated with significantly increased mortality in ALS.<br><br>SIGNIFICANCE: Sonographic muscle measurement is a novel estimator of ALS mortality and has the potential to serve as an additional biomarker in future multi-variable prognostication models, clinical decision making and research.}, }
@article {pmid41998851, year = {2026}, author = {Passarelli, F and Boeri, L and Pozzi, E and Negri, F and Raffo, M and Corsini, C and Bertini, A and d'Arma, A and Montanari, E and Montorsi, F and Salonia, A}, title = {Are Reference Intervals for Calculated Free Testosterone in Healthy Men Reliable Also in Men With Erectile Dysfunction? Findings From a Cross-Sectional Study.}, journal = {Andrology}, volume = {}, number = {}, pages = {}, doi = {10.1111/andr.70235}, pmid = {41998851}, issn = {2047-2927}, support = {//the IRCCS San Raffaele Hospital/ ; }, abstract = {BACKGROUND: Reference intervals for calculated free testosterone (cFT) in healthy, nonobese men have been released, but have not been validated in men with erectile dysfunction (ED).<br><br>OBJECTIVES: To assess the clinical impact of new cFT reference intervals in men with new-onset ED.<br><br>METHODS: Data from 410 healthy, nonobese men were analyzed (2015-2023). cFT was assessed using Vermeulen's formula and compared to Jasuja et&#xa0;al.'s (2022) reference values, using the 2.5th percentile as a pathological threshold. At baseline, all patients completed the International Index of Erectile Function (IIEF) and Beck Depression Inventory (BDI). Descriptive statistics and linear regression analyses were applied.<br><br>RESULTS: Median (IQR) age and total testosterone at presentation were 48 (38-59) years and 4.7 (3.3-6.1) ng/mL. Median IIEF-EF score was 18 (8-23), with 134 patients (32.8%) reporting severe ED. Percentiles of cFT in ED men were: 2.5th = 10, 10th = 50, 50th = 90, 90th = 150, and 97.5th = 227.5 pg/mL, compared to 66, 91, 141, 240, and 309 pg/mL in healthy controls. Seventy-four had cFT between 10 and 66 pg/mL, normal for ED distribution but pathological by healthy reference. This group was older (p<0.01), had lower IIEF-EF (p<0.001), and higher BDI (p<0.01) versus those with cFT >66 pg/mL, though other parameters were similar. Severe ED rates were 72.7%, 44.6%, and 28.7% in men with cFT <10, 10-66, and >66 pg/mL (p<0.01). At multivariable regression, cFT >66 pg/mL was linked to higher IIEF-EF (p = 0.02), while cFT >66 pg/mL (p = 0.03) and younger age (p = 0.01) were associated with lower BDI scores.<br><br>CONCLUSIONS: Reference thresholds for cFT derived from healthy men identify, among men with ED, a subgroup showing a less favorable erectile and psychometric profile. These findings suggest that healthy-derived cFT reference values may provide clinically useful information in the assessment of men presenting with ED.}, }
@article {pmid41998853, year = {2026}, author = {Qian, W and Zhu, D and Yang, S}, title = {Spray Coating of Thick Perovskite Films for Photodetectors: The Aerosol-Liquid-Solid Mechanisms and Sensing Applications.}, journal = {Chemical record (New York, N.Y.)}, volume = {}, number = {}, pages = {e202500358}, doi = {10.1002/tcr.202500358}, pmid = {41998853}, issn = {1528-0691}, support = {22261160370//National Natural Science Foundation of China/ ; U2001217//National Natural Science Foundation of China/ ; 22579004//National Natural Science Foundation of China/ ; 12505294//National Natural Science Foundation of China/ ; 2508085QA021//Natural Science Foundation of Anhui Province/ ; KQTD2016053015544057//Shenzhen Peacock Plan/ ; SYSRD20250529113001002//Shenzhen Key Lab of Glass-based Optoelectronic Thin Film Materials/ ; //Shenzhen Bay Lab Concept Validation Fund/ ; }, abstract = {Spray coating has emerged as a transformative technique for fabricating high-quality perovskite thick films, which are essential for advanced photodetectors such as X-ray and narrowband sensors. This review surveys and systematically elucidates the physicochemical mechanisms underlying the aerosol-liquid-solid (ALS) transformation during spray deposition, focusing on three core stages: aerosol generation (via pneumatic, electrospray, or ultrasonic methods), droplet deposition and wetting dynamics, and liquid-to-solid crystallization. The interplay among precursor properties, spray parameters, and substrate characteristics dictates film morphology, crystallinity, and defect density. We highlight optimization strategies, including solvent engineering, additive incorporation, and process control, that enable the growth of dense, vertically aligned, and large-grained perovskite films with thicknesses up to hundreds of micrometers. Furthermore, the integration of dimensional engineering and heterojunction design through sequential spray deposition enhances charge transport, suppresses ion migration, and improves detection performance. Applications of these films are demonstrated in direct X-ray detectors and filter-free narrowband photodetectors with high sensitivity, low detection limits, and excellent spatial resolution. Remaining challenges are also discussed in understanding dynamic phase transitions and ensuring large-area uniformity of the spray-deposited films. Advancing in situ characterization and intelligent process control will accelerate the transition of spray coating from a laboratory technique to a scalable precision-manufacturing platform for next-generation perovskite optoelectronics.}, }
@article {pmid42000222, year = {2026}, author = {Thate, S and Lubasch, JS and Plata, C and Gülöz, K and Eisenreich, EW and Röhrig, R and Seeger, I}, title = {[Low-priority emergency calls: planned and actual dispatching of resources in a German Emergency Dispatch Center (EDC) following the introduction of a standardized emergency call query. A retrospective analysis of EDC data].}, journal = {Zeitschrift fur Evidenz, Fortbildung und Qualitat im Gesundheitswesen}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.zefq.2026.03.006}, pmid = {42000222}, issn = {2212-0289}, abstract = {BACKGROUND: A significant proportion of calls to Emergency Dispatch Centers (EDCs) are classified as low-priority calls (LPCs). This study examines LPCs detected in an EDC through a standardized emergency call query and the degree of fulfilment between planned and actual dispatching.<br><br>METHOD: This retrospective prevalence study uses descriptive and exploratory data analysis to examine data from the routine documentation of the emergency dispatch system (EDS) and the standardized emergency call system of an EDC. The primary endpoint of the study is the frequency of LPCs for assistance and their standardized assignment to the appropriate care structures of medical on-call services (provided by the Association of Statutory Health Insurance Physicians, ASHIP) and community paramedics (CPs).<br><br>RESULTS: Just under 10% of the calls handled with a standardized emergency call query were LPCs. Of these, 54.0% fell within the remit of the ASHIP and 41.1% within the remit of EMS. In areas without CPs, an ALS ambulance was dispatched twice as often as in areas with such a system (85.9% versus 41.6%). Also, a difference was found regarding the subsequent transport to a hospital (57.4% vs. 29%). There were only minor differences in utilization between day (49.2%) and night (50.8%).<br><br>CONCLUSION: The data examined support the current approach to reforming cross-sectoral emergency care services. Detecting LPCs will only lead to a needs-based care if suitable downstream resources are available at all times. The control of all outreach care resources by the EDC could prevent disruptions at sector boundaries.}, }
@article {pmid42000269, year = {2026}, author = {Desnuelle, C and Couratier, P and Corcia, P and Duburcq, A and Torreton, E and Baffert, S and Nevoret, C and Turgeman, S}, title = {Treatment pathway, healthcare resource utilization and direct cost of ALS in France: A nationwide claims database study.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2026.02.159}, pmid = {42000269}, issn = {0035-3787}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease, associated with high clinical burden. The aim of this study was to estimate ALS-related healthcare resource utilization (HCRU), associated direct costs and their determinants in France.<br><br>METHODS: A retrospective cohort study was conducted among newly diagnosed patients with ALS identified between 2012 and 2022 (11 years) in the French National Health Data System (SNDS) through a validated algorithm. This incident population was compared with non-ALS controls (1:2) matched on age, sex, and region. Direct all-cause healthcare reimbursable costs were estimated. Survival, HCRU and direct costs were analyzed over the first five years after diagnostic.<br><br>RESULTS: A total of 16,814 newly diagnosed ALS patients were identified who could be matched with 33,628 non-ALS controls. The median age was 68.0 year and 55.3% were males. Over the first year after diagnosis, the direct all-cause medical cost per patient was &#x20ac;19,497 of which 47.2% was related to inpatient care, compared to &#x20ac;4,921 for controls which led to an ALS-attributable cost of &#x20ac;14,474 per patient per year. ALS patients had significantly (P<0.0001) higher HCRU than controls in all items of inpatient and outpatient care but especially for utilization of medical devices, frequencies of nurse and physiotherapist visits and acute care hospitalizations. The annual direct cost per patient who survived the successive annual period after diagnosis increased during the second, third and fourth year to &#x20ac;22,358, &#x20ac;22,276 and &#x20ac;21,372 respectively and then declined in year 5 to &#x20ac;19,720. These results largely underestimated the real cost of the management of ALS by not considering the out-of-pocket expenses associated with informal care and home renovation as well as productivity loss.<br><br>CONCLUSIONS: Patients with ALS had higher HCRU and direct medical cost, compared with controls. The economic burden of ALS was substantial even when restricted to the medical costs covered by the public health insurance system. There is an important need for novel therapies that might lower disease progression in early disease stages.}, }
@article {pmid42002556, year = {2026}, author = {Selvam, AK and Loganathan, A}, title = {An intelligent EEG-based ensemble framework for communication assistance in Locked-In Syndrome patients.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-47041-4}, pmid = {42002556}, issn = {2045-2322}, }
@article {pmid42003855, year = {2026}, author = {Casey, M and Coghlan, D and Carroll, &#xc1; and Buckley, T and Stokes, D}, title = {Assessing Quality of Action Research Using the Quality Assessment Action Research Checklist (QuARC): A Hybrid Systematic Narrative Review.}, journal = {Journal of advanced nursing}, volume = {}, number = {}, pages = {}, doi = {10.1111/jan.70607}, pmid = {42003855}, issn = {1365-2648}, abstract = {AIM: To evaluate the quality of action research studies using the Quality Assessment Action Research Checklist (QuARC) and to assess its utility as a tool for quality appraisal.<br><br>DESIGN: A hybrid systematic narrative review following Turnbull et&#xa0;al.'s six-stage methodology and reported in accordance with PRISMA 2020 guidance.<br><br>DATA SOURCES: Scopus was searched for author self-identified action research studies published between January 2020 and March 2024.<br><br>REVIEW METHODS: Two reviewers independently selected studies meeting inclusion criteria: health science action research papers addressing any or all of QuARC's four quality factors. A scoring system was used to capture each of QuARC's 17 quality items, which was scored as 0 (absent), 0.5 (partial) or 1 (comprehensive). Narrative synthesis was undertaken across the four QuARC domains.<br><br>RESULTS: Thirty-two studies met the inclusion criteria. Reporting frequencies across QuARC were: Context (92.5%, mean&#x2009;=&#x2009;3.7/4), Quality of Relationships (55% mean&#x2009;=&#x2009;2.2/4), Quality of Action Research Process (62.5% mean&#x2009;=&#x2009;2.5/4), and Quality of Outcomes (62.5% mean&#x2009;=&#x2009;3.1/5). Reporting gaps were most evident in reflexive co-analysis, relational evaluation and explicit theoretical contribution.<br><br>CONCLUSION: Global reporting of rigour and quality in action research remains inconsistent. QuARC functioned both as an appraisal instrument and as an analytic lens, revealing systematic patterns in how action research privileges practical change over theoretical articulation and reflexive relational work. Further refinement and validation are recommended to strengthen its reliability as an appraisal tool.<br><br>IMPLICATIONS: Findings highlighted a critical need to establish a standardised, validated approach to assess quality in action research. Adoption of QuARC can enhance consistency, clarity and comparability across studies, strengthening the evidence base for action research methodologies.<br><br>IMPACT: This first systematic synthesis of QuARC's application provides an evidence base for its further development. This lays foundations for international standards in quality appraisal, strengthening the credibility, reproducibility and influence of action research.}, }
@article {pmid41997149, year = {2026}, author = {Wu, T and Yuan, L and Sasaki, Y and Chen, SJ and Buchser, W and Bloom, AJ and DiAntonio, A and Milbrandt, J}, title = {SARM1 executes neuronal parthanatos and promotes excitotoxic cell death.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2026.03.027}, pmid = {41997149}, issn = {1097-4199}, abstract = {The nicotinamide adenine dinucleotide (NAD[+]) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD[+] ratio. DNA damage induces NAD[+] loss and an increased NMN/NAD[+] ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct DNA-damaging agents activate SARM1 and induce axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of hyperactivated PARP1, which are pathognomonic of parthanatos, including mitochondrial depolarization, nuclear translocation of apoptosis-inducing factor (AIF), and cell death. Hence, SARM1 is an essential component of neuronal parthanatos. Moreover, complex neurodegenerative stimuli whose mechanisms include activation of parthanatos, such as 1-methyl-4-phenyl-pyridinium (MPP[+]) dopaminergic neuron toxicity and N-methyl-D-aspartate (NMDA) excitotoxicity, are potently protected by SARM1 inhibition. These findings place SARM1 at the nexus of multiple mechanisms driving neuronal cell death, thereby greatly expanding the potential clinical utility of SARM1 inhibitors beyond diseases of axon loss.}, }
@article {pmid41996956, year = {2026}, author = {Li, M and Han, M and Li, X and Yu, N and Zhang, X and Zhao, L and Liu, Q and Liu, H and Wu, J and Han, Z and Dong, H and Liu, Y}, title = {Sleep spindle alterations as a novel biomarker for phenotypic stratification in sporadic amyotrophic lateral sclerosis.}, journal = {Sleep medicine}, volume = {144}, number = {}, pages = {108961}, doi = {10.1016/j.sleep.2026.108961}, pmid = {41996956}, issn = {1878-5506}, abstract = {OBJECTIVE: To quantitatively evaluate sleep spindle alterations in sporadic amyotrophic lateral sclerosis (ALS) and explore their potential as biomarkers for diagnosis and phenotypic stratification.<br><br>METHODS: In this cross-sectional study, overnight sleep electroencephalography was recorded in 97 sporadic ALS patients and 73 matched healthy controls. Sleep spindle parameters (amplitude, duration, density, frequency) were automatically analyzed at frontal leads. Multiple comparisons were controlled using the false discovery rate (FDR) approach. We used least absolute shrinkage and selection operator (LASSO) regression for diagnostic modeling and employed K-means clustering to define spindle-based subtypes. Bootstrap internal validation was performed to assess model optimism.<br><br>RESULTS: After FDR correction, ALS patients showed significant spindle abnormalities predominantly in the bipolar FP12 derivation, including reduced slow spindle density (p-FDR&#xa0;=&#xa0;0.007), reduced overall spindle density (p-FDR&#xa0;=&#xa0;0.007), and shortened slow spindle duration (p-FDR&#xa0;=&#xa0;0.017). A diagnostic model incorporating Epworth Sleepiness Scale score, wake after sleep onset, sleep efficiency, FP12 slow spindle density, and education years showed promising discriminative ability (apparent AUC&#xa0;=&#xa0;0.931; optimism-corrected AUC&#xa0;=&#xa0;0.923). Unsupervised clustering consistently revealed two distinct spindle phenotypes. The "spindle-deficient" phenotype, characterized by poorer spindle integrity, was independently associated with lower ALSFRS-R scores (OR 1.101, 95% CI 1.024-1.202, p&#xa0;=&#xa0;0.017), lower percentage of predicted forced vital capacity (OR 1.035, 95% CI 1.010-1.065, p&#xa0;=&#xa0;0.011), and absence of drinking history (OR 3.03, 95% CI 1.02-9.46, p&#xa0;=&#xa0;0.049).<br><br>CONCLUSIONS: Sleep spindle alterations may represent a core electrophysiological feature of ALS, potentially reflecting thalamocortical dysfunction. These exploratory findings suggest that spindle parameters could serve as candidate biomarkers for disease stratification, though validation in independent longitudinal cohorts is needed before clinical application.}, }
@article {pmid41996987, year = {2026}, author = {Priya, R and Tanti, GK and Jain, BP}, title = {Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.}, journal = {Biochemical and biophysical research communications}, volume = {818}, number = {}, pages = {153723}, doi = {10.1016/j.bbrc.2026.153723}, pmid = {41996987}, issn = {1090-2104}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weakness, paralysis, and respiratory failure. Dysregulation of RNA metabolism and splicing has emerged as a central mechanism in ALS pathogenesis. TARDBP (TAR DNA-binding protein), FET family proteins (FUS, EWSR1, TAF15), SOD1 (Superoxide Dismutase 1), and C9orf72 (Chromosome 9 Open Reading Frame 72) are key genes associated with ALS that regulate RNA processing, alternative splicing, and nuclear-cytoplasmic transport. Mutations or mislocalization of these proteins result in nuclear loss-of-function and cytoplasmic gain-of-function toxicity, promoting protein aggregation, sequestering spliceosomal components, and impairing spliceosome assembly. This leads to the aberrant inclusion of cryptic exons in essential neuronal genes, such as STMN2 (Stathmin 2) and UNC13A (Unc-13 Homolog A), resulting in the production of truncated proteins, defective axonal maintenance, and impaired synaptic function. TDP-43 pathology, a hallmark of ALS, disrupts splicing and RNA transport, while C9orf72 repeat expansions and FET protein mutations exacerbate cytoplasmic aggregation and stress granule dynamics. Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical studies. Complementary approaches, including the inhibition of stress kinases and the activation of autophagy, reduce cytoplasmic protein aggregation and support neuronal homeostasis. This review provides a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS. Understanding the interplay among splicing defects, RNA-binding protein pathology, and neuronal degeneration is critical for developing next-generation multimodal therapies to restore RNA processing, reduce toxic protein accumulation, and promote motor neuron survival.}, }
@article {pmid41989758, year = {2026}, author = {Ahmed, M and Volkening, K and Mclellan, C and Shoesmith, C and Balci, TB and Strong, MJ}, title = {Emerging strategies for interpreting variants of uncertain significance (VUS) in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/21678421.2026.2655734}, pmid = {41989758}, issn = {2167-9223}, abstract = {As the use of genetic testing for neurological diseases increases exponentially, interpreting variants of uncertain significance (VUS) has become a challenging problem. Nowhere has this become more evident than in amyotrophic lateral sclerosis (ALS) and the frontotemporal dementias (FTDs), both of which are complex heterogeneous disorders in which an increasing array of disease-causative and modifying genetic variants are observed. Moreover, while traditionally identified as distinct clinical syndromes, ALS and FTD are increasingly recognized to exist along a spectrum of clinical syndromes (termed the frontotemporal spectrum disorders of ALS; ALS-FTSD) with shared genetic risk. While VUS are generally not used in clinic for decision-making or counseling given their obvious limitations in being medically actionable, their correct interpretation is dynamic and rapidly evolving. VUS are increasingly the subject of intensive study as potential determinants of biological outcomes. It is timely therefore to review the current state of VUS interpretation and to critically evaluate how this can be applied to enhance both patient care and treatment decisions in the broader context of neurological disorders and more specifically in the context of ALS and ALS-FTSD. In doing so, we also explore the evolving challenge of defining pathogenicity of oligogenic inheritance in the context of multiple VUS detection in a single individual using an illustrative case example.}, }
@article {pmid41991114, year = {2026}, author = {Zhang, W and Zhang, D and Han, L and Wang, D and Huo, D and Tan, X and Su, X and Wang, M and Xu, J and Cheng, J and Feng, H}, title = {The neuroprotective effect of guanabenz combined with α-lipoic acid in the hSOD1-G93A amyotrophic lateral sclerosis model.}, journal = {Brain research bulletin}, volume = {239}, number = {}, pages = {111890}, doi = {10.1016/j.brainresbull.2026.111890}, pmid = {41991114}, issn = {1873-2747}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and although its pathogenesis is not yet clear, the multifactorial mechanisms that affect motor neuron death are intertwined, exacerbating the disease. Here, we explore the effectiveness and mechanism of a combination medication that combines guanabenz with α-lipoic acid in an in vitro as well as in vivo model of ALS. In this research, we initially determined the independent action targets and synergistic action targets of the two drugs through network pharmacology and molecular docking. Subsequently, we further investigated their specific action mechanisms in both in vivo and in vitro studies. In NSC34 cells transfected with hSOD1-G93A, we observed that the combined drugs could more effectively safeguard against cell damage and the production of reactive oxygen species (ROS) generated by mutant hSOD1, superior to monotherapy. This was achieved by upregulating the p-AKT/HO-1 pathway and synergistically suppressing the GRP78/CHOP pathway. Moreover, we found that combination drugs can effectively delay the decline in motor function of hSOD1-G93A transgenic mice by synergistically inhibiting GRP78/CHOP pathway. They can protect the motor neurons in the anterior horn of the spinal cord and suppress gliosis in hSOD1-G93A transgenic mice. In summary, our research indicates that the combination therapy of guanabenz and α-lipoic acid can serve as a viable treatment option for ALS.}, }
@article {pmid41991228, year = {2026}, author = {Shukla, A and Jaiswal, P and Ashraf, F}, title = {Bannayan-Riley-Ruvalcaba syndrome with arteriovenous malformation.}, journal = {BMJ case reports}, volume = {19}, number = {4}, pages = {}, doi = {10.1136/bcr-2025-269126}, pmid = {41991228}, issn = {1757-790X}, mesh = {Humans ; Male ; *Hamartoma Syndrome, Multiple/diagnosis/surgery/complications ; *Arteriovenous Malformations/surgery/diagnosis/complications ; Child ; *Femoral Artery/surgery/abnormalities ; }, abstract = {Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal dominant PTEN hamartomatous tumour syndrome characterised by macrocephaly, genital lentiginosis and intestinal polyposis, often with mucocutaneous, skeletal and vascular anomalies. We report a preadolescent boy with macrocephaly, oral papillomatosis, palmar keratoses, penile lentiginosis, pectus excavatum, hepatosplenomegaly, gastrointestinal hamartomatous polyps and intracranial vascular changes. A large high-flow arteriovenous malformation (AVM) of the right superficial femoral artery was surgically excised with skin graft reconstruction, resulting in a viable graft and no complications. The diagnosis was made using Parisi et al's BRRS criteria and Pilarski's PTEN syndrome guidelines. AVMs are rare in BRRS, reported in ≤10% of cases, typically high-flow and limb-located. This case underscores the need for multidisciplinary evaluation and surveillance for PTEN-associated malignancies and highlights surgical intervention's role in preventing complications while expanding BRRS's recognised vascular phenotype. Early recognition facilitates timely, targeted management.}, }
@article {pmid41992463, year = {2026}, author = {Veith, PD and Leeming, MG and Chen, YY and Reynolds, EC}, title = {Cargo Secreted by the Type IX Secretion System of Porphyromonas gingivalis Are Tethered to O-Lipopolysaccharides via a Pentasaccharide Linker.}, journal = {MicrobiologyOpen}, volume = {15}, number = {2}, pages = {e70296}, doi = {10.1002/mbo3.70296}, pmid = {41992463}, issn = {2045-8827}, support = {1123866//Australian National Health and Medical Research Council/ ; DP200100914//Australian Research Council/ ; 20080108//Australian Government Department of Industry, Innovation and Science/ ; }, mesh = {*Porphyromonas gingivalis/metabolism/genetics/chemistry ; *Lipopolysaccharides/chemistry/metabolism ; *Bacterial Secretion Systems/metabolism ; Mass Spectrometry ; *Bacterial Proteins/metabolism ; *O Antigens/metabolism/chemistry ; Virulence Factors/metabolism ; }, abstract = {The Gram-negative oral pathogen, Porphyromonas gingivalis, uses the Type IX Secretion System (T9SS) to secrete major virulence factors (cargo proteins) and anchor them to the cell surface via a novel linking sugar, 2-N-seryl, 3-N-acetylglucuronamide (SAGA), which is a component of a specific type of lipopolysaccharide, A-LPS. The reported structure of the polysaccharide component (A-PS) was a repeating phosphorylated mannan whereas the PS of conventional O-LPS (O-PS) is a repeating Gal-Glu-Rha-GalNAc unit. Here, we have performed extensive mass spectrometric analyses of cargo protein-linked LPS with and without proteinase K treatment to determine the structure of A-LPS. Limited acid hydrolysis of the PS backbone with trifluoromethanesulfonic acid enabled long PS fragments linked to cargo-derived peptides to be identified for the first time. Unexpectedly, rather than finding A-PS units, up to eleven O-PS repeating units were found linked to cargo via a novel pentasaccharide linker designated A-LS, composed of SAGA-Hex-dHex(C4H4O3)(Pent)-Hex. In addition, samples from a wzzP/porT double mutant that produced free truncated O-PS were specifically hydrolyzed to cleave lipid A prior to MS analysis. In these samples A-LS was found attached to a limited number of O-PS repeating units that in turn were associated with a putative core oligosaccharide that included the LPS-specific sugar, 3-deoxy-d-manno-octulosonic acid (Kdo). The proposed structure of A-LPS explains all 11 genes specific to A-LPS biosynthesis, and provides the first structural evidence that cargo proteins such as the gingipains are anchored to the cell surface via a complete LPS molecule.}, }
@article {pmid41992971, year = {2026}, author = {Cheng, H and Zheng, G and Yang, Y and Xu, C and Tang, G and Huang, C}, title = {Incorporating artificial intelligence into morphological diagnosis of acute leukemias: Current landscape, challenges and prospects (Review).}, journal = {Oncology reports}, volume = {55}, number = {6}, pages = {}, doi = {10.3892/or.2026.9120}, pmid = {41992971}, issn = {1791-2431}, mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Leukemia/diagnosis/pathology ; Microscopy/methods ; Data Mining/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology ; }, abstract = {Acute leukemias (ALs) are a diverse group of hematological malignancies characterized by the abnormal proliferation of immature cells. Microscopic observation of cell morphology based on the French‑American‑British classification remains a fundamental diagnostic method for ALs. However, manual screening from bone marrow smear images is often inefficient, laborious and prone to subjective bias, leading to potential misdiagnosis or missed diagnosis. Artificial intelligence (AI), particularly machine learning (ML), has expanded human capabilities in analyzing complex datasets, leading to breakthroughs in multiple fields, including medical research and clinical practice. Increasingly, ML applications are being developed to diagnose hematological diseases by extracting and aggregating morphological characteristics from peripheral blood and bone marrow smears. However, applying ML methods to recognize cell morphology in hematological diseases presents unique challenges compared with other pathology subspecialties. The present review provided an overview of AI and ML applications in ALs diagnosis, focusing on cell segmentation and data mining methods from microscopy images, and highlights their advantages over manual microscopy.}, }
@article {pmid41993388, year = {2026}, author = {Sahoo, BR and Bhattrai, J and Sharma, A and Jakob, U and Bardwell, JC}, title = {Microprotein Regulates G-quadruplex Driven RNA Aggregation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.10.717804}, pmid = {41993388}, issn = {2692-8205}, abstract = {Repeat expansions of the hexanucleotide GGGGCC in C9orf72 form aberrant phase transitions that have been linked to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. RNA structures such as G-quadruplexes and hairpins play important roles in these processes. Here, we show that the human microprotein ZNF706 acts as a modulator of G-quadruplex formation and RNA phase behavior. ZNF706 antagonizes pathological gel-solid transitions by melting hexanucleotide repeat G-quadruplex structures converting gel-like aggregates into more dynamic condensates. Loss of ZNF706 enhances the cellular production clearance of hexanucleotide repeat-mediated dipeptide repeat proteins, while overexpression suppresses their production and promotes clearance. Mechanistically, ZNF706 influences hexanucleotide repeat condensate fluidity and viscoelasticity. We find ZNF706 acts as an RNA chaperone that remodels repeat RNA structures and solubilizes RNA aggregates. This activity represents one mechanism whereby cells can regulate G-quadruplex driven phase transitions linked to neurodegenerative diseases.}, }
@article {pmid41993486, year = {2026}, author = {Ramos, MEP and Singh, BK and Shelest, O and Tindel, I and Zogu, B and Dawson, A and Mathkar, P and Bell, S and Ho, R}, title = {A region-delineated snRNA-seq atlas of mouse spinal cord across lifespan resolves the interaction of normative aging programs with SOD1-G93A ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.08.717296}, pmid = {41993486}, issn = {2692-8205}, abstract = {Aging is the strongest risk factor for amyotrophic lateral sclerosis (ALS), yet how normative aging programs intersect with disease mechanisms remain unclear. Here we generated a lifespan-resolved, cell type- and region-specific single-nucleus RNA-sequencing atlas of the mouse spinal cord spanning embryonic development through advanced age in WT mice and end-stage disease in the SOD1-G93A ALS model. This resource enabled systematic comparison of physiological aging trajectories with disease-associated transcriptional changes across spinal cord cell types and rostrocaudal regions. We found that SOD1-G93A transcript and protein states differed markedly across spinal regions during disease onset and progression, and these molecular patterns paralleled the relative resilience of cervical regions and the heightened vulnerability of lumbar regions to degeneration in this transgenic mouse model. Prior to disease onset, we identified reduced ubiquitin expression that primed region-specific disruption of proteostasis in the SOD1-G93A spinal cord. Despite these disease-associated changes, aging-related transcriptional programs were largely preserved across most cell types, arguing against a global acceleration of aging in ALS. Instead, microglia emerged as a key exception, exhibiting accelerated and rewired aging- and disease-associated gene expression modules regulated by MITF and NRF2. Together, these findings provide an anatomically, cellularly, and temporally resolved framework for understanding how aging programs interact with disease-specific pathways to shape regional dysfunction and neurodegeneration in ALS.}, }
@article {pmid41993496, year = {2026}, author = {Chin, N and Zhang, Q and Zou, J and Cheng, KC and Zheng, W and Ye, Y}, title = {Nuclear export modulates TDP-43 phase transitions and cytoplasmic aggregation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.16.694670}, pmid = {41993496}, issn = {2692-8205}, abstract = {RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase behavior may influence its aggregation propensity and neurotoxic activity. The mechanism(s) that modulates the transition of TDP-43 from a liquid to solid phase is poorly defined. Here we combine chemical and genome-wide genetic screenings to identify cellular factors that modulate the phase behavior of an RNA-binding defective TDP-43 mutant that mimics an Amyotrophic Lateral Sclerosis (ALS)-associated variant. Our screens uncover multiple cellular processes including RNA splicing, protein translation, proteostasis imbalance and nuclear export as TDP-43 phase regulators. Importantly, TDP-43 phase transition can be dynamically recapitulated in vitro in a semi-permeabilized cell system, which reveals that the inhibition of nuclear export reshapes the nuclear environment in favor of an RNA-dependent TDP-43 liquid-liquid phase separation (LLPS) state, which mitigates cytoplasmic TDP-43 aggregation. We validated this mechanism in a brain organoid model bearing an ALS-associated mutation, showing that nuclear export deficiency can limit pathogenic phospho-TDP-43 accumulation. These findings establish nuclear export as a key regulator of TDP-43 phase transitions and define a mechanistic framework that links altered nuclear transport and phase dynamics to TDP-43 aggregation potential.}, }
@article {pmid41993642, year = {2026}, author = {Zhou, H and Meng, T and Liang, D and Wang, Y}, title = {The effect of statins on the survival of patients with amyotrophic lateral sclerosis: a meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1753992}, pmid = {41993642}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying therapies and a poor overall prognosis. Statins, are commonly used for dyslipidemia, and have been proposed to exert cholesterol-independent actions including anti-inflammatory and potential neuroprotective effects. Prior studies, However, existing studies offer conflicting results regarding their impact on ALS survival. This systematic review and meta-analysis aimed to evaluate the association between statin use and survival outcomes in patients with ALS.<br><br>METHODS: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science from inception to September 2025. Studies were included if they reported survival outcomes for statin users vs. non-users among patients with ALS. Data on hazard ratios (HRs) were extracted and pooled using fixed- or random-effects models, depending on heterogeneity. Meta-regression and sensitivity analyses were performed to explore the influence of covariates such as age and gender.<br><br>RESULTS: Six studies with 3,739 participants (889 statin users) met the inclusion criteria. The pooled analysis showed no statistical significant association between statin use and ALS survival [Log(HR) = -0.04; 95% CI: -0.18 to 0.10], with moderate heterogeneity (I [2] = 24.85%).<br><br>CONCLUSION: The pooled estimate in this meta-analysis did not show a statistically significant association between statin use and ALS survival; however, the evidence is limited by heterogeneity in statin exposure definitions and likely residual confounding in predominantly observational data. Further high-quality studies with large sample sizes are needed to determine whether specific subgroups may benefit/harm from statin therapy.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251160344; PROSPERO: CRD420251160344.}, }
@article {pmid41994333, year = {2026}, author = {Stein, DN and Gendelman, HE}, title = {CAR Treg therapies for neurodegenerative diseases.}, journal = {iScience}, volume = {29}, number = {3}, pages = {114988}, pmid = {41994333}, issn = {2589-0042}, abstract = {Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.}, }
@article {pmid41994661, year = {2026}, author = {Shah, T and Babcock, J}, title = {Tailored Interventions for Intimate Partner Violence: Examining the Differential Effectiveness of Randomized Communication Skills Exercises with Situationally and Characterologically Violent Couples.}, journal = {Journal of family violence}, volume = {}, number = {}, pages = {}, pmid = {41994661}, issn = {0885-7482}, abstract = {PURPOSE: This study examines the differential effectiveness of communication skills interventions for situationally and characterologically violent male-perpetrated intimate partner violence (IPV).<br><br>METHOD: Using data from Babcock et al.'s (2011) proximal change experiment, latent class analysis was used to categorize IPV perpetrators into situational or characterological groups based on patterns of physical aggression, psychological abuse, and coercive control. Differential effectiveness of two communication-based interventions, "Accepting Influence," and "Editing out the Negative," and a placebo control condition was tested between the two groups.<br><br>RESULTS: We found that men in the situationally violent group reported significantly higher levels of increases in positive affect after both interventions compared to men in the characterologically violent group. On psychophysiological outcomes, significant interactions emerged showing that both active interventions led to a greater increase in post-intervention skin conductance for situationally violent men than for characterologically violent men. However, there was no evidence for differential responding based on other physiological variables, observed behaviors, or partners' self-report.<br><br>CONCLUSIONS: The current study contributes to scalable and practical solutions for treatment matching in experimental designs for IPV.}, }
@article {pmid41995858, year = {2026}, author = {Miki, T and De Bertier, S and Amador, MD and Nicolas, M and Guissart, C and Deret, M and Teyssou, E and Muratet, F and Bohl, D and Lobsiger, CS and Boillée, S and Esselin, F and Salachas, F and Millecamps, S and Seilhean, D}, title = {Neuropathological analysis of an ALS patient carrying a SOD1 missense variant and a C9orf72 repeat expansion.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41995858}, issn = {1432-0533}, support = {EQU202103012581//the Fondation Recherche M&#xe9;dicale (FRM)/ ; #19466//the Association Fran&#xe7;aise contre les Myopathies (AFM)/ ; }, }
@article {pmid41995990, year = {2026}, author = {Simula, ER and Garcia-Montojo, M and Canu, M and Chessa, V and Ercoli, T and Ruiu, E and Solla, P and Nath, A and Sechi, LA}, title = {Downregulation of miRNAs Accompanies Increased HERV-K (HML-2) Expression in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41995990}, issn = {1559-1182}, support = {legge regionale 12 22 December 2022 n. 22//Regione Autonoma della Sardegna/ ; PNRR-MCNT1-2023-12376993//Ministero Della Salute/ ; 2022BP837R//PRIN 2022/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/virology/blood ; *MicroRNAs/genetics/metabolism ; *Down-Regulation/genetics ; Male ; Middle Aged ; Female ; *Endogenous Retroviruses/genetics/metabolism ; Aged ; Leukocytes, Mononuclear/metabolism ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease with limited treatments. Evidence suggests that reactivation of the HERV-K (HML-2) subgroup contributes to its pathogenesis. This study explores the role of microRNAs (miRNAs) in regulating HML-2 expression. We identified dysregulated miRNAs in ALS and, among them, those predicted to target the HML-2 transcript. The expression levels of selected miRNAs were validated in peripheral blood leukocytes of ALS individuals and healthy controls. Co-transfection experiments were then performed to determine the regulatory potential of these miRNAs on HML-2 expression. We found that the HML-2 envelope gene expression levels were elevated in peripheral blood mononuclear cells of ALS individuals compared to controls (p = 0.02), and they negatively correlated with the levels of previously identified miRNAs, which were downregulated in patients compared to healthy controls (miR-15a-3p, p = 0.04; miR-15a-5p, p = 0.01; miR-150-5p, p = 0.001; miR-182-5p, p = 0.012; miR-192-3p, p = 0.034; miR-221-3p, p = 0.011), except miR-181a-2-3p that was upregulated in ALS compared to controls (p = 0.006). Among these miRNAs, we found, by co-transfection, that miR-182-5p and miR-221-3p were capable of binding the HML-2 transcript. This interaction resulted in a significant downregulation of the expression of its genes, with a pronounced effect observed on the envelope gene. Our findings suggest a link between miRNAs and HML-2 expression. In particular, the observed increase in HML-2 levels in ALS may result from the downregulation of key miRNAs, such as miR-221, that normally help restrain HML-2 expression under physiological conditions.}, }
@article {pmid41996350, year = {2026}, author = {Tendulkar, S and Wu, T and Strickland, A and Hackett, AR and Sato-Yamada, Y and Mao, X and Sasaki, Y and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0347135}, doi = {10.1371/journal.pone.0347135}, pmid = {41996350}, issn = {1932-6203}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Lactic Acid/metabolism ; Mice, Knockout ; Motor Neurons/metabolism/pathology ; Humans ; *L-Lactate Dehydrogenase/genetics/metabolism/deficiency ; Risk Factors ; Neuromuscular Junction/pathology/metabolism ; Schwann Cells/metabolism/pathology ; Male ; Isoenzymes/genetics/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. Schwann cell (SC)-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants- TDP43Q331K and Sod1D83G knock-in alleles-to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.}, }
@article {pmid41313264, year = {2026}, author = {Chancel, A and Fort, P and Maciel, RM and Duval, B and Malcey, J and Bellini, S and Schmidt, MH and Luppi, PH}, title = {Comparative distribution of the hypothalamic neurons activated during wakefulness and paradoxical (REM) sleep using male TRAP2-red mice: contribution of orexin, MCH, Lhx6, and a new marker Meis2.}, journal = {Sleep}, volume = {49}, number = {4}, pages = {}, doi = {10.1093/sleep/zsaf368}, pmid = {41313264}, issn = {1550-9109}, mesh = {Animals ; Male ; Orexins/metabolism ; *Neurons/physiology/metabolism ; Mice ; *Hypothalamus/physiology/cytology/metabolism ; *Hypothalamic Hormones/metabolism/physiology ; *Melanins/metabolism/physiology ; *Wakefulness/physiology ; *Pituitary Hormones/metabolism/physiology ; *Sleep, REM/physiology ; *Transcription Factors/metabolism/physiology ; *Nerve Tissue Proteins/metabolism/physiology ; *Homeodomain Proteins/metabolism/physiology ; LIM-Homeodomain Proteins/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Mice, Transgenic ; Neuropeptides/physiology ; }, abstract = {STUDY OBJECTIVES: Paradoxical sleep (PS) is a state involving numerous hypothalamic neuronal subpopulations, many remaining neurochemically uncharacterized. Our goal was to compare hypothalamic neurons active during wakefulness or PS rebound (PSR) and explore their potential overlap, with a focus on melanin-concentrating hormone (MCH), Orexin (Orx), Lhx6, and a new contingent of Meis2-expressing neurons.<br><br>METHODS: In the same male TRAP2-red mouse, neurons activated during wakefulness (4&#xa0;h) and PSR (2&#xa0;h) express TdTomato and c-Fos, respectively. Double-labeling and triple immunofluorescence with neurochemical markers were performed to characterize and quantify cell populations in hypothalamic structures.<br><br>RESULTS: Twelve hypothalamic structures showed distinct activation patterns. The anterior hypothalamic area (AHA), zona incerta (ZI), and tuberal nucleus contained more activated neurons during PSR than wakefulness, whereas the paraventricular hypothalamic, supraoptic, parasubthalamic nuclei, and retrochiasmatic area were predominantly activated during wakefulness. MCH and Lhx6 neurons were mainly recruited during PSR, whereas Orx neurons were more activated during wakefulness. The ventral subpopulation of MCH neurons showed higher activation during PSR than the dorsal subpopulation. Additionally, ~30 per cent of the c-Fos+ neurons in ZI and ~20 per cent in LHA expressed Meis2. Overall, ~20 per cent of all hypothalamic neurons activated during PSR are now neurochemically identified.<br><br>CONCLUSIONS: Our study identifies new neuronal populations activated during PSR in AHA, ZI, and tuberal nucleus. We further provide evidence that Meis2 is expressed in novel populations of neurons activated during PSR. In summary, our results using male TRAP2-red mice characterize the cell populations activated during wakefulness and PSR, opening experimental paths for determining their function regarding vigilance states. Statement of Significance Wakefulness and paradoxical sleep are very similar at the electroencephalographic level. It remains relevant to determine the potential overlap of the neurons active during each vigilance state. We here took advantage of the powerful transgenic male TRAP2-red mice to directly compare in the same animal the brain cell activation during both states, with a focus on the hypothalamus. A deeper knowledge of each individual subpopulation of hypothalamic neurons within complex brain circuits underlying the sleep-waking cycle will help the understanding and validation of treatments of sleep disorders, at least those directly linked to demonstrated hypothalamic dysfunction such as narcolepsy (Orx neurons), amyotrophic lateral sclerosis (MCH and Orx signaling) or neurodegenerative diseases (Parkinson's and Alzheimer diseases).}, }
@article {pmid41985299, year = {2026}, author = {Raka, RN and Zhang, Z and Xiao, J and Wu, H}, title = {Integrative network pharmacology delineates dual GPCR and non-GPCR mechanisms of blended and individual Taikong Blue lavender and Pingyin rose essential oils in neurodegenerative and psychiatric disorders.}, journal = {Computers in biology and medicine}, volume = {208}, number = {}, pages = {111681}, doi = {10.1016/j.compbiomed.2026.111681}, pmid = {41985299}, issn = {1879-0534}, abstract = {Neurodegenerative and psychiatric disorders share overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and neurotransmitter dysregulation. Essential oils from Lavandula angustifolia (TLEO) and Rosa rugosa (PREO) contain neuroactive compounds with therapeutic potential, but their mechanisms remain poorly defined. This study aimed to elucidate the shared and distinct molecular targets and pathways of TLEO and PREO using a multi-scale computational strategy. Compounds identified by GC-MS were evaluated through ADMET profiling, target prediction, and disease-target intersection analysis. Enrichment, network, docking, and dynamics analyses were performed on shared protein-coding targets between essential oils and twelve brain disorders, including seven neurodegenerative conditions (Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy) and five psychiatric disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia). A total of 110 compounds yielded 252 common targets, with CHRM2 (GPCR) and NR1H3 (non-GPCR) identified as key hubs. Docking suggested strong binding affinities for caryophyllene oxide at CHRM2 (-7.3 kcal/mol) and α-himachalene at NR1H3 (-8.5 kcal/mol). Molecular dynamics simulations confirmed stable, compact complexes with low RMSD and SASA values. MM/PBSA free energy calculations quantitatively validated these interactions, revealing favorable binding energetics driven predominantly by van der Waals and hydrophobic contributions, consistent with the terpenoid chemical profiles. Functional enrichment highlighted involvement in cholinergic signaling, lipid metabolism, and inflammatory regulation. This study demonstrates that PREO and TLEO can modulate multiple targets relevant to brain disorders through both GPCR and non-GPCR mechanisms. These findings provide a computationally inferred mechanistic framework for the potential neuroprotective synergy of these oils and highlight essential oil-derived compounds as promising leads for further experimental investigation.}, }
@article {pmid41985725, year = {2026}, author = {Wintz, K and Lechtape, PL and Klenzendorf, J and Schemmert, S and Dingley, AJ and Willuweit, A and Kutzsche, J}, title = {Elucidation of the influence of the CaV2.2 calcium channel on ALS disease progression in the SOD1*G93A mouse model.}, journal = {Neurobiology of disease}, volume = {224}, number = {}, pages = {107396}, doi = {10.1016/j.nbd.2026.107396}, pmid = {41985725}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal neurodegenerative disease affecting upper and lower motor neurons in the central nervous system. Drugs like riluzole, edaravone, and tofersen treat disease symptoms or are designed for a specific pathological mutation (e.g., SOD1), but they cannot prevent or halt the disease. For this reason, the search for new therapeutic strategies continues. The voltage-gated calcium channel CaV2.2 might be a novel target in ALS treatment as the channel was shown to be overexpressed in murine SOD1*G93A cortical neurons, resulting in higher mortality. Further, murine SOD1*G93A motor neurons showed increased calcium currents mainly by an increased expression of the CaV2.2 channel. In addition, inhibition of the channel was hypothesized as mode of action for the all-d-enantiomeric peptide RD2RD2, a novel drug candidate for the treatment of ALS, which already demonstrated its efficacy in SOD1*G93A mice. To investigate the influence of the CaV2.2 channel on the progression of disease symptoms in the SOD1*G93A mouse model, a new double-transgenic line was created, combining the ALS phenotype with a knockout of the CaV2.2 channel. The study showed that the CaV2.2 knockout on the SOD1*G93A background led to reduced SHIRPA and splay scores, and a delayed disease onset. Additionally, differences were detected between wildtype and single-transgenic CaV2.2 knockout mice. However, survival was not affected. Post mortem analysis of human tissue found more CaV2.2 in ALS cases in comparison to healthy control subjects confirming involvement of the channel in human ALS. These results indicate that the CaV2.2 calcium channel may play an influential role in early disease progression of ALS.}, }
@article {pmid41986690, year = {2026}, author = {Zhou, Z and Kim, J and Huang, AY and Nolan, M and Park, J and Doan, R and Shin, T and Miller, MB and Bae, M and Zhao, B and Kim, J and Chhouk, B and Morillo, K and Yeh, RC and Kenny, C and Neil, JE and Lee, CZ and Ohkubo, T and Ravits, J and Ansorge, O and Ostrow, LW and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {41986690}, issn = {1546-1718}, support = {R01 NS032457/NS/NINDS NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; K08 AG065502/AG/NIA NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; W81XWH2010028//U.S. Department of Defense (United States Department of Defense)/ ; 23CDA1046074//American Heart Association (American Heart Association, Inc.)/ ; RS-2023-00217881//National Research Foundation of Korea (NRF)/ ; RS-2025-02215360//National Research Foundation of Korea (NRF)/ ; }, abstract = {Although mutations in many genes cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), most cases are sporadic (sALS and sFTD) with unclear etiology. Here we tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-sequencing data from an additional cohort identified deleterious somatic variants in DYNC1H1 and LMNA, genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.}, }
@article {pmid41987036, year = {2026}, author = {Nagy, ZF and Géresi, A and Grosz, Z and Trombitás, B and Pál, M and Nagy, D and Salamon, A and Balicza, P and Dézsi, L and Klivényi, P and Széll, M and Molnár, MJ}, title = {Genetic epidemiology of C9orf72 repeat expansion associated amyotrophic lateral sclerosis in Hungary.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1186/s10020-026-01465-w}, pmid = {41987036}, issn = {1528-3658}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. The most common genetic cause of ALS is the hexanucleotide repeat expansion in the C9orf72 gene, which is associated with earlier disease onset, faster progression, and an increased frequency of cognitive and psychiatric involvement. Data on population-specific characteristics of C9orf72-associated ALS remains limited in Central and Eastern Europe.<br><br>METHODS: Between 2011 and 2024, a total of 959 ALS patients fulfilling established diagnostic criteria were screened for C9orf72 repeat expansions at two Hungarian centers. Hexanucleotide repeat expansions were analyzed using repeat-primed long-read PCR. Repeat numbers exceeding 30 were considered pathogenic. Clinical, demographic, and disease course data were retrospectively collected and analyzed.<br><br>RESULTS: Pathogenic C9orf72 repeat expansions were identified in 63 of 959 patients, corresponding to a prevalence of 6.57% among Hungarian ALS patients. Bulbar onset was the most common presentation and was associated with faster progression and shorter survival (mean survival: 27.8&#xa0;months). Cognitive impairment and psychiatric comorbidities were present in a substantial proportion of patients and were associated with slower functional decline. Regional differences in survival were observed, likely reflecting disparities in healthcare access rather than biological factors.<br><br>CONCLUSIONS: This study provides the first comprehensive national characterization of C9orf72 repeat expansion-associated ALS in Hungary, based on a genetically defined cohort assembled over 13&#xa0;years. Despite limitations related to retrospective data collection and cohort size, this ethnically homogeneous dataset offers valuable insight into population-specific clinical and epidemiological features and complements larger international studies. Systematic characterization and longitudinal follow-up of genetically defined, trial-ready ALS cohorts will be essential as targeted therapies for C9orf72-associated ALS approach clinical implementation.}, }
@article {pmid41987881, year = {2026}, author = {Li, R and Wang, L and Bu, W and Zhang, X and Li, X and Li, J and Shen, J and Li, J and Cai, Z}, title = {Autologous SVF therapy modulates neuroinflammation in ALS: phase I trial demonstrating safety and CSF biomarker dynamics.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1784115}, pmid = {41987881}, issn = {1663-4365}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with limited treatments. Stromal vascular fraction (SVF), a cell population derived from autologous adipose tissue, exhibits multimodal immunomodulatory and neuroprotective properties, positioning it as a promising therapeutic candidate.<br><br>METHODS: This trial aimed to assess autologous stromal vascular fraction (SVF) safety and efficacy in patients with ALS. 26 patients received combined intravenous (0.5 &#xd7; 106 cells/kg) and intrathecal (20 &#xd7; 10[6] cells) autologous SVF (An exploratory second dose of SVF was administered intrathecally to three patients 45 days later). The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2400091754).<br><br>RESULTS: SVF administration was well-tolerated. Five mild adverse events (adverse events, AEs) (subcutaneous bleeding, headache, and low-grade fever) occurred, with no serious AEs reported. Although ALSFRS-R scores showed non-significant improvement post-treatment, 15/26 participants (57.7%) self-reported symptomatic improvement after treatment. Critically, cerebrospinal fluid biomarker analysis revealed significant reductions in neurofilament light chain (NfL; &#x394;530.29 pg/mL, P = 0.039) and glial fibrillary acidic protein (GFAP; &#x394;622.23 pg/mL, P = 0.038), indicating attenuation of neuroaxonal degeneration and astroglial activation. While ALSFRS-R scores showed no significant change (&#x394;-0.53, P = 0.384), prognostic modeling identified female sex (OR = 0.011, P = 0.008) and shorter disease duration (OR = 1.35/month, P = 0.005) as predictors of response. Three patients who underwent the second treatment were well tolerated without any adverse events.<br><br>CONCLUSION: These findings indicate that Autologous SVF therapy might possess an acceptable safety profile for patients with ALS. The significant reduction in CSF NfL and GFAP levels provides objective evidence of their potential neuroprotective effects that modulates ALS-relevant neuroinflammation pathways. Female participants and those with shorter disease duration may derive greater benefits.}, }
@article {pmid41988392, year = {2026}, author = {Khan, SF and Rasool, W and Khan, MH and Kumar, G and Ijaz, A and Amjad, M and Sheikh, MQ and Rath, S and Kunwar, D and Akbar, A}, title = {The Impact of Chemical Toxicants and Air Pollutants on Neurodegenerative Disorders and Their Underlying Potential Mechanisms: A Literature Review.}, journal = {Health science reports}, volume = {9}, number = {4}, pages = {e72256}, pmid = {41988392}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Neurodegenerative disorders are marked by progressive deterioration of neurons, affecting cognitive, memory, and motor functions. This decline creates substantial personal and social challenges, making early identification of risk factors essential for effective intervention. Environmental toxicants, such as chemicals and air pollutants, are suspected to negatively impact brain health. This review critically examines the relationship between environmental toxicants and neurodegenerative disorders, exploring their potential mechanisms and providing recommendations for future research.<br><br>METHODS: A PubMed search was performed for all available data until April 2024 using keywords related to environmental toxicants and neurodegenerative diseases. The search was limited to peer-reviewed articles in English, focusing on human studies that investigate the association between toxicants and neurodegenerative disorders. A narrative synthesis was conducted based on the neurodegenerative disorder, specific toxicants, and mechanisms of action.<br><br>RESULTS: This review highlights the detrimental effects of chemical toxicants and air pollutants on diseases, such as Parkinson's, Alzheimer's, multiple sclerosis, and Huntington's disease. Key mechanisms discussed include oxidative stress, protein aggregation, and mitochondrial dysfunction.<br><br>CONCLUSION: The findings emphasize the need to understand the mechanisms by which environmental toxicants contribute to neurodegenerative diseases. Early detection and management, including reduced exposure to harmful substances, are vital. Further research is essential for improving screening techniques and developing targeted interventions.}, }
@article {pmid41989583, year = {2026}, author = {Wang, X and Wu, F and Zhang, J and Song, X and Liu, P and Liu, Z and Wang, J and Zhang, Y and Grecucci, A and Yi, X and Chen, BT}, title = {Cerebral metabolic patterns on [18]F-FDG PET are associated with clinical heterogeneity and prognosis in amyotrophic lateral sclerosis: a genetic and transcriptomic perspective.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {41989583}, issn = {1619-7089}, support = {2024PT5109//the Scientific Research Program of FuRong Laboratory/ ; 2021YFA0805202//National Key R&amp;D Program of China/ ; 2024ZZTS0954//Fundamental Research Funds for Central Universities of the Central South University/ ; 2020XJ88//Scientific research project of Xiangnan University/ ; 2023JJ50382//Natural Science Foundation of Hunan Province/ ; D202303077714//Scientific research project of Hunan Provincial Health Commission/ ; IIT2025-00111//the Joint Research Fund of Chongqing University Three Gorges Hospital-Peking University Human Dajiaweikang Pharmaceutical Industry Co.,Ltd./ ; }, }
@article {pmid41980342, year = {2026}, author = {Dubbioso, R}, title = {Beyond motor output: disrupted kinesthesia reveals hidden sensory-cognitive dysfunction in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {187}, number = {}, pages = {2111885}, doi = {10.1016/j.clinph.2026.2111885}, pmid = {41980342}, issn = {1872-8952}, }
@article {pmid41980818, year = {2026}, author = {Shah, NM and Kaltsakas, G}, title = {Non-invasive ventilation timing in ALS: one size does not fit all.}, journal = {Thorax}, volume = {}, number = {}, pages = {}, doi = {10.1136/thorax-2026-224807}, pmid = {41980818}, issn = {1468-3296}, }
@article {pmid41981045, year = {2026}, author = {Neumann, M and Kothare, H and Bartlett, M and Roesler, O and Suendermann-Oeft, C and Hosamath, A and Arbatti, L and Pautler, D and Suendermann-Oeft, D and Cadavid, D and Scannevin, RH and Hoffmann, I and Tarachandani, A and Haley, T and Raines, S and Damme, PV and Tienari, P and Solje, E and Jokela, M and Genge, A and O'Connell, C and Eijk, RPAV and Berg, LHVD and Ramanarayanan, V}, title = {Speech-based digital endpoints track ALS progression and align with standard clinical outcomes: evidence from the VRG50635 trial.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-48100-6}, pmid = {41981045}, issn = {2045-2322}, abstract = {We report on the utility of speech-based digital endpoints measured during a Phase 1b study of VRG50635 in Amyotrophic Lateral Sclerosis (ALS). Fifty-four participants with ALS were enrolled and participated in an 8-week pretreatment run-in, followed by three 8-week dosing periods and an 8-week follow-up. They completed a speech assessment every two weeks in the clinic or at home. We observed moderate to high correlations between digital measures of speech timing and articulatory motor function, and the ALS Functional Rating Scale-Revised, slow vital capacity and plasma neurofilament light chain. Furthermore, speech measures can show functional decline before the ALSFRS-R does, while also capturing differences between participants with bulbar symptoms and those without. The results support the feasibility and utility of digital speech endpoints to study disease impact in ALS clinical trials.}, }
@article {pmid41981822, year = {2026}, author = {Luo, X and Alias, BS and Adnan, NH}, title = {Active learning strategies and student engagement in undergraduate medical education: A systematic review (2015-2025).}, journal = {Anatomical sciences education}, volume = {}, number = {}, pages = {}, doi = {10.1002/ase.70231}, pmid = {41981822}, issn = {1935-9780}, support = {JYZ202412//Hubei Enshi College/ ; }, abstract = {Active learning strategies (ALS) are increasingly employed in undergraduate medical education to promote student engagement across behavioral, emotional, and cognitive dimensions; however, there remains limited integrative understanding of the pedagogical mechanisms through which ALS activate engagement and the contextual conditions shaping this process. This systematic review synthesized empirical studies published between 2015 and June 2025 to examine how ALS activate multidimensional student engagement and to develop an integrative, mechanism-oriented framework for engagement activation in undergraduate medical education. Following PRISMA 2020 guidelines, six academic databases were systematically searched for quantitative, qualitative, and mixed-methods studies involving undergraduate medical students, yielding 22 eligible studies. Thematic synthesis indicated that strategies such as gamification, scenario-based learning, team-based learning, and audience response systems demonstrated robust engagement activation when instructional designs integrated authentic tasks, structured collaboration, and timely feedback, rather than through instructional format alone. Across studies, discrepancies were frequently observed between perceived engagement and actual learning outcomes, highlighting the limitations of relying on self-report measures. Contextual moderators, including instructional culture, facilitation practices, and learning environments, further shaped how engagement was activated, expressed, and sustained across settings. These findings informed the development of the Active Learning Engagement Activation model, which conceptualizes engagement as a dynamic, context-sensitive process arising from interactions among instructional design features, learner-interface mechanisms, and contextual moderators, providing a mechanism-oriented framework to support engagement-informed curriculum design and future research in undergraduate medical education.}, }
@article {pmid41981990, year = {2026}, author = {Vavers, E and Kopanchuk, S and Veiksina, S and Jonane, J and Mathur, C and Nasirova, N and Midekessa, G and Rinken, A}, title = {Simultaneous Expression of Sigma-1 Receptor and Tetraspanins Highlights Pathways of Receptor Sorting Into Extracellular Vesicles.}, journal = {Journal of neurochemistry}, volume = {170}, number = {4}, pages = {e70426}, doi = {10.1111/jnc.70426}, pmid = {41981990}, issn = {1471-4159}, support = {SJD34//Estonian Research Council/ ; }, mesh = {*Receptors, sigma/metabolism/biosynthesis/genetics ; Sigma-1 Receptor ; *Extracellular Vesicles/metabolism ; Humans ; *Tetraspanins/metabolism/biosynthesis/genetics ; Tetraspanin 29 ; Protein Transport/physiology ; Tetraspanin 28 ; }, abstract = {Sigma-1 receptor (Sig1R) is an endoplasmic reticulum (ER) chaperone protein involved in regulating ER function, cellular stress responses, and autophagy, and disturbed Sig1R function has been associated with neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Although Sig1R has been implicated in secretory pathways and detected extracellularly, its direct presence in isolated extracellular vesicles (EVs) has not been clearly established. In this study, we aimed to confirm Sig1R in isolated EVs by co-expressing it alongside tetraspanin EV markers. Expression of fluorescently tagged Sig1R together with fluorescent protein-labeled tetraspanins CD9, CD63, and CD81 in both cells and isolated EVs was verified using live-cell imaging, emission spectrum measurements, and Western blotting. Efficient expression of these proteins in cells was achieved by using the MultiBacMam expression system and their presence in EVs was detected through advanced TIRF-based multi-well single-particle EV analysis. We observed significantly higher levels of Sig1R in CD63- and CD9-labeled EVs in comparison with CD81-labeled EVs. The obtained data suggest that Sig1R may be released into the extracellular space via exocytotic pathways linked to exosome secretion. The presence of Sig1R in exosomes underscores its potential as a biomarker in neurological disorders, emphasizing the need for further exploration of its diagnostic and other applications.}, }
@article {pmid41983194, year = {2026}, author = {Qi, M and Hu, N and Ding, J and Niu, J and Long, B and Liu, M}, title = {Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1755814}, pmid = {41983194}, issn = {2296-634X}, abstract = {OBJECTIVE: To explore the dynamic changes in excitability and viability of induced pluripotent stem cells (iPSC)-derived motor neurons from sporadic amyotrophic lateral sclerosis (ALS) and compare them with SOD1-related ALS patients and healthy control.<br><br>METHODS: Peripheral blood samples were collected from ALS patients and healthy controls (HC) to establish the iPSC-derived motor neurons (MNs). Whole-cell patch-clamp recordings at different culture stages was made using an Axopatch 700B amplifier in combination with pClamp 11 software (Molecular Devices). The frequency of action potentials (APs) was recorded. Additionally, Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) Nick-End Labeling (TUNEL) was used to assess the apoptosis of MNs.<br><br>RESULTS: ALS patient-derived MNs exhibited significantly higher firing rates compared to HCs at both 4-7 weeks (p = 0.004) and 7-9 weeks (p = 0.009). Further analysis revealed that SOD1-derived MNs showed significantly higher firing frequencies than sALS (p = 0.009) and HCs (p < 0.001) in 4-7 weeks. In 7-9 weeks, it remained significant between SOD1 and HC-derived MNs (p = 0.015), but became insignificant between SOD1 and sALS (p = 0.855). The apoptotic rate of sALS (Day 30: 61.37% &#xb1; 9.63%; Day 60: 78.41% &#xb1; 6.63%) and SOD1 (Day 30: 73.69% &#xb1; 8.81%; Day 60: 60.37% &#xb1; 11.53%) -derived MNs was significantly higher than those of HCs at both Day 30 (30.72% &#xb1; 7.57%) and Day 60 (50.85% &#xb1; 19.36%) (p < 0.001).<br><br>CONCLUSION: MNs derived from both patients with mutant SOD1 and sporadic ALS exhibited increased excitability compared to HCs. The increased excitability of MNs derived from ALS patients with mutant SOD1 occurred earlier, and over time, became consistent with the excitability observed in MNs derived from sporadic ALS. The apoptosis rates of MNs showed similar trends. iPSC-derived MNs from both sporadic and mutant ALS may serve as useful cell models for ALS in future studies.}, }
@article {pmid41983529, year = {2026}, author = {Nagasse, HY and Okuda, EK and Coltri, PP}, title = {TDP43 and hnRNP K Regulate Alternative Splicing of DNAJC5.}, journal = {Cell biology international}, volume = {50}, number = {4}, pages = {e70158}, doi = {10.1002/cbin.70158}, pmid = {41983529}, issn = {1095-8355}, support = {2019/21874-5//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; }, mesh = {Humans ; *Heterogeneous-Nuclear Ribonucleoprotein K/metabolism/genetics ; *Alternative Splicing/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; *HSP40 Heat-Shock Proteins/genetics/metabolism ; HEK293 Cells ; HeLa Cells ; }, abstract = {Alternative splicing is a finely regulated process which defines the final maturation of pre-mRNAs. Modulation of trans-acting spliceosome proteins changes specific patterns of splicing and contributes to the development of diseases. During Amyotrophic Lateral Sclerosis (ALS) disease progression, loss of nuclear trans-acting splicing protein TDP43 leads to accumulation of cryptic exons in mRNAs, which inhibits expression of proteins and aggravates the disease. One of the affected genes is DNAJC5, which codes for a protein responsible for clearance of misfolded proteins in the cytoplasm. We first observed that TDP43 knockdown regulates DNAJC5 transcript splicing. A similar phenotype was observed upon hnRNP K knockdown. We hypothesized canonical splicing of DNAJC5 is dependent on the activity of both TDP43 and hnRNP K. Our results confirmed TDP43 and hnRNP K interaction is dependent on RNA. We also confirmed that DNAJC5 canonical splicing is dependent on its internal TDP43 and hnRNP K binding sites. Taken together, our work enrolls both TDP43 and hnRNP K on splicing regulation of DNAJC5 transcript, affecting activity of the protein encoded by DNAJC5 on endosomal traffic. As a result, activity of both TDP43 and hnRNP K and their association are important for ALS progression.}, }
@article {pmid41985097, year = {2026}, author = {Liu, CX and Blair, BA and Tenney, ER}, title = {Registered Report: Can Agentic Black Women Get Ahead? An Experiment Revisited.}, journal = {Psychological science}, volume = {}, number = {}, pages = {9567976261436988}, doi = {10.1177/09567976261436988}, pmid = {41985097}, issn = {1467-9280}, abstract = {In 2012, Livingston et al. found that Black women were buffered against gender backlash; whether Black women were dominant or supportive toward an employee did not affect people's perceptions of them as leaders in an organization. Conversely, White women incurred a status penalty for being dominant. Twelve years later, no direct replication has been published, and related research reached different conclusions: that Black women experience the most gender backlash for being dominant (as politicians) or that race does not affect gender backlash (for expressing anger). Given the seemingly contradictory results and limitations of previous research, the relationship between race and gender backlash warrants reexamination. In this registered report, we conducted a high-powered direct replication and extension of Livingston et al. with adult participants online (N = 1,996). We found that both Black and White women (as well as men) suffered a status penalty for displaying dominance, suggesting a failure to replicate Livingston et al.'s findings. We discuss implications for theories of intersectional gender backlash.}, }
@article {pmid41985161, year = {2026}, author = {Pervushina, EV and Rushkevich, YN and Turuspekova, ST and Kutlubaev, MA}, title = {Challenges in medical care for amyotrophic lateral sclerosis: a survey of physicians from Republic of Bashkortostan (Russia), Belarus, and Kazakhstan.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2652327}, pmid = {41985161}, issn = {2167-9223}, abstract = {OBJECTIVE: To identify and compare the main challenges in diagnosing and managing amyotrophic lateral sclerosis (ALS) from the perspective of neurologists in Republic of Bashkortostan (Russia), Belarus, and Kazakhstan.<br><br>METHODS: An anonymous online survey was distributed to neurologists via professional networks from May to October 2025. The questionnaire collected data on demographics, diagnostic and therapeutic approaches, barriers, and suggestions for improvement.<br><br>RESULTS: The survey included 294 neurologists. Over half (58.2%) diagnosed ALS less than once a year. Major diagnostic barriers were limited access to key investigations like electromyography (62.6%) and a lack of specialized ALS centers (37.8%). For treatment, 48% prescribed riluzole, while only 12.9% used edaravone. Critically low rates of gastrostomy placement and respiratory support provision (<10% of terminal patients) were noted by over 80% of respondents. Significant cross-country differences were found: neurologists in Kazakhstan utilized genetic testing and edaravone more frequently; neurologists in Belarus employed muscle/tongue ultrasound more often; neurologists in the Republic of Bashkortostan (Russia) reported higher use of speech therapy and gastrostomy. The most frequently proposed solutions were establishing specialized ALS centers (34%), enhancing physician training (20%), and improving palliative care services (16.5%).<br><br>CONCLUSIONS: This multinational survey provides important insights into ALS care in the studied countries, identifying key areas for further development. The results point to opportunities for enhancing diagnostic resources, therapeutic strategies, and palliative care approaches. Enhancing the quality of ALS care requires the development of specialized clinical pathways, the implementation of consensus-based protocols, and the expansion of professional education in multidisciplinary management.}, }
@article {pmid41787359, year = {2026}, author = {Dumbrell, J and Masterton, W and Carver, H and Parkes, T}, title = {Realist review of nature-based interventions for men: understanding the contexts and mechanisms necessary for successful outcomes.}, journal = {BMC public health}, volume = {26}, number = {1}, pages = {}, pmid = {41787359}, issn = {1471-2458}, abstract = {BACKGROUND: Men face significant health disparities, including higher rates of premature death, mental health challenges, and substance use disorders. Nature-based interventions hold promise for improving men’s health and wellbeing by leveraging natural environments and structured activities aligned with men’s preferences for practical, action-oriented solutions. This realist review explores the contexts, mechanisms, and outcomes of nature-based interventions, providing a gender-specific perspective on how these interventions benefit men.<br><br>METHODS: A realist synthesis was conducted following Pawson et al.&#x2019;s iterative framework and the RAMESES reporting standards. Initial programme theories were constructed through early interrogation of the men&#x2019;s health and greenspace literatures, and expert consultations. Data extraction focused on identifying context-mechanism-outcome configurations to refine programme theories. Analysis involved synthesising findings from qualitative, quantitative, and grey literature to demonstrate how nature-based interventions influence men&#x2019;s wellbeing.<br><br>RESULTS: The review identified nine refined programme theories, encompassing three domains: Being, Doing, and Growing Together. Calming natural settings (PT1) and tailored physical activities (PT2) reduced stress, improved fitness, and enhanced resilience. Purposeful engagement (PT3) and skill development in peer-led, supportive environments (PT4) fostered self-efficacy, identity reformation, and empowerment. Strengths-based, inclusive approaches (PT5, PT6) built social bonds and community cohesion, while structured cognitive engagement (PT7) enhanced problem-solving and collaborative skills. Foundational contexts, including safe, non-judgemental, culturally sensitive spaces (PT8) and tailored, multidisciplinary support (PT9), underpinned these mechanisms, enabling sustained health and wellbeing outcomes.<br><br>CONCLUSIONS: Nature-based interventions offer a powerful and gender-responsive solution to men&#x2019;s mental health challenges, combining restorative natural environments, purposeful activities, and peer-led support. Tailored interventions that align with men&#x2019;s cultural identities and values significantly enhance engagement, self-efficacy, and social cohesion. These findings provide actionable insights for designing inclusive, impactful nature-based interventions, addressing longstanding health disparities. Future research should explore adapting nature-based interventions to diverse populations and contexts to maximise their reach and effectiveness.<br><br>PROTOCOL REGISTRATION: CRD42023487594<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-026-26867-7.}, }
@article {pmid41787423, year = {2026}, author = {Öngü, &#x130;N and Arkan, B and Kirli, S}, title = {The Turkish version of the quality in psychiatric care-inpatient scale: translation, cross-cultural adaptation, and psychometric evaluation.}, journal = {BMC health services research}, volume = {26}, number = {1}, pages = {}, pmid = {41787423}, issn = {1472-6963}, abstract = {BACKGROUND: Effective mental health services require high-quality psychiatric inpatient care. To evaluate care from patients’ perspective, culturally validated tools are needed that also reflect local healthcare and psychiatric nursing services. This aim of this study was to validate the Turkish version of Quality in Psychiatric Care-Inpatient scale, to support its use by psychiatric nurses in assessing the quality of inpatient care.<br><br>METHODS: This methodological study included 280 psychiatric inpatients from two hospitals. The scale was translated, back-translated and reviewed by experts following Beaton et al.&#x2019;s adaptation framework and the Consensus-based Standards for Selecting Health Status Measurement Instruments guidelines. Content validity, construct validity, and internal consistency were assessed.<br><br>RESULTS: The Turkish scale comprised 22 items across four sub-dimensions, explaining 53.5% of the total variance. The alpha coefficient was 0.86, demonstrating high internal consistency. Fit indices supported the four-factor model.<br><br>CONCLUSIONS: The scale demonstrated promising psychometric properties and is suitable for psychiatric inpatient nursing practice.<br><br>CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid41974001, year = {2026}, author = {Beaulieu, D and Smith, K and Ross, C and Yip, S and Felizardo, TC and Fournier, C and Glass, JD and Berry, JD and Fowler, DH and Ennist, DL and , }, title = {Development of a machine learning-based survival prediction model for ALS inclusive of the advanced-stage population.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2026.2652322}, pmid = {41974001}, issn = {2167-9223}, abstract = {OBJECTIVE: Develop a machine learning-based model for survival prediction in ALS, including advanced-stage patients (≤50% predicted normal vital capacity [VC50]).<br><br>METHODS: Training data from the PRO-ACT Database (n&#x2009;=&#x2009;6896) was supplemented with advanced-stage ALS patients (n&#x2009;=&#x2009;678), with model validation on distinct advanced-stage ALS patients (n&#x2009;=&#x2009;403). Baseline patient characteristics, including slopes from symptom onset, were used to train a random forest model to identify parameters with the greatest relative importance (RI) for predicting survival outcomes. These parameters were used to train a gradient-boosting machine (GBM) model that generated patient-level survival predictions (log-hazard). Model discrimination and calibration were quantified by C-index and calibration-in-the-large plus calibration slope, respectively. Kaplan-Meier curves were generated, with patient stratification into tertiles based on the predicted survival risk score.<br><br>RESULTS: Baseline characteristics with the highest RI for driving survival predictions included: VC% slope (20.2%); age (12.4%); VC% (9.9%); VC(L) (7.5%); ALSFRS-R (6.6%); and ALSFRS-R slope (5.1%). Model performance upon external validation was satisfactory for both discrimination (C-index, 0.709 [95% CI, 0.671-0.746]) and calibration (calibration-in-the-large, 0.083 [95% CI, -0.073-0.232]; calibration slope, 0.992 [95% CI, 0.789-1.198]). At 8-months from baseline, the model successfully stratified patients by survival prognosis, with low-, average-, and high-risk population tertiles having observed median survival probabilities of 85, 69, and 43%, respectively.<br><br>CONCLUSIONS: This model accurately predicts survival prognosis in ALS, including patients with severely impaired respiratory function. This new understanding of patient-specific factors that drive survival prognostication will be invaluable for reducing patient heterogeneity in clinical trials evaluating novel therapeutic modalities in early- and advanced-stage ALS.}, }
@article {pmid41974046, year = {2026}, author = {Willemse, SW and Hollak, CEM and Reijnhout, ND and Reparon-Schuijt, CC and Pisters-van Roy, AAMG and Demaegd, KC and van Eijk, RPA and van Den Berg, LH and van Es, MA}, title = {Fast and controlled access to tofersen for SOD1-related amyotrophic lateral sclerosis in The Netherlands; experiences using the orphan drug access protocol.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2655738}, pmid = {41974046}, issn = {2167-9223}, }
@article {pmid41974458, year = {2026}, author = {Facciabene, A and Ellsworth, SG}, title = {Gut-targeted strategies at the intersection of radiotherapy and immunotherapy.}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {4}, pages = {}, doi = {10.1136/jitc-2025-014211}, pmid = {41974458}, issn = {2051-1426}, mesh = {Humans ; *Gastrointestinal Microbiome/radiation effects/immunology ; *Immunotherapy/methods ; *Neoplasms/immunology/therapy/radiotherapy ; *Radiotherapy/methods ; }, abstract = {The gut microbiota has emerged as a critical determinant of therapeutic immunity, shaping responses to immune checkpoint inhibitors, adoptive cellular therapies, and radiotherapy (RT). Interest has grown in whether interventions targeting the microbiota might deliberately amplify anticancer immunity.Chen and colleagues recently proposed an unconventional approach: using low-dose intestinal irradiation (ILDR) to remodel the gut microbiota and thereby enhance responsiveness to programmed death-ligand 1 blockade in patients with metastatic cancer. Their report, though preliminary, suggests that directed RT to the intestine can in fact act to favorably modulate the intestinal microbiota. Importantly, current evidence remains largely correlative and does not establish a causal relationship between ILDR, microbiota remodeling, and enhanced systemic antitumor immunity. This concept is provocative, but it raises fundamental questions: does gut-directed RT truly enhance systemic antitumor immunity, or might additional confounding variables, organ-specific effects, and potential toxicities influence the signal?In this Commentary, we balance enthusiasm with caution. We first outline the conceptual framework linking RT, microbiota, and immune activation; then highlight the specific pitfalls revealed by Chen et al's study, including challenges in attribution, heterogeneity, and immunosuppression. We also discuss complementary translational approaches, including direct microbiota modulation through targeted antibiotics and other gut-directed strategies, as potential tools to experimentally interrogate the microbiota-RT-immunotherapy axis in patients.}, }
@article {pmid41975445, year = {2026}, author = {Xue, FS and Wang, DF and Zheng, XC}, title = {Intraoperative use of sodium oxybate to prevent postoperative delirium in older patients undergoing major orthopedic surgery.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41975445}, issn = {1741-7015}, mesh = {Humans ; *Orthopedic Procedures/adverse effects ; Aged ; *Delirium/prevention &amp; control/etiology ; *Sodium Oxybate/therapeutic use/administration &amp; dosage ; *Postoperative Complications/prevention &amp; control ; *Intraoperative Care/methods ; }, abstract = {BACKGROUND: This matters arising article addresses the recently published article in BMC Medicine by Cui et al., titled "Prophylactic effect of intraoperative sodium oxybate on postoperative delirium in older patients undergoing major orthopedic surgery: a randomized clinical trial."<br><br>MAIN BODY: The work by Cui et al. demonstrated that intraoperative administration of sodium oxybate only significantly reduced postoperative delirium (POD) incidence in the&#xa0;participants undergoing morning surgery but not in those with afternoon surgery. Although this trial provided evidence that sodium oxybate may reduce POD, we raise several concerns regarding methodology and generalizability, such as incomplete control of perioperative risk factors, underestimated incidence of POD, subgroup analysis without multiple adjustments of confounding factors, and inadequate postoperative pain strategy. To verify the findings of this trial in further researches, we advocate the implementation of multi-center randomized clinical trials with large sample sizes, strict control of perioperative confounding factors, precise assessment of POD episodes, and the inclusion of subgroup analysis with multiple adjustments.<br><br>CONCLUSION: This matters arising does not seek to deny the results of Cui et al.'s trial. The main purpose of the authors is to emphasize that above methodological refinements are crucial for translating this valuable evidence into generally clinical practice and improving final outcomes of patients.}, }
@article {pmid41975461, year = {2026}, author = {Abbas, AEF and Talib, NFA and Elghobashy, MR and Al Kamaly, O and Halim, MK}, title = {Candexch algorithm-enhanced chemometric determination of a novel anti-COVID-19 therapeutics in plasma and paxlovid formulation using advanced multivariate modeling: a sustainability-centered bioanalytical approach.}, journal = {BMC chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13065-026-01788-z}, pmid = {41975461}, issn = {2661-801X}, support = {PNURSP2026R917//Princess Nourah Bint Abdulrahman University/ ; }, abstract = {This work reports the development of an algorithm-assisted chemometric spectrophotometric method for the concurrent quantification of anti-COVID-19 therapeutics nirmatrelvir, ritonavir, and the active molnupiravir metabolite N4-hydroxycytidine in pharmaceutical formulations and human plasma. A structured fractional five-level factorial calibration design consisting of 25 mixtures was employed to construct the calibration dataset, while the external validation set was generated using D-optimal sample selection via the Candexch algorithm to ensure uniform coverage of the experimental domain and minimize sampling bias relative to random dataset partitioning. Quantitative modeling was performed using four multivariate regression strategies: Principal Component Regression (PCR), Genetic Algorithm-assisted Partial-Least Squares (GA-PLS), Firefly Algorithm-assisted Partial-Least Squares (FA-PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Model optimization, including latent variable selection, wavelength selection, and parameter tuning, was performed exclusively using the calibration dataset through internal cross-validation (LOO-CV) based on minimum RMSECV, while the external validation set was kept completely independent and used only for final prediction. Among the models that were assessed, the MCR-ALS algorithm demonstrated the best overall predictive performance, yielding correlation coefficients exceeding 0.9997 and root mean square prediction errors ranging from 0.076 to 0.213 µg mL[-1]. NAS-based sensitivity assessment produced detection limits between 0.109 and 0.876 µg mL[-1], demonstrating adequate sensitivity within the investigated concentration ranges. Matrix-matched validation employing 25 calibration and 13 external validation mixtures prepared in fortified human plasma confirmed predictive robustness across both plasma and Paxlovid[®] dosage matrices. Multidimensional sustainability appraisal revealed favorable environmental and operational attributes. The method satisfied all National Environmental Methods Index criteria, achieved a Greenness Evaluation Metric for Analytical Methods score of 7.502, and displayed a calculated carbon footprint of 0.021 kg CO2/sample. Complementary operational and innovation assessments yielded Blue Applicability Grade Index and Violet Innovation Grade Index scores of 90.00 and 80.00, respectively, while the integrated Normalized Quality Score reached 83%. Collectively, the developed platform provides a cost-efficient and environmentally considerate analytical approach suitable for pharmaceutical quality control and preliminary bioanalytical screening in fortified plasma matrices, particularly in laboratories lacking access to advanced chromatographic instrumentation.}, }
@article {pmid41975595, year = {2026}, author = {Tedeschi, V and Ciancio, R and Piccirillo, S and Preziuso, A and Serfilippi, T and Terenzi, V and Magi, S and Lariccia, V and Castaldo, P and Vinciguerra, A and Piccialli, I and Canzoniero, LMT and Pannaccione, A and Secondo, A}, title = {Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01754}, pmid = {41975595}, issn = {1673-5374}, abstract = {Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.}, }
@article {pmid41975602, year = {2026}, author = {Szewczyk, B and Hermann, A and Zimyanin, V}, title = {From cell cycle re-entry to checkpoint failure: Rethinking DNA damage response in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01740}, pmid = {41975602}, issn = {1673-5374}, }
@article {pmid41976821, year = {2026}, author = {Suzuki, H}, title = {Speculum-Induced Intraocular Pressure Elevation During Cataract Surgery and Its Association with Axial Length: A Retrospective Clinical Study.}, journal = {Journal of clinical medicine}, volume = {15}, number = {7}, pages = {}, pmid = {41976821}, issn = {2077-0383}, abstract = {Background/Objectives: This study aimed to characterize eyelid speculum-induced intraocular pressure (IOP) elevation during cataract surgery and identify ocular biometric factors that stratify susceptibility to this pressure response. This study was conducted at Zengyo Suzuki Eye Clinic, Kanagawa, Japan. Methods: In this retrospective observational study, we analyzed 100 eyes that underwent routine cataract surgery. IOP was measured immediately before and within 10 s of speculum opening in the seated position using a rebound tonometer. The eyelid speculum was opened to a maximal opening position, and the opening width was recorded. Biometric parameters included axial length (AL), central corneal thickness, white-to-white distance, anterior chamber depth, and temporal angle-opening distance. Associations between IOP elevation and biometric factors were analyzed. IOP elevation rate was quantified as the percentage increase from baseline. The discriminatory performance of axial length was evaluated using receiver operating characteristic (ROC) analysis. Results: Overall, 100 patients (100 eyes) were included in the analysis. Mean IOP increased significantly from 15.75 ± 2.77 mmHg before speculum placement to 21.42 ± 5.54 mmHg after placement. The mean IOP elevation rate was 36.0 ± 27.4%. Shorter AL was consistently associated with a greater proportional IOP elevation. ROC analysis demonstrated consistent stratification of IOP elevation susceptibility by AL (area under the curve [AUC] = 0.645), with eyes shorter than 23.84 mm showing greater pressure elevation (sensitivity, 73.1%; specificity, 56.0%). Eyes in the upper quartile of the IOP elevation rate exhibited relatively greater pressure elevation. Conclusions: Eyelid speculum placement imposes a clinically meaningful IOP load during cataract surgery, with shorter ALs making eyes more biomechanically susceptible to IOP elevation.}, }
@article {pmid41977262, year = {2026}, author = {Mîndreanu, R and Chiș, IC and Sevastre-Berghian, A and Login, C and Stan, A and Stan, T and Clichici, S and Suciu, &#x218;}, title = {N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, doi = {10.3390/ijms27073076}, pmid = {41977262}, issn = {1422-0067}, mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy ; Translational Research, Biomedical ; Antioxidants/therapeutic use ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Multiple Sclerosis/drug therapy ; Brain Injuries, Traumatic/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.}, }
@article {pmid41977439, year = {2026}, author = {Bougea, A}, title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, doi = {10.3390/ijms27073260}, pmid = {41977439}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; *RNA, Untranslated/genetics ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics ; Genetic Therapy/methods ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.}, }
@article {pmid41978251, year = {2026}, author = {Malmström, N and Ozanne, A and Nilsson, S and Öhlén, J and Jakobsson Larsson, B}, title = {Support interventions for families facing parental life-threatening illness - A scoping review.}, journal = {Palliative &amp; supportive care}, volume = {24}, number = {}, pages = {e78}, doi = {10.1017/S1478951526101837}, pmid = {41978251}, issn = {1478-9523}, mesh = {Humans ; Child ; *Parents/psychology ; *Social Support ; Infant ; }, abstract = {OBJECTIVES: Despite the urgent need for support interventions for families facing parental life-threatening illness, research is limited - particularly in progressive neurological diseases. This scoping review aimed to systematically map existing interventions to inform the development of tailored support in the neurological context.<br><br>METHODS: A scoping review was conducted, including articles published between 2013 and 2025, identified through searches in PubMed, CINAHL, PsycINFO, and Web of Science, along with manual screening of reference lists. Extracted data were systematically charted and descriptively summarized.<br><br>RESULTS: Of 5172 articles, 15 were included, describing 6 unique interventions aimed at supporting children (0-25&#xa0;years) and/or parents in families where a parent had a life-threatening illness. While cancer was the predominant diagnosis among ill parents, progressive neurological diseases, such as amyotrophic lateral sclerosis (ALS) and Huntington's disease, were represented to a limited extent. The interventions targeted children (n&#xa0;=&#xa0;4), parents in their parenting role (n&#xa0;=&#xa0;4), or the entire family (n&#xa0;=&#xa0;7) and were primarily based on psychosocial, psychoeducational, or peer support. Overall, the interventions were positively received by both children and parents and perceived as helpful in navigating their challenging life situations in various ways.<br><br>SIGNIFICANCE OF RESULTS: This review confirms a particular lack of knowledge and tailored support for families affected by progressive neurological diseases. While support interventions for other life-threatening illnesses are also limited, those that exist may offer valuable insights to inform the development of support within neurological care contexts. The findings underscore the need for early, proactive, and accessible approaches that address both individual and family needs across the disease trajectory, aligning with core principles of high-quality palliative care.}, }
@article {pmid41978357, year = {2026}, author = {La, N and Rattanapitoon, NK and Thanchonnang, C and Rattanapitoon, SK}, title = {Refining interpretation of national trends in lung cancer screening discussions.}, journal = {Translational behavioral medicine}, volume = {16}, number = {1}, pages = {}, doi = {10.1093/tbm/ibag012}, pmid = {41978357}, issn = {1613-9860}, mesh = {Humans ; *Lung Neoplasms/diagnosis ; *Early Detection of Cancer/trends ; United States ; *Mass Screening/trends ; *Physician-Patient Relations ; Practice Guidelines as Topic ; }, abstract = {This letter comments on Williamson et al.'s nationally representative analysis of patient-clinician discussions on LCS across the 2013-2021 USPSTF guideline periods. We highlight that changes in survey wording and approximated eligibility criteria may partially explain the reported decline in discussions, rather than a true reduction in clinician engagement. We emphasize the behavioral and measurement implications of terminology awareness and eligibility approximation, and propose analytic considerations for future surveillance efforts to support equitable translation of LCS guidelines.}, }
@article {pmid41978444, year = {2026}, author = {Stokholm, JB and Küchen, SHL and Møller, K and Gätke, MR and Svenstrup, K and Staehr-Rye, AK}, title = {Outpatient versus inpatient initiation of home mechanical ventilation in patients with amyotrophic lateral sclerosis - a protocol for a randomised trial.}, journal = {Danish medical journal}, volume = {73}, number = {4}, pages = {}, doi = {10.61409/A09250733}, pmid = {41978444}, issn = {2245-1919}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Noninvasive Ventilation/methods ; Telemedicine ; *Hospitalization ; *Home Care Services ; Quality of Life ; *Ambulatory Care/methods ; Male ; Randomized Controlled Trials as Topic ; Female ; Patient Satisfaction ; Middle Aged ; Patient Compliance ; *Hypoventilation/therapy/etiology ; }, abstract = {INTRODUCTION: In-home non-invasive ventilation (NIV) is associated with prolonged life and improved quality of life in patients with hypoventilation due to amyotrophic lateral sclerosis (ALS). The initiation of NIV is scheduled for a 1-2-night hospital stay. Telemedicine enables remote monitoring and adjustment of respiratory treatment. These possibilities should be examined to improve patients' experiences and adherence to treatment while freeing up resources in the healthcare system. We hypothesise that outpatient initiation of NIV combined with close telemonitoring in patients with ALS is non-inferior to standard initiation of NIV in adherence to treatment.<br><br>METHODS: This is a randomised, controlled, non-inferiority study. A total of 46 patients with ALS scheduled for initiation of NIV are randomised to start NIV either as an outpatient combined with close telemonitoring or during hospitalisation for 1-2 nights. The primary outcome is NIV adherence after three months, measured as minutes per day for the past seven days. Secondary outcomes are patient satisfaction with NIV treatment and its initiation after three months, assessed on a 1-5 rating scale.<br><br>CONCLUSIONS: The study is the first randomised, controlled study assessing the combination of outpatient initiation of NIV and close telemedical follow-up in patients with a progressive neuromuscular disease. The results may be applicable to other patient populations initiating NIV, e.g., patients with obesity hypoventilation syndrome.<br><br>FUNDING: The study was supported by grants from ALS-fonden and Muskelsvindfonden.<br><br>TRIAL REGISTRATION: NCT05829330.}, }
@article {pmid41979429, year = {2026}, author = {Patel, J and Eisenberg-Godsey, SR and Tipton, PW}, title = {Exploring the phenotypic spectrum of frontotemporal lobar degeneration.}, journal = {Neurologia i neurochirurgia polska}, volume = {}, number = {}, pages = {}, doi = {10.5603/pjnns.109796}, pmid = {41979429}, issn = {0028-3843}, abstract = {Frontotemporal lobar degeneration (FTLD) refers to a spectrum of neuropathology preferentially affecting the frontal and temporal lobes manifesting with progressive behavioral, language, and motor impairment. These clinical symptoms linked to FTLD are collectively referred to as frontotemporal spectrum disorders (FTSD) and include behavioral-variant frontotemporal dementia, nonfluent/agrammatic primary progressive aphasia, semantic variant primary progressive aphasia, right temporal variant frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and amyotrophic lateral sclerosis-frontotemporal spectrum disorders. While some patients with FTLD present with a single, well-defined syndrome, others exhibit features of multiple syndromes, and clinical phenotypes frequently evolve over time. Moreover, there is substantial phenotypic overlap between FTSD and other neurological disorders, contributing to frequent misdiagnosis and diagnostic delays. To address these challenges, we provide a practical, clinically oriented framework for the diagnosis of FTSD. We review common and nuanced clinical features, pertinent diagnostic testing, and the role of genetic testing in the context of current understanding of neuropathological correlates. Despite the absence of disease-modifying therapies, we also outline evidence-informed strategies for the symptomatic management of FTSD.}, }
@article {pmid41980047, year = {2026}, author = {Hawkins, SC and Williams, J and Bennett, BL and Islas, A and Quinn, R}, title = {Out-of-Hospital Management of Suspected Spinal Cord Injuries: How Much Evidence Does it Take to Change Practice?.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/10903127.2026.2655989}, pmid = {41980047}, issn = {1545-0066}, abstract = {We read with interest Millin et al.'s literature review and analysis as well as the letter in response from Calland et al. We were particularly interested in their contention that multidisciplinary teams, including spine surgeons, should be assembled to address this important question. Directly addressing Calland et al.'s concerns about multidisciplinary teams, the Wilderness Medical Society has assembled clinical practice guidelines expert panels addressing spinal injuries since 2011. This analysis included at least one emergency physician, EMS physician, sports medicine physician, paramedic, PhD, EMT, wilderness physician, and military medical specialist as well as orthopaedic surgeon. The lead/senior author of the original 2013 and 2014 guidelines, and co-author on all subsequent versions, is an academic orthopaedic department chair who has decades of experience managing spine trauma and performing spine surgery. Additionally, he led the evidence-based medicine unit (and the associated clinical practice guidelines) of the American Academy of Orthopaedic Surgeons for five years. Inclusion of authors from those subspecialties (a much broader collection than suggested by Calland et al.) still did not change an analysis or recommendation similar to Millin et al.'s: that spinal immobilization was an inappropriate intervention which was demonstrably harmful and had no evidence-based demonstrable benefit. Calland et al. also cite "decades of accumulated clinical experience" as evidence that further study is needed, not "premature abandonment of established practice." What is the degree to which evidence becomes mature enough to change established practice? We have now passed the quarter century mark of accumulated evidence. As Millin et al. have demonstrated, that quarter century of "further study" has only further confirmed the same conclusion. Millin et al. ask how many more peer-reviewed manuscripts need to be published demonstrating harm before spinal immobilization is discarded. We would add, how many decades of data are needed before it is considered "mature"? Additionally, how many professional societies and multidisciplinary teams need to be assembled that come to this same conclusion before the harmful practice of spinal immobilization is discontinued? And finally, to frame this in its most appropriate and patient-centered context-how many patients need to be harmed?}, }
@article {pmid41980219, year = {2026}, author = {Galizzi, G}, title = {MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1342}, pmid = {41980219}, issn = {2152-5250}, abstract = {Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca[2+]) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.}, }
@article {pmid41967717, year = {2026}, author = {Erol Mart, HM and Akay, BN}, title = {Response to Navarrete-Dechent et al.'s "Ultraviolet-induced fluorescent dermoscopy for the diagnosis of skin tumors: A multicenter study.".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.01.106}, pmid = {41967717}, issn = {1097-6787}, }
@article {pmid41968313, year = {2026}, author = {Ghanem, HN and El-Zaher, AA and Taha, EA and Abbas, AEF and Mahmoud, ST}, title = {MATLAB-candexch algorithm-enhanced UV spectrophotometric-chemometric models for green, blue, and white determination of cinnarizine, domperidone, and carcinogenic impurity in pharmaceuticals: NQS assessment and UN-SDGs integration.}, journal = {BMC chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13065-026-01779-0}, pmid = {41968313}, issn = {2661-801X}, abstract = {Novel analytical methodologies integrating UV spectrophotometric techniques with chemometric models were developed for the simultaneous determination of cinnarizine (CIN), domperidone (DOM), and benzophenone (BNZ), a carcinogenic degradation product of CIN, without prior separation. Despite their clinical significance, no existing methods have been reported for their simultaneous quantification. This approach aligns with green and white analytical chemistry principles, offering an environmentally sustainable solution. Predictive models were constructed using Classical Least Squares (CLS), Partial Least Squares (PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). A key methodological advancement was the application of D-optimal design via MATLAB's Candexch algorithm, generating a strategically balanced validation dataset of 13 mixtures and overcoming limits of conventional data splitting in chemometric modelling. The methods demonstrated robust linearity across concentration ranges of 4-20 µg/mL for CIN, 3-15 µg/mL for DOM, and 1-5 µg/mL for BNZ. Calibration performance was excellent, with root mean square errors of calibration (RMSEC) values of 0.036-0.062 for CLS, 0.013-0.024 for PLS, and 0.009-0.012 for MCR-ALS. Notably, MCR-ALS exhibited the smallest and most consistent RMSEC range, demonstrating superior accuracy and stability compared to other chemometric models. Validation studies confirmed excellent method performance with recovery rates between 98 and 102%. The root mean square errors of prediction (RMSEP) for the validation set were 0.042-0.201 for CLS, 0.035-0.187 for PLS, and 0.022-0.154 for MCR-ALS, with MCR-ALS consistently exhibiting exceptional predictive capability. The environmental sustainability credentials of the methodology were comprehensively evaluated using nine distinct evaluation tools: NEMI, Complex GAPI, AGREE, BAGI, RGB12, SDAGI, Carbon Footprint Analysis, GSST, and NQS. These rigorous assessments confirmed the method's exceptional environmental compatibility while maintaining analytical excellence, positioning this approach as an ideal sustainable alternative for pharmaceutical quality control applications aligned with UN Sustainable Development Goals.}, }
@article {pmid41968317, year = {2026}, author = {Algmaal, SE and Boltia, SA and El Saharty, YS and Ghoniem, NS}, title = {Chemometric and learning-based multivariate models for quantifying a challenging quaternary mixture of bupropion, dextromethorphan, and their related impurities by UV-Vis spectrophotometry.}, journal = {BMC chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13065-026-01784-3}, pmid = {41968317}, issn = {2661-801X}, abstract = {This study presents a robust, green, sustainable and time-efficient approach for the simultaneous determination of Bupropion HCl (BUP) and Dextromethorphan HBr (DEX) along with their related impurities 3-Chlorobenzoic acid and N, N-Dimethylaniline. Principal component regression (PCR) and partial least-squares (PLS), in addition to advanced chemometric models, namely multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural networks (ANN), are the four green smart multivariate spectrophotometric models that were proposed and validated. The suggested models were successful in examining the mixture of BUP and DEX in the presence of their impurities. Therefore, the suggested analytical methods can be applied to pharmaceutical formulation analysis without the need for a separation step. The proposed strategy offers a novel analytical platform for quality control laboratories to manage complex formulations involving interfering substances. To further ensure greenness and sustainability of the proposed approach, several assessment tools were applied, including the Modified National Environmental Methods Index (NEMI), Eco-Scale, the Analytical GREEnness (AGREE) metric, the Hexagon algorithm, the Green Analytical Procedure Index (GAPI), the Modified GAPI (MoGAPI), the Blue Applicability Grade Index (BAGI), White Analytical Chemistry (WAC), and the Click Analytical Chemistry Index (CACI). Many traditional analytical techniques pose undesirable dangers to the environment and the analyst, such as using hazardous solvents. This gave analysts the incentive to use green methodologies that take into account the use of safe chemicals, the production of the least amount of trash, substantial time savings, and enhanced analyst safety.}, }
@article {pmid41968679, year = {2026}, author = {Li, A and Xiao, X and Qin, D and Su, H}, title = {Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.}, journal = {Autophagy}, volume = {}, number = {}, pages = {}, doi = {10.1080/15548627.2026.2659295}, pmid = {41968679}, issn = {1554-8635}, abstract = {Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in Pharmacological Research, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.}, }
@article {pmid41969219, year = {2026}, author = {Byrd, EJ and Crossley, JA and Chau, CCC and Actis, P and Calabrese, AN}, title = {An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {5}, pages = {e70565}, doi = {10.1002/pro.70565}, pmid = {41969219}, issn = {1469-896X}, support = {220628/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; 090932/Z/09/Z/WT_/Wellcome Trust/United Kingdom ; WT104918MA/WT_/Wellcome Trust/United Kingdom ; RGS\R2\222357//Royal Society/ ; BB/Y00034X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/X003086/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/M012573/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *DNA-Binding Proteins/genetics/chemistry/metabolism ; *Amyloid/chemistry/genetics/metabolism ; Protein Conformation, alpha-Helical ; Mutation ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) plays a critical role in RNA metabolism and is incorporated into biomolecular condensates called stress granules. In amyotrophic lateral sclerosis (ALS) and several other neurodegenerative disorders, TDP-43 undergoes aberrant phase transitions, forming insoluble amyloid aggregates, including fibrils composed of solely its intrinsically disordered C-terminal domain (CTD). Despite its central role in disease, the conformational dynamics of the CTD remain poorly understood due to its heterogeneous and transient conformational landscape. Here, we employ native ion mobility-mass spectrometry (IM-MS) using nanopipette sub-micron nano electrospray ionization (nanoESI) emitters to characterize the conformational landscape of wild-type and ALS-associated TDP-43 CTD variants (Q331K and R361S) under different solution conditions. Our data suggest that mutations and salt concentration modulate the CTD's conformations. Combined with thioflavin T fluorescence, light scattering, and microscopy, we reveal that these conformational shifts correlate with altered amyloid assembly kinetics and propensity to form condensates. Notably, the Q331K variant, which has a mutation in the transient α-helical region in the CTD, has reduced propensity to form biomolecular condensates but can undergo amyloid assembly in the absence of condensate formation, suggesting that sequence alterations in this α-helical region can tune the molecular mechanism of amyloid assembly. This study demonstrates the power of IM-MS in probing disordered proteins and reveals mechanistic insights into how disease-associated mutations differentially tune TDP-43 CTD amyloid assembly mechanisms.}, }
@article {pmid41969305, year = {2026}, author = {Chan, KO and Grismer, LL}, title = {Extending GroupStruct2: a Bayesian and machine-learning framework for testing taxonomic hypotheses using morphometric data.}, journal = {ZooKeys}, volume = {1276}, number = {}, pages = {125-138}, pmid = {41969305}, issn = {1313-2989}, abstract = {Despite considerable advances in statistical methods, taxonomic delimitation using morphometric data (morphometric delimitation) has not significantly progressed beyond the use of simple summary statistics or univariate tests to quantify differences among predefined operational taxonomic units (OTUs). These methods typically rely on visual inspection of graphs or p-value thresholds to determine if character means are statistically different. Tiburtini et al. (2025) introduced a conceptually different approach for morphometric delimitation using Bayesian model-testing and Gaussian Mixture Models (GMM). This approach can infer morphological clusters with or without a priori OTU groupings and jointly evaluates the fit of alternate taxonomic hypotheses to the data, providing a probabilistic, model-based framework that moves beyond traditional significance testing. Additionally, a machine-learning method was proposed to identify diagnostic characters based on a Random Forest classification algorithm. Initially developed for plant morphometrics, we adapted Tiburtini et al.'s approach for any morphometric dataset and integrated it into GroupStruct2, a Shiny R-based application with a full graphical user interface that also includes conventional statistical methods (e.g. univariate/multivariate tests, PCA, DAPC, MFA). We demonstrate that a more robust, nuanced, and comprehensive perspective on morphological variation and character diagnoses can be achieved using GroupStruct2's integrative workflow that combines classical statistical analyses with Bayesian GMM and machine-learning methods. The integration of frequentist and Bayesian methods within a user-friendly graphical interface democratizes access to robust statistical analyses and enables researchers to adopt quantitative rigor in taxonomic studies.}, }
@article {pmid41970050, year = {2026}, author = {Ren, Y and Han, X and Zhang, K and Niu, S and Chen, B and Wang, X and Jian, F and Pan, H and Zhang, Z and Chen, X}, title = {MRI abnormal patterns of lumbar paraspinal muscles in patients with amyotrophic lateral sclerosis and lumbosacral radiculopathy: a comparative study.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1751139}, pmid = {41970050}, issn = {1664-2295}, abstract = {BACKGROUND: Recent evidence highlights the potential predictive value of paraspinal muscle degeneration in amyotrophic lateral sclerosis (ALS). However, the magnetic resonance imaging (MRI) characteristics of degeneration in lumbar paraspinal muscles in ALS and lumbosacral radiculopathy (LR) remain unclear.<br><br>METHODS: Comparison of fatty infiltration (FI) and relative cross-sectional area (rCSA) of the paraspinal muscles was conducted between 38 ALS patients and 32 LR patients.<br><br>RESULTS: The mean rCSA of the multifidus (MF), erector spinae (ES), and psoas major (PM) muscles was lower on the symptomatic onset side compared to the contralateral side at the L3-L5 segments in patients with ALS. On the symptomatic onset side, the FI of the ES (L1-L4 segments), MF (L4 segment), and PM muscles (L1, L2, and L4 segments) was significantly higher in ALS patients who had pathological spontaneous activity (PSA) than in those without PSA. At the L3-L5 segments on the symptomatic onset side, the mean rCSA of the MF, ES, and PM muscles was significantly higher in LR patients compared to ALS patients (p&#x202f;<&#x202f;0.01). Similar differences in the rCSA of the MF, ES, and PM muscles were observed between lower limb-onset ALS patients and LR patients (p&#x202f;<&#x202f;0.05). In addition, mild associations were observed between declines in the ALS functional rating scale (ALSFRS)-lower score and decreases in the rCSA of MF and PM muscles, as well as increased FI of the MF and ES muscles.<br><br>CONCLUSION: The decrease in the rCSA of the paraspinal muscles on the symptomatic onset side suggests progressive involvement of muscle fibers in ALS patients. The presence of PSA in the paraspinal muscles appears to be more valuable and sensitive for evaluating fatty substitution than muscle atrophy in ALS. MRI parameters of the paraspinal muscles may be useful for monitoring disease progression in ALS and distinguishing ALS, especially lower limb-onset cases, from pauci-symptomatic LR.}, }
@article {pmid41971996, year = {2026}, author = {Apostol, CV and Li, A and Daniels, P and Griffith, L and Cooper-Knock, J and Aguilar-Martinez, E and Yonchev, ID and Whelan, AGR and Shaw, PJ and Sudbery, IM and Wilson, SA}, title = {hnRNPUL1 has a dead polynucleotide kinase domain that regulates RNA and protein interactions.}, journal = {iScience}, volume = {29}, number = {4}, pages = {115360}, pmid = {41971996}, issn = {2589-0042}, abstract = {hnRNPUL1 is a nuclear RNA-binding protein involved in both pre-mRNA splicing and DNA double-strand break repair. Using AlphaFold, we show that hnRNPUL1 has a central folded region consisting of tightly juxtaposed SPRY and dead polynucleotide kinase (dPNK) domains flanked by intrinsically disordered regions (IDRs). The dPNK domain binds both nucleotides and RNA. Remarkably, polynucleotide kinase activity can be reactivated with a single amino acid substitution. Mutations altering nucleotide binding also change the ability of the entire protein to bind RNA and regulate homotypic versus heterotypic protein interactions driven by the IDRs. A mutation that prevents nucleotide binding also destabilizes the protein. In a small number of amyotrophic lateral sclerosis patients, we identify rare coding variants in the HNRNPUL1 gene, which alter the ability of hnRNPUL1 to bind nucleotides, RNAs, and FUS. Together, these data establish that hnRNPUL1 utilizes its dPNK domain to regulate interactions with itself, RNA, and other proteins.}, }
@article {pmid41973722, year = {2026}, author = {Ge, D and Wu, L and Yang, J and Sun, J and Wang, J and Wang, J and Song, H and Wei, R and Xu, Z and Zhao, B and Sun, R and Wang, Y}, title = {Adverse events in different administration routes of Edaravone: A pharmacovigilance study based on the FDA adverse event reporting system.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346797}, doi = {10.1371/journal.pone.0346797}, pmid = {41973722}, issn = {1932-6203}, mesh = {*Edaravone/adverse effects/administration &amp; dosage ; Humans ; United States ; United States Food and Drug Administration ; *Adverse Drug Reaction Reporting Systems ; *Pharmacovigilance ; Female ; Male ; Middle Aged ; Administration, Oral ; Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Administration, Intravenous ; Adult ; *Drug-Related Side Effects and Adverse Reactions/epidemiology ; }, abstract = {The U.S. Food and Drug Administration (FDA) approved intravenous edaravone for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, followed by the approval of the oral formulation in 2022. This study aims to utilize the FDA#39;s Adverse Event Reporting System (FAERS) to investigate the spectrum and timing of adverse events (AEs) associated with edaravone administration, employing repeatability analysis, the Reporting Odds Ratio (ROR) approach, Weibull distribution, and stratification methods. The investigation focuses on data collected from the first quarter of 2017 through the fourth quarter of 2024, aiming to identify adverse event signals and their temporal patterns related to both intravenous and oral edaravone administration. In total, 3,262 records of edaravone-related adverse reactions were identified; among these, 1,534 incidents were associated with intravenous administration, while 453 incidents pertained to oral administration. The analysis revealed distinct adverse reaction profiles for the two routes of administration. Notably, the spectrum of adverse reactions resulting from oral administration predominantly involved the respiratory system, digestive system, and skin damage. In contrast, intravenous administration was more frequently linked to complications associated with invasive procedures and local tissue damage. Furthermore, the timing of adverse reactions exhibited significant variability between the two routes. Weibull distribution analysis indicated that the median onset time for adverse reactions following intravenous administration was 35 days, whereas for oral administration, it was 27 days. Both analytical approaches identified early failure signals, suggesting that the risk of adverse events diminishes over time.}, }
@article {pmid41973791, year = {2026}, author = {Kindbom Land, J and van den Berg, R and Hofvander, B and Sellbom, M and Pauli, M}, title = {Field reliability of the Psychopathy Checklist-Revised among life-sentenced prisoners in Sweden: A follow-up study.}, journal = {Law and human behavior}, volume = {}, number = {}, pages = {}, doi = {10.1037/lhb0000664}, pmid = {41973791}, issn = {1573-661X}, abstract = {OBJECTIVE: The Psychopathy Checklist-Revised (PCL-R) is widely used in forensic and clinical contexts, yet its reliability in high-stakes legal settings remains uncertain. In Sweden, it is routinely applied in court-ordered assessments for life-sentenced prisoners seeking commutation, making score consistency crucial. Sturup et al. (2014) found lower interrater reliability in this context compared with controlled research studies. This study examines whether reliability has increased since their publication and evaluates the incremental contribution of these assessments to structured professional judgment risk classifications.<br><br>HYPOTHESES: Due to increased training and experience, we expected improved reliability compared with that of Sturup et al.'s study.<br><br>METHOD: We estimated interrater reliability of PCL-R total and facet scores using intraclass correlation coefficients (ICC) for 76 life-sentenced prisoners (75 males, one female) who had participated in 217 risk assessments by the Swedish National Board of Forensic Medicine (2013-2023). Associations between PCL-R, Historical-Clinical-Risk Management-20, and structured professional judgment risk classifications were tested with ordinal mixed-effects models.<br><br>RESULTS: The results mirror those of Sturup et al., indicating no substantial improvement in interrater reliability over the last decade. Specifically, the PCL-R total score had an ICC = .73, and the facet-level ICCs were .88 (antisocial), .65 (interpersonal), .59 (affective), and .59 (lifestyle). Only 27% of score differences between assessments fell within one standard error of measurement, indicating more variability than expected based on the manual. Moreover, Historical-Clinical-Risk Management-20 scores were better predictors of the risk classification than the PCL-R scores, indicating limited incremental value of the latter.<br><br>CONCLUSIONS: Reliability of the PCL-R in Swedish forensic assessments has not improved over the past decade and remains moderate. Moreover, structured violence risk factors may weigh more heavily in final judgments than psychopathy ratings. While this reliance may limit the impact of variability in PCL-R scoring, caution is warranted when using psychopathy assessments in high-stakes legal decisions. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid41963814, year = {2026}, author = {Sýkora, R and Chvojka, J and Kukačková, N and Šimečková, V and Smetana, J}, title = {Early resuscitation priorities in two-provider EMS crews: an interpretive commentary.}, journal = {BMC emergency medicine}, volume = {26}, number = {1}, pages = {}, pmid = {41963814}, issn = {1471-227X}, abstract = {BACKGROUND: International resuscitation guidelines are grounded in physiological principles and outcome-based evidence, but they implicitly assume staffing levels that allow multiple time-critical interventions to be delivered in parallel. In many emergency medical systems, however, advanced life support is initially provided by a two-provider crew working alone for a substantial period. Under these conditions, the parallel task execution described in guidelines may become structurally impossible because of capacity constraints. This commentary therefore focuses on adult non-traumatic out-of-hospital cardiac arrest managed according to standard adult ALS guidelines.<br><br>INTERPRETIVE FRAMEWORK: This article is presented as an interpretive commentary and is intended to provide an explanatory perspective on how early guideline-consistent care is enacted under conditions of limited personnel and cognitive capacity, rather than as a prescriptive care algorithm. It applies exclusively to the initial, transient phase of out-of-hospital resuscitation in which advanced life support is delivered by a two-provider professional crew working alone. Its applicability ends once additional trained personnel arrive, stable task allocation becomes possible, or the initial defibrillation cycles have been completed. Deviations from ideal task sequencing are conceptualised as forced deviations, an emergent property of system-level capacity limits rather than individual performance failure. Resuscitation actions are therefore considered in terms of their relative short-term physiological penalty when delayed or interrupted: (1) critical perfusion-dependent actions, where interruption is associated with immediate physiological harm; (2) actions with lower short-term physiological penalty when briefly deferred; and (3) bounded uncertainty domains, particularly ventilation, where physiological effects are non-linear and context dependent.<br><br>CONCLUSION: This interpretive commentary does not modify existing resuscitation guidelines. Instead, it clarifies how their physiological intent may be understood and preserved during the earliest phase of two-provider advanced life support, when parallel task execution is not feasible. By providing a shared interpretive model for early resuscitation under capacity constraint, this approach may help reduce harmful variability, cognitive overload, and misinterpretation of performance at a system level in real-world emergency medical systems.}, }
@article {pmid41964251, year = {2026}, author = {Anastasakis, DG and Hafner, M}, title = {RNA G-Quadruplex-protein interactions: from nuclear RNA processing to cytoplasmic stress response and neurodegeneration.}, journal = {RNA biology}, volume = {}, number = {}, pages = {}, doi = {10.1080/15476286.2026.2658922}, pmid = {41964251}, issn = {1555-8584}, abstract = {RNA G-quadruplexes (rG4s) are stable secondary structures formed by non-canonical Hoogsteen base-pairing of guanine-rich sequences in precursor and mature messenger and non-coding RNAs. We review evidence that rG4s exist in two functionally distinct worlds. In the nucleus, rG4s fold co-transcriptionally to regulate gene expression and RNA processing and organizing membraneless organelles through liquid-liquid phase separation. Splicing regulation by rG4s is restricted to vertebrates and co-evolved with transcriptome complexity. In the cytoplasm, rG4s are actively maintained in an unfolded state by dedicated helicases and RNA-binding proteins, but fold upon stress to nucleate stress granules, that sequester mRNAs and sustain cell survival. When compartmentalization of rG4-protein interactions fails, cells lose both nuclear RNA processing control as well as cytoplasmic translational regulation and proper stress response. The same biophysical properties that make rG4s effective scaffolds for reversible phase separation in RNA processing, proteostasis, and acute stress become liabilities under chronic conditions: in ageing neurons, failure of rG4-protein homoeostasis transforms protective condensates into irreversible aggregates associated with α-synuclein, tau, TDP-43, and FUS pathology. We discuss the implications of a dynamic equilibrium of folded and unfolded rG4s in health and disease, with particular focus on their emerging roles in neurodegeneration.}, }
@article {pmid41964384, year = {2026}, author = {Hodgson, AKO and McDermott, CJ and Shaw, PJ and Alix, JJP}, title = {The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70239}, pmid = {41964384}, issn = {1097-4598}, support = {//NIHR Sheffield Biomedical Research Center (BRC)/ ; }, abstract = {INTRODUCTION/AIMS: Recent work suggests that nerve excitability testing has diagnostic potential in amyotrophic lateral sclerosis (ALS). The diagnostic performance of nerve excitability across hand muscles is currently unknown. This study aimed to assess if muscles of the so-called split hand (abductor pollicis brevis [APB], first dorsal interosseous [FDI], and abductor digiti minimi [ADM]) manifest differences in diagnostic performance.<br><br>METHODS: We prospectively recruited 60 consecutive patients investigated for ALS. Nerve excitability, motor unit number and size (MScanFit), needle electromyography (EMG), and standard clinical data were collected. ALS and non-ALS groups were compared using t tests, area under receiver operating characteristic curves (AUROC), and multivariate modeling.<br><br>RESULTS: Forty-eight patients completed testing of all three muscles, 25 were diagnosed with ALS. The most prominent nerve excitability changes were in superexcitability (APB p&#x2009;=&#x2009;0.001, FDI p&#x2009;=&#x2009;0.0001, ADM p&#x2009;=&#x2009;0.002). Diagnostic performance with superexcitability was similar across the three muscles (p&#x2009;>&#x2009;0.05). Reductions in motor unit number were observed in ALS patients. Changes in excitability were evident without loss of motor units, most frequently in APB (40% of recordings). Improvements to the AUROC were obtained using combined excitability/motor unit parameters from APB/FDI (AUROC 0.97, p&#x2009;=&#x2009;0.01 vs. FDI superexcitability alone). Combined excitability and motor unit modeling outperformed detection of EMG abnormalities.<br><br>DISCUSSION: Disturbances to nerve excitability are similar across the split hand muscles at the time of ALS diagnosis. These occurred prior to motor unit loss and traditional EMG changes. Combining excitability and motor unit parameters in the lateral hand can identify early pathology and potentially lead to earlier diagnosis.}, }
@article {pmid41964401, year = {2026}, author = {Baron, L and Diba, K and Amarasingham, A}, title = {The Role of Plasticity in Replay: Stability Through Anti-Hebbian Rules.}, journal = {Hippocampus}, volume = {36}, number = {3}, pages = {e70089}, pmid = {41964401}, issn = {1098-1063}, support = {R01MH139216/MH/NIMH NIH HHS/United States ; 2423995//National Science Foundation/ ; PHY-230195//National Science Foundation/ ; }, mesh = {*Neuronal Plasticity/physiology ; *Models, Neurological ; *Hippocampus/physiology ; Animals ; Action Potentials/physiology ; Humans ; Synapses/physiology ; *Neurons/physiology ; Memory/physiology ; }, abstract = {Hippocampal replay is now considered to be a cornerstone of memory consolidation, yet the synaptic plasticity rules governing its dynamics remain elusive. Under the standard asymmetric Hebbian spike-timing dependent plasticity (STDP) model, the same spike patterns that promote activity propagation along one direction of sequential activation undermine propagation in the reverse direction, compromising "bidirectional" replay. On the other hand, symmetric potentiation rules, as recently proposed for region CA3, risk corrupting the memory trace by saturating synaptic weights. Using Ecker et al.'s recurrent network model of place cells that spontaneously generate replays during ripples, we systematically investigated how different STDP plasticity rules modulate offline replays. We developed a classification framework to study the mechanisms relating different STDP kernels to key replay characteristics, including directionality, speed, and stability. Our results confirmed that symmetric potentiation rules during offline states saturate synapses, inducing rigid attractors that corrupt the memory trace, and that an asymmetric Hebbian STDP kernel induces strong biases in the directionality of replay, leading to rapid replay acceleration and replay degradation. Notably, we found that an asymmetric anti-Hebbian STDP kernel preserves replay bi-directionality and stabilizes replay speed. We further identified the negative timing component of the STDP rule as the primary driver of replay speed: potentiation causes deceleration, while depression causes acceleration. These findings provide a mechanistic explanation for empirically observed replay deceleration and suggest a role for anti-Hebbian synaptic depression in stabilizing replay dynamics.}, }
@article {pmid41964735, year = {2026}, author = {Matsuda, C and Nakayama, Y and Haraguchi, M and Morishima, R and Itagaki, Y and Bokuda, K and Hayashi, K and Takahashi, K and Shimizu, T}, title = {Weight maintenance following enteral nutrition is associated with prolonged survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {5}, pages = {}, pmid = {41964735}, issn = {1432-1459}, support = {Grant-in-Aid for Scientific Research [B] No. 23K24656//Japan Society for the Promotion of Science/ ; Grant-in-Aid for Scientific Research[C] No. 23K09948//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/physiopathology ; Male ; Female ; *Enteral Nutrition ; Retrospective Studies ; Middle Aged ; Aged ; Body Mass Index ; *Energy Intake/physiology ; *Body Weight/physiology ; Kaplan-Meier Estimate ; Proportional Hazards Models ; Adult ; }, abstract = {OBJECTIVE: To investigate the association between energy intake at the initiation of enteral nutrition (EN), subsequent changes in body mass index (BMI), and survival in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: This retrospective study included 121 patients with ALS who received EN. Annual BMI decline rates (&#x2206;BMI, kg/m[2]/year) were calculated for three periods: from symptom onset to diagnosis (T1-T2), from diagnosis to EN initiation (T2-T3), and from EN initiation to post-EN assessment (T3-T4). Energy intake per weight (E/W, kcal/kg/day) at EN initiation was also assessed. Survival after EN initiation was analyzed using Kaplan-Meier methods and Cox proportional hazards models.<br><br>RESULTS: Post-EN BMI decline (&#x2206;BMIT3-T4) showed a significant negative correlation with E/W at T3 (p&#x2009;<&#x2009;0.001). Patients with lower post-EN BMI decline (&#x2206;BMI&#x2009;<&#x2009;0.8&#xa0;kg/m[2]/year) had significantly longer survival after EN initiation than those with greater BMI decline (p&#x2009;<&#x2009;0.001). Multivariate Cox analysis identified &#x2206;BMIT3-T4 and pre-EN respiratory decline as independent predictors of post-EN survival. Subgroup analyses demonstrated that patients who maintained body weight after EN had better survival irrespective of energy intake at EN initiation.<br><br>CONCLUSION: Weight maintenance following EN was associated with prolonged survival in ALS, whereas energy intake at EN initiation alone was not. These findings suggest that the survival benefit of nutritional intervention may be mediated through stabilization of body weight rather than caloric intake per se.}, }
@article {pmid41966055, year = {2026}, author = {Russell, ND and Downie, JM and Bromberg, MB and Pulst, SM and Jorde, LB}, title = {Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100614}, doi = {10.1016/j.xhgg.2026.100614}, pmid = {41966055}, issn = {2666-2477}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and exome sequencing data from 1,034 ALS cases were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA polymerase, emerged as a top candidate gene. RNA-seq analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways such as translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected controls. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mitochondrial DNA maintenance. Additionally, POLG variant carriers had elevated mitochondrial DNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mitochondrial DNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to ALS etiology.}, }
@article {pmid41967177, year = {2026}, author = {Dhandapani, R and Bakavayev, S and Armoza, A and Bersudsky, M and Shlifer, A and Yehezkel, G and Tsitrina, A and Barak, Z and Sintov, AC and Engel, S}, title = {Nose-to-brain delivery of a SOD1-stabilizing small molecule ameliorates pathology in an ALS mouse model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {3}, pages = {e00904}, doi = {10.1016/j.neurot.2026.e00904}, pmid = {41967177}, issn = {1878-7479}, abstract = {Exposure of a pathogenic β6/β7 loop neo-epitope has been proposed to contribute to the pathogenesis of misfolded Cu/Zn superoxide dismutase (SOD1) in amyotrophic lateral sclerosis (ALS) by mediating early events in its noxious structural transformation and prion-like activity. Antibody-mediated blockade of this epitope was shown to ameliorate disease phenotype in an ALS animal model. Here, as an alternative strategy, we sought to block this epitope using a small molecule designed to occupy the inter-subunit cavity framed by the two β6/β7 loops. Using a structure-based virtual screen targeting this cavity, we identified a small molecule, N-[3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]-4-sulfamoylbenzamide (C7), that preferentially bound the native-like conformation of SOD1, reduced β6/β7 loop epitope accessibility, and inhibited irreversible apo-SOD1 misfolding in vitro. Delivered to presymptomatic hSOD1[G93A] mice via a nanoparticle-based nose-to-brain delivery system, C7 significantly delayed the onset of motor abnormalities and modestly extended survival. At disease onset, spinal cord analysis revealed reduced misfolded SOD1 inclusions and attenuated astro- and microgliosis. Analysis of C7 concentrations in combined brain and spinal cord tissue indicated rapid but saturable nose-to-CNS uptake and slow clearance. Our findings demonstrate that targeting the surface cavity shaped by the β6/β7 loops of SOD1 with a reversibly-binding small molecule can ameliorate ALS-like disease in vivo, potentially by counteracting early misfolding events and/or limiting prion-like propagation of molecular pathology. However, saturable nose-to-CNS uptake of C7 restricts CNS exposure and likely constrains therapeutic efficacy, underscoring the need to define the rate-limiting pharmacokinetic step and to optimize the nanoparticle formulation and/or physicochemical properties of the C7 scaffold.}, }
@article {pmid41961863, year = {2026}, author = {Emond, A and Laflamme, C and Therrien, M and Liao, M and Maios, C and Labarre, A and Drapeau, P and Parker, JA}, title = {Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346613}, doi = {10.1371/journal.pone.0346613}, pmid = {41961863}, issn = {1932-6203}, mesh = {Animals ; *Zebrafish/genetics ; *Caenorhabditis elegans/genetics ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/pathology ; Disease Models, Animal ; Gene Knockout Techniques ; Humans ; CRISPR-Cas Systems ; Motor Neurons/pathology/metabolism ; Larva ; Animals, Genetically Modified ; Phenotype ; }, abstract = {Intronic hexanucleotide repeat expansions in the C9orf72 gene represent the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This expansion decreases C9orf72 expression in affected patients, indicating that loss of C9orf72 function (LOF) acts as a pathogenic mechanism. Several models using Danio rerio (zebrafish) for C9orf72 depletion have been developed to explore disease mechanisms and the consequences of C9orf72 LOF. However, inconsistencies exist in reported phenotypes, and many have yet to be validated in stable germline ablation models. To address this, we created a zebrafish C9orf72 knockout model using CRISPR/Cas9. The C9orf72 LOF model demonstrates, in a generally dose-dependent manner, increased larval mortality, persistent growth reduction, and motor deficits. Additionally, homozygous C9orf72 LOF larvae exhibited mild overbranching of spinal motoneurons. To identify potential therapeutic compounds, we performed a screen on an established Caenorhabditis elegans (C. elegans) C9orf72 homologue (alfa-1) LOF model, identifying 12 compounds that enhanced motility, reduced neurodegeneration, and alleviated paralysis phenotypes. Motivated by the shared motor phenotype, 2 of those compounds were tested in our zebrafish C9orf72 LOF model. Pizotifen malate was found to significantly improve motor deficits in C9orf72 LOF zebrafish larvae. We introduce a novel zebrafish C9orf72 knockout model that exhibits phenotypic differences from depletion models, providing a valuable tool for in vivo C9orf72 research and ALS therapeutic validation. Furthermore, we identify pizotifen malate as a promising compound for further preclinical evaluation.}, }
@article {pmid41962593, year = {2026}, author = {Ran, X and Wang, M and Huang, J and Kuang, N and Tian, P and Wu, J and Feng, F and Luo, Y and Huang, N}, title = {Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103133}, doi = {10.1016/j.arr.2026.103133}, pmid = {41962593}, issn = {1872-9649}, abstract = {One essential post-transcriptional regulatory mechanism that increases protein diversity in eukaryotes is alternative splicing. This process is crucial for maintaining nervous system function and is highly active in neurons. Dysregulation of alternative splicing is a common pathogenic factor in many neurodegenerative diseases. For example, splicing variants of tau protein and amyloid precursor protein are implicated in Alzheimer's disease; aberrant splicing of α-synuclein (SNCA) and upregulation of specific transcript variants of the Parkin (PARK2) gene occurs in Parkinson's disease; and aberrant splicing of Stathmin-2 (STMN2) pre-mRNA leads to the loss of axonal maintenance proteins in amyotrophic lateral sclerosis and frontotemporal dementia. This process is precisely regulated by trans-acting factors, a class of RBPs that specifically recognize and bind to cis-acting elements on precursor mRNA (pre-mRNA). These factors are primarily categorized into two major groups: serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Although hnRNPs and SR proteins have been shown to regulate neuronal alternative splicing, their complex regulatory networks and associated disease mechanisms remain incompletely understood, hindering the development of targeted therapies. This review summarizes the molecular mechanisms of alternative splicing and its regulatory features in neurodegenerative diseases. It also summarizes recent advances in splicing-based therapies and biomarkers, providing insights into disease mechanisms and therapeutic development.}, }
@article {pmid41964083, year = {2026}, author = {Viswanathan, M and Yin, L and Kurmi, Y and Chai, S and Jiang, X and Huo, Y and Xu, J and Chen, L and Gore, JC and Zu, Z}, title = {Enhanced Quantitative Phosphocreatine MR Imaging of Skeletal Muscle Using a Global-Local Two-Branch Deep Learning Model.}, journal = {Magnetic resonance in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/mrm.70386}, pmid = {41964083}, issn = {1522-2594}, support = {R01NS140757/NH/NIH HHS/United States ; R01EB036574/NH/NIH HHS/United States ; R01EB029443/NH/NIH HHS/United States ; R21AG089699/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Phosphocreatine (PCr) is an essential marker of muscle metabolism, and accurate quantification of its (fs) and its exchange rate (ksw) is essential for diagnosing various muscular and neuromuscular diseases. Although chemical exchange saturation transfer (CEST) MRI can detect the saturation transfer effect from PCr, quantification of the underlying PCr fs and ksw, particularly at low fields, remains challenging due to significant overlapping confounding effects in tissues when using conventional fitting approaches. Deep learning (DL) presents a promising alternative, yet traditional DL models often struggle to capture subtle PCr-specific variations induced by changes in fs or ksw. Furthermore, these models are typically trained on either fully synthetic data, which may not adequately mimic tissues, or in vivo data which lack ground truth.<br><br>METHODS: This study introduces a global-local two-branch DL model to effectively eliminate confounding effects and capture subtle variations in the PCr CEST effect. Furthermore, our model was trained on partially synthetic data that offers both simulation flexibility and fidelity. Model accuracy was evaluated by using both digital and physical phantoms, and the model was applied to skeletal muscle of healthy rats and rats with amyotrophic lateral sclerosis (ALS).<br><br>RESULTS: Phantom experiments demonstrate that our approach surpasses all fitting methods, the state-of-the-art model, and other combinations of DL models and training data. In vivo, the model identified a significant reduction in PCr fs in ALS rats, which other methods fail to detect.<br><br>CONCLUSIONS: Our global-local two-branch DL model trained using partially synthetic data enhances PCr quantification in skeletal muscle.}, }
@article {pmid41964193, year = {2026}, author = {Grabarczyk, &#x141;}, title = {Comprehensive Review of Anesthetic Strategies for Patients With Neurodegenerative Diseases.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {32}, number = {}, pages = {e950453}, doi = {10.12659/MSM.950453}, pmid = {41964193}, issn = {1643-3750}, mesh = {Humans ; *Neurodegenerative Diseases/surgery/physiopathology ; *Anesthesia/methods ; *Anesthetics/therapeutic use ; Neuromuscular Blockade/methods ; Perioperative Care/methods ; }, abstract = {Patients with neurodegenerative diseases (NDDs) represent a unique and challenging population from an anesthesiological perspective due to their neurological vulnerability. This issue is becoming increasingly relevant as the incidence of certain NDDs rises with population aging. Effective perioperative management in patients with NDDs requires detailed preoperative evaluation, with emphasis on neurological status, cardiopulmonary function, and a thorough review of current medications. Intraoperatively, careful selection of anesthetic agents and monitoring strategies is essential because of altered drug sensitivity, increased susceptibility to malignant hyperthermia, and potential drug interactions. Particular attention must be given to neuromuscular blockade. The use of nondepolarizing neuromuscular blocking agents is generally risky due to their potentially prolonged and unpredictable effects; their use may be considered under strictly controlled conditions. In contrast, propofol and inhalational agents have demonstrated safety and efficacy in this patient population. This article aims to review the perioperative anesthetic management of patients with NDDs, including Huntington disease, (spino)cerebellar ataxia, Friedreich ataxia, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.}, }
@article {pmid41862849, year = {2026}, author = {Elfe, C and Meer, T and Hövener, C and Theuring, S}, title = {Understanding barriers for refugees and migrants when accessing abortion care in Europe: a scoping review.}, journal = {BMC public health}, volume = {26}, number = {1}, pages = {}, pmid = {41862849}, issn = {1471-2458}, abstract = {BACKGROUND: Access to safe abortion care has been the subject of international policy deliberation for several decades and was included in the World Health Organization’s essential healthcare services in 2020. It differs across Europe, with legal barriers like gestational age limits and the conscientious objection persisting in most European countries. Refugees and migrants can encounter additional barriers when accessing healthcare services for various reasons, such as health system exclusion and language barriers. The aim of this study was to map existing evidence on refugees’ and migrants’ access to abortion care in Europe.<br><br>METHODS: Adopting a scoping review methodology, we conducted a systematic search in PubMed, complemented by web-based hand searches and citation tracking to identify the relevant literature. We included qualitative and quantitative studies as well as grey literature published in English between 2014 and 2025, addressing how refugees and migrants accessed abortion services across Europe. Data were charted according to Levesque et al.&#x2019;s dimensions of healthcare access framework. Results were reported using a narrative synthesis approach.<br><br>RESULTS: We identified 19 studies in eleven different European countries and one EU-wide report (n&#x2009;=&#x2009;20), including twelve qualitative, five mixed, and three quantitative designs. While some studies focused specifically on migrant women seeking reproductive healthcare, others focused on abortion seekers in general while highlighting barriers unique to migrant populations. Prominent barriers were lack of information and insufficient availability of translation services. Availability of services was often restricted by regional disparities and restrictive laws. Affordability issues were amplified by variations in cost entitlements and the precarious status of undocumented migrants. Quality of care was compromised by discriminatory attitudes held by providers.<br><br>CONCLUSIONS: Refugees and migrants in Europe face barriers in access to abortion tied to their migration context. Gaps in coverage for refugees and migrants constitute a violation of universal human rights. Ensuring access requires improved outreach efforts, free availability of translation services, decriminalization, and integration of abortion care into a Universal Health Coverage framework, while combating racism in health care and amplifying the voices of marginalized groups.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-026-27031-x.}, }
@article {pmid41956875, year = {2026}, author = {Ye, M and Song, C}, title = {Microbiome eavesdropping: root-knot nematodes decode rhizosphere volatile dialogues.}, journal = {Trends in plant science}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tplants.2026.03.007}, pmid = {41956875}, issn = {1878-4372}, abstract = {Root-knot nematodes navigate the underground chemical landscape to find their hosts. Building on Wu et al.'s discovery that plant metabolites shape microbial cues guiding nematode behavior, this commentary explores how rhizosphere chemical communication integrates plant, microbial, and parasite interactions within a shared 'information network'.}, }
@article {pmid41956959, year = {2026}, author = {Koterazawa, Y and Goto, H and Aoki, T and Sugita, Y and Ikeda, T and Harada, H and Otowa, Y and Urakawa, N and Hasegawa, H and Kanaji, S and Yamashita, K and Matsuda, T and Kakeji, Y}, title = {Biological Age Reflects Physical Condition and Predicts Postoperative Complications Beyond Chronological Age in Patients With Esophageal Squamous Cell Carcinoma Undergoing Minimally Invasive Esophagectomy.}, journal = {World journal of surgery}, volume = {}, number = {}, pages = {}, doi = {10.1002/wjs.70363}, pmid = {41956959}, issn = {1432-2323}, support = {24K19359//JSPS KAKENHI/ ; }, abstract = {BACKGROUND: Chronological age is an important indicator of the physical condition; however, it may not fully capture their physiological status. Recently, biological age has gained attention as a more accurate predictor of physical condition. This study aimed to investigate the association between biological age and postoperative outcomes in patients with esophageal squamous cell carcinoma (ESCC).<br><br>METHODS: This study included 345 patients with ESCC who underwent minimally invasive esophagectomy at Kobe University Hospital. Biological age was estimated using Levine et&#xa0;al.'s model based on data from nine commonly used blood tests. Patients were stratified by biological age: &#x2265; 75&#xa0;years and < 75&#xa0;years.<br><br>RESULTS: Patients with biological age &#x2265; 75&#xa0;years (N&#xa0;=&#xa0;59) were more likely to be male (p&#xa0;=&#xa0;0.012) and had lower serum albumin levels (p&#xa0;=&#xa0;0.0003) and higher creatinine levels (p&#xa0;=&#xa0;0.0009) than those with biological age < 75&#xa0;years (N&#xa0;=&#xa0;286). Regarding postoperative complications, patients aged &#x2265; 75&#xa0;years had higher rates of pulmonary complications (p&#xa0;=&#xa0;0.032) and anastomotic leakage (p&#xa0;=&#xa0;0.038). No significant differences were observed in overall survival between the &#x2265; 75 and&#xa0;<&#xa0;75 age groups, regardless of disease stage. In patients with advanced ESCC, 93% of those with chronological age < 75&#xa0;years and biological age &#x2265;&#xa0;75&#xa0;years (N&#xa0;=&#xa0;27) received preoperative chemotherapy. Conversely, only 80% of patients with chronological age &#x2265; 75&#xa0;years and biological age < 75&#xa0;years (N&#xa0;=&#xa0;20), who had better general condition, received preoperative chemotherapy.<br><br>CONCLUSIONS: Biological age is associated with postoperative complications. Assessing physical condition using biological age may help determine patients' eligibility for preoperative chemotherapy.}, }
@article {pmid41957276, year = {2026}, author = {Fang, L and Bai, Z and Yang, D and Sun, B and Zhao, X and Deng, J}, title = {Elimination of senescent cells fails to attenuate disease progression in an ALS mouse model.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {5}, pages = {}, pmid = {41957276}, issn = {1590-3478}, support = {2025NSFJQ0057//the Department of Science and Technology of Sichuan Province/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/therapy/physiopathology/genetics ; Mice, Transgenic ; Disease Progression ; Disease Models, Animal ; *Cellular Senescence/physiology ; Mice ; Humans ; Superoxide Dismutase-1/genetics ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving progressive motor neuron degeneration, resulting in muscle weakness and paralysis. Current therapeutic options provide only modest benefit, and the etiology of ALS remains incompletely understood. Emerging evidence implicates cellular senescence in the central nervous system (CNS) of ALS pathogenesis, with senescent astrocytes identified in both animal models and patients.<br><br>METHODS: We employed transgenic mice overexpressing the human superoxide dismutase 1 gene with a glycine-to-alanine substitution at codon 93 (hSOD1[G93A]) as the experimental model. To eliminate senescent cells, mouse-derived natural killer group 2, member D (NKG2D) chimeric antigen receptor T (CAR-T) cells were engineered to target NKG2D ligands (NKG2DLs) [+] senescent cells. The efficacy of senescent cell clearance was assessed by SA-&#x3b2;-gal staining on frozen tissue sections and by quantifying the expression of senescence-associated markers (e.g., p16[INK4a], p21). Disease progression in mice was evaluated by monitoring changes in body weight, behavioral performance, and motor function.<br><br>RESULTS: We found that NKG2DLs[+] senescent cells accumulate in symptomatic transgenic mice. NKG2D CAR-T cells can selectively eliminate senescent cell populations in symptomatic hSOD1[G93A] mice. A single infusion effectively reduced senescent cell burden and suppressed Senescence-Associated Secretory Phenotype (SASP) features within central nervous system tissues. However, no significant improvements in motor function or survival were observed.<br><br>CONCLUSION: These results indicate that while senescence is a pathogenic feature of ALS, it operates within an integrated disease network. Early senolytic intervention or combinatorial approaches may represent promising future strategies for ALS.}, }
@article {pmid41957959, year = {2026}, author = {Jha, I and Arora, S and Ravi, SK}, title = {Comparison of Neurophysiological Parameters Between Menstruating and Menopausal Females at Different Frequencies.}, journal = {Annals of African medicine}, volume = {}, number = {}, pages = {}, doi = {10.4103/aam.aam_835_25}, pmid = {41957959}, issn = {0975-5764}, abstract = {INTRODUCTION: An important impact of gonadal hormones on the auditory pathway has been found. Few neurophysiological research study has been done during different phases of menstrual cycle and menopause. This study was conducted to compare the brainstem auditory evoked potential (BAEP) between menstruating females during the follicular phase and the menopausal group.<br><br>MATERIALS AND METHODS: This was a case-control study. Group 1 included n = 30 menstruating females in the follicular phase and aged between 18 and 25 years. Group 2 included 30 menopausal females and aged between 42 and 50 years. For analysis, Student's unpaired t-test and Chi-square test were applied. BAEP recording was done using standard protocol. Mean wave latencies: I, III, and V and interpeak latencies (IPLs): I-III, III-V, and I-V were recorded.<br><br>RESULTS: Mean &#xb1; standard deviation of absolute latencies (ALs) of brainstem auditory evoked potential (BERA) waves III and V and all IPL at 80 dB and 2, 4, 6 KHz in Group 2 menopausal females were delayed and significant as compared to Group 1 menstruating females. All parameters were highly significant at 6 KHz as compared to 2 KHz in menopausal Group 2.<br><br>CONCLUSION: Brainstem audiometry evoked potential detects hearing loss early in menopausal females at higher frequencies, i.e. at 6 KHz, due to a decrease in estrogen level.}, }
@article {pmid41958917, year = {2026}, author = {Rifai, OM and Waldron, FM and O'Shaughnessy, J and Read, FL and Gilodi, M and Pastore, A and Shneider, NA and Tartaglia, GG and Zacco, E and Spence, H and Gregory, JM}, title = {Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag104}, pmid = {41958917}, issn = {2632-1297}, abstract = {Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALS-FTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43. Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion (12/30) of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS). Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell-type predominance and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43[APT]), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron. Intra-neuronal pTDP-43 and cytoplasmic TDP-43[APT] pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43[APT] staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43[APT] pathology, representing a potential region-specific imaging biomarker (e.g. volumetric or susceptibility-weighted MR imaging) of early disease in ALS.}, }
@article {pmid41959630, year = {2026}, author = {Renga, V and Jeffreys, CA and Kersey, GE and Stommel, EW}, title = {Connectivity in ALS II (CoALS II): a study of structural and functional connectivity in ALS.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1743723}, pmid = {41959630}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a network-level neurodegenerative disease involving distributed disruptions across structural and functional systems. While previous studies have often examined white matter integrity or functional connectivity in isolation, the nature of structure-function coupling and its reorganization in ALS remains poorly understood.<br><br>METHODS: We conducted a multimodal connectomic analysis in ALS patients and matched controls, integrating cortical thickness-based structural covariance networks, diffusion MRI tractography, and resting-state and task-based functional MRI. Graph-theoretical metrics were derived, and cross-modal structure-function correspondence was quantified using ROI-wise correlation analyses. A comprehensive 104-node parcellation scheme based on the Desikan-Killiany atlas was employed.<br><br>RESULTS: ALS participants showed preserved global network topology (p > 0.05 for efficiency and small-worldness) but evidence of selective reorganization, particularly within motor and interhemispheric pathways. Cortical covariance networks exhibited minimal association with functional dynamics, whereas diffusion-derived white matter connectivity remained closely aligned with functional organization. This structure-function coupling was maintained or even enhanced during task performance (p = 0.005), suggesting adaptive reconfiguration rather than uniform disconnection.<br><br>CONCLUSIONS: Structure-function coupling in ALS is not globally diminished but reorganized, with robust white matter-functional relationships coexisting alongside weak cortical covariance-functional associations. These findings refine the traditional disconnection model and highlight the utility of multimodal metrics for understanding disease mechanisms and developing biomarkers for progression and therapeutic response.}, }
@article {pmid41960733, year = {2026}, author = {Han, JJ and Hayward, LJ and Adams, C and Perez-Ibarra, J}, title = {Reachable Workspace as a Clinical Outcome for Upper Extremity Function: A Narrative Review.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70190}, pmid = {41960733}, issn = {1097-4598}, support = {U01 AR065113-01/AR/NIAMS NIH HHS/United States ; //Fulcrum Therapeutics/ ; }, abstract = {Motion sensing technology can be utilized to capture detailed upper extremity (UE) motion to reconstruct an individual's three-dimensional (3D) reachable workspace (RWS). The RWS can be quantified as relative surface area (RSA), providing an innovative surrogate measure to assess UE mobility and function. Numerous studies have shown that RSA can reliably distinguish between healthy and impaired UE function and also is able to detect clinically relevant longitudinal changes, with sufficient sensitivity to detect small differences even in slowly-progressive conditions. After more than a decade of experience in clinical studies, RWS has been shown to be a valid, reliable, and sensitive UE clinical outcome assessment (COA) tool, with clinical utility in various neuromuscular diseases in which UE impairment is significant, including facioscapulohumeral dystrophy (FSHD), Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS). RWS and its performance outcome (PerfO) measure RSA have demonstrated strong associations with established clinical measures of disease severity, patient-reported outcomes (PROs), and functional performance, further supporting its clinical relevance. As an UE functional assessment tool, RWS has also shown its generalizable application in various other conditions with UE impairment, such as stroke, orthopedic conditions, and other musculoskeletal disorders. With significant body of work supporting sensor-based RWS as a clinically useful assessment of UE function, future developments incorporating increasingly-capable mobile sensing technologies for remote monitoring and applying machine learning and artificial intelligence (AI) approaches to the sensor-acquired motion data promise further exciting possibilities to enhance clinical studies and patient care.}, }
@article {pmid41951265, year = {2026}, author = {Marques Couto, C and Gomes, SAMC and Carvalho, RS and Nascimento, OJ}, title = {Disappearing corticospinal tract on routine MRI: dynamic signal evolution in primary lateral sclerosis.}, journal = {BMJ case reports}, volume = {19}, number = {4}, pages = {}, doi = {10.1136/bcr-2025-270652}, pmid = {41951265}, issn = {1757-790X}, mesh = {Humans ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Motor Neuron Disease/diagnostic imaging ; Female ; Male ; *Motor Cortex/diagnostic imaging/pathology ; Disease Progression ; }, abstract = {Primary lateral sclerosis (PLS) may show corticospinal tract (CST) hyperintensity on fluid-attenuated inversion recovery and motor cortex hypointensity on susceptibility-weighted imaging (SWI); however, its longitudinal evolution remains poorly understood. Here, we describe two cases with definite PLS, who were followed up for 15 and 6 years and assessed using qualitative visual magnetic resonance imaging (MRI) scores. Both patients initially exhibited CST hyperintensity. Despite progressive clinical deterioration due to wheelchair/walker dependence, serial MRI demonstrated complete CST normalisation (score 0/16). Concurrently, SWI revealed progressive motor cortex hypointensity, consistent with iron deposition. These cases illustrate a possible dissociation between conventional and susceptibility-based MRI markers, suggesting dynamic pathophysiological processes and potentially early inflammation followed by gliotic remodelling, although technical factors cannot be excluded. A normal-appearing CST should not exclude advanced PLS, and progressive motor cortex hypointensity may provide a more stable marker. Prospective studies with standardised protocols are required to validate these observations.}, }
@article {pmid41951934, year = {2026}, author = {Spinelli, G and Lupker, S}, title = {Focusing on conflict in item-specific adaptive control: Insights from a proportion-neutral manipulation.}, journal = {Memory &amp; cognition}, volume = {}, number = {}, pages = {}, pmid = {41951934}, issn = {1532-5946}, support = {A6333//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada/ ; }, abstract = {Jacoby et al. (Psychonomic Bulletin &amp; Review, 10, 638-644, 2003) reported that, in Stroop tasks, stimuli that more frequently involve targets combined with a congruent distractor (e.g., the word RED in the color red) produce larger Stroop effects than stimuli that more frequently involve targets combined with an incongruent distractor (e.g., RED in green). This pattern suggests that adaptive control can be item-specific in addition to item-nonspecific, and reactive in addition to proactive (although this conclusion has been challenged). This adaptive-control process has often been assumed to be driven by the conflict associated with incongruent stimuli; however, the typical experimental manipulations investigating this issue allow the facilitation associated with congruent stimuli to also play a role. Here, we modified those manipulations in order to focus exclusively on conflict, removing any impact of congruency facilitation, by contrasting targets presented with either neutral (letter strings) or incongruent distractors. Neutral stimuli were presented more frequently than incongruent ones in the Mostly-Neutral (MN) condition and vice versa in the Mostly-Incongruent (MI) condition. Paralleling the original pattern, Stroop interference was larger in the MN condition, suggesting that item-specific conflict frequency can be used to adapt attention accordingly. Importantly, this effect was replicated after experimentally controlling for stimulus frequency, a confound that was found to explain part, but not all, of the general pattern. These results support Jacoby et al.'s claims that (a) control can be adapted in an item-specific fashion and (b) conflict plays a key role in that process.}, }
@article {pmid41952063, year = {2026}, author = {Saim, M}, title = {Letter to the Editor: Methodological Concerns in Bryant et al.'s Network Meta-Analysis on Residual Disease Thresholds in Advanced Ovarian Cancer.}, journal = {American journal of therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1097/MJT.0000000000002133}, pmid = {41952063}, issn = {1536-3686}, }
@article {pmid41952193, year = {2026}, author = {Linse, K and Lulé, D and Schöberl, F and Reilich, P and Ilse, B and Metelmann, M and Eickhoff, C and Bublitz, S and Lorenzl, S and Boentert, M and Petri, S and Rödiger, A and Smesny, U and Wolf, J and Weyen, U and Zeller, D and Dorst, J and Maier, A and Meyer, T and Lingor, P and Hermann, A and Regensburger, M and Großkreutz, J and Runge, C and Lapp, HS and Freigang, M and Vidovic, M and Aust, E and Weber, C and Günther, R}, title = {Between guidelines and reality: expert neurologists' perspectives on structural resources for ALS care in Germany.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {41952193}, issn = {2524-3489}, }
@article {pmid41952858, year = {2026}, author = {Calderón-Garcidueñas, L and Hernández-Luna, J and Galaz-Montoya, CI and Clouston, SAP and Aiello-Mora, MV and Amaro de Gante, J and Stommel, EW and Torres-Jardón, R and Nalbantoglu, OU}, title = {Cortical, subcortical, and cerebellar atrophy and cognition deficits in Metropolitan Mexico City teens and young adults exposed to fine particulate matter (PM2.5) - neurodegeneration is in progress.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1772916}, pmid = {41952858}, issn = {1664-2295}, abstract = {Exposure to environmental fine particulate matter (PM2.5), ultrafine PM (UFPM) and nanoparticles (NPs) are associated with accumulation of amyloid-β1-42 peptides, phosphorylated-Tau, alpha-synuclein and transactive response DNA binding-protein-43 misfolded aberrant proteins, consistent with the biological definitions of overlapping Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) in 99% of ≤40-year-old Metropolitan Mexico City (MMC) forensic autopsies. Structural and volumetric brain responses in vivo are critical in young MMC residents. We performed volumetric and whole-brain correlation analyses in 75 healthy volunteers: 45 MMC 31.2 ± 14.7 y old and 30 low-pollution 31.8 ± 4.8 y old controls, matched by ethnicity, socioeconomic status, nutrition, and BMI. MMC residents exhibited fronto-parietal and temporal lobes, precentral gyrus, hippocampi, basal ganglia, thalamus, amygdala and cerebellar atrophy. The most common atrophy pattern was cortical first parietal and fronto-parietal lobes, combined with gray matter (GM) atrophy in cerebellar lobules IV and V left and right III, IV and V and VI.MMC participants had mild cognitive impairment (Montreal Cognitive Assessment Score 22.8 ± 3.2). GM atrophy involving right globus pallidus and pulvinar and cerebellar white matter (WM) bilaterally were associated with lower cognitive performance and high BMI to subiculum, posterior orbital gyrus and insula, inferior temporal gyrus, supplementary motor cortex, and cuneus WM atrophy. PM2.5 exposure and BMI appear to play key roles in early neurodegenerative disease biology and may contribute to adverse effects on academic and occupational performance, neuropsychiatric disorders, behavioral regulation, risk of substance use initiation, and psychopathy. Neuroradiologists across the world need to know cortical and subcortical, including extensive hippocampal, stratium and cerebellar atrophy identifies overlapping patterns of regional atrophy associated with MCI, AD, bvFTD, PD and ALS, in young urbanites. There is an urgent need for early pediatric neuroprevention interventions, non-invasive AD, PD and TDP-43 biomarkers, in-depth characterization of emission pollutants exposures and their effective control. Denial is no longer an option.}, }
@article {pmid41953830, year = {2026}, author = {Baby, P and John, J and Binesha, PB and Keerthipriya, MS and Ramazanu, S and Nashi, S and Menon, D and Vengalil, S and Thomas, PT and Nalini, A}, title = {Amyotrophic Lateral Sclerosis: A Cross-sectional Survey on Sialorrhoea.}, journal = {Indian journal of palliative care}, volume = {32}, number = {1}, pages = {85-90}, pmid = {41953830}, issn = {0973-1075}, abstract = {OBJECTIVES: One of the major distressing symptoms related to Amyotrophic Lateral Sclerosis (ALS) is excessive drooling of saliva, also termed sialorrhoea. Evaluating its prevalence and severity among Indian patients with ALS is essential for understanding the magnitude and impact of the problem. A cross-sectional survey was conducted to estimate the prevalence and severity of sialorrhoea among individuals diagnosed with ALS. We also intended to assess the current pharmacological management practice for sialorrhoea in ALS patients.<br><br>MATERIALS AND METHODS: Patients with ALS enrolled in the Neuropalliative Registry of a quaternary care centre for neurological disorders were included in the study. As part of routine follow-up, telephonic interviews were conducted with either the patients or their next of kin. The extent of sialorrhoea was assessed using the sialorrhoea scoring scale.<br><br>RESULTS: Seventy patients were included in the study. The mean age at presentation was 51.8 (standard deviation [SD]-12.8) years. The majority were males (74.3%). The mean duration of illness was 21.6 (SD 15.7) months. The majority (80%) had limb onset ALS. Forty per cent of the patients in the study had some degree of sialorrhoea. Mild drooling was present in 15 patients (21.4%), moderate in 9 (12.9%), severe in 2 (2.9%) and profuse drooling in another 2.9% of patients. A total of 9 patients (12.9%) were receiving anticholinergic medication. Patients diagnosed with bulbar onset ALS had a significantly greater degree of sialorrhoea than those with limb onset presentation (P = 0.008). In addition, a longer duration of illness showed a positive correlation with the severity of sialorrhoea (r = 0.30, P = 0.012).<br><br>CONCLUSION: Sialorrhoea is a prevalent and clinically significant symptom in individuals with ALS. The severity of sialorrhoea is greater in patients with bulbar onset ALS and tends to increase with longer illness duration. A substantial proportion of patients may benefit from recommended treatment for excessive salivation and saliva-related issues. This study underscores the need for screening of distressing symptoms as sialorrhoea, in ALS patients. The treating teams need to have a heightened awareness regarding the same so that treatment options can be offered to the patients.}, }
@article {pmid41953903, year = {2026}, author = {Ansari, MS and Heidari, S and Pourgholi, E and Bahramian, S and Tootoonchi, N and Vahabi, SM}, title = {Janus Kinase Inhibitors for Treatment of Palmoplantar Pustulosis, Generalized Pustular Psoriasis, and Palmoplantar Pustular Psoriasis: A Systematic Review of the Literature.}, journal = {Health science reports}, volume = {9}, number = {4}, pages = {e72301}, pmid = {41953903}, issn = {2398-8835}, abstract = {INTRODUCTION: Palmoplantar pustulosis (PPP) is a chronic, recurrent, inflammatory disease and assumed to be a subtype of psoriasis. Pustular psoriasis (PP) is a chronic inflammatory disease that is further subclassified into various entities with different presentations including generalized pustular psoriasis (GPP) and palmoplantar pustular psoriasis (PPPP). Given the central role of the JAK-STAT pathway in cytokine signaling, this systematic review evaluated the effectiveness and safety of Janus kinase inhibitors (JAK-I) in these PP subtypes.<br><br>METHODS: Following PRISMA 2020 guidelines, a systematic search was conducted across PubMed/Medline, Scopus, Web of Science, and Embase up to November 13, 2025. Eligible studies included assessing JAK-I in PPP, GPP, or PPPP. Exclusion criteria were reviews, articles without full-text, SAPHO syndrome, and animal/in vitro studies. Risk of bias was assessed using the NHLBI quality assessment tool for clinical studies and Murad et al.'s checklist for case reports/series.<br><br>RESULTS: Thirty-seven studies were included (29 case reports, 4 case series, and 4 clinical studies), encompassing 157 patients (60.5% female; mean age 46.8 years). Treatments involved tofacitinib, upadacitinib, baricitinib, abrocitinib, and topical ruxolitinib. In PPP, pooled meta-analysis demonstrated a PPPASI-50 response rate of 85.5% (95% CI, 71.3-93.3), with upadacitinib achieving 90.9% (95% CI, 81.7-95.7). Case reports and series showed 88.1% clearance or near-clearance within a mean of 2.5 months. GPP patients (n&#x2009;=&#x2009;5) achieved rapid clearance or marked improvement within 2-12 weeks. Adverse events (18.7%) were generally mild, most commonly acneiform eruptions, headache, and transient liver enzyme elevations, with no severe events reported.<br><br>CONCLUSION: JAK-I demonstrate high response rates and rapid improvement with manageable safety profiles. However, the current evidence is limited by small sample sizes, short follow-up durations, and reliance on case-based data. They represent a promising therapeutic option and warrant further evaluation in larger controlled studies to establish long-term efficacy and safety.}, }
@article {pmid41954708, year = {2026}, author = {Luo, S and Zheng, Q and Wang, M and Wang, X and Ma, B and Liu, D and Li, L and Lu, Y and Sang, D and Yang, L}, title = {Synergistic Neuroprotection of MFSD2A Overexpression and DHA Supplementation in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41954708}, issn = {1559-1182}, support = {202304295107020076//Clinical Medicine Research and Translational Project of Anhui Province/ ; 2022AH051480//University Natural Science Research Project of Anhui Province/ ; 2022//Anhui Province "Jianghuai Famous Doctors" Cultivation Project/ ; 2020byzd169//Natural Science Key Project of Bengbu Medical College/ ; BB21B032//Bengbu Think Tank Construction and Social Science Planning Project/ ; 20230131//Bengbu science and technology innovation guidance project/ ; BBWK2024B204//Bengbu Health and Health Research Project Intestinal Transplantation Technology Clinical Special General Project/ ; AHWJ2024Aa30089//Anhui Province Health and Health Research Project Youth Project/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Docosahexaenoic Acids/pharmacology/therapeutic use/administration &amp; dosage ; Male ; *Neuroprotection/drug effects ; *Dietary Supplements ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss, with limited effective therapies. Docosahexaenoic acid (DHA) exhibits neuroprotective effects, but its limited transport across the blood-brain barrier (BBB) restricts clinical utility. Major facilitator superfamily domain-containing protein 2A (MFSD2A) is the primary transporter of DHA into the central nervous system, yet its role in ALS remains unclear. This study investigated the therapeutic potential and mechanisms of MFSD2A overexpression combined with DHA supplementation in male SOD1^G93A ALS mice. We found that MFSD2A expression was markedly reduced in ALS mice and correlated with impaired motor function and neuronal damage. DHA supplementation or MFSD2A overexpression partially improved behavioral deficits, while their combination produced synergistic benefits. Histological analyses revealed attenuated neuronal degeneration and reduced muscle fibrosis following combined treatment. Furthermore, MFSD2A physically interacted with the E3 ubiquitin ligase TRIM21, regulating glycolytic metabolism by modulating key enzymes (GLUT1, HK2, LDHA, PDK1) and products (lactate/pyruvate and NADH/NADPH ratio). TRIM21 knockdown reversed MFSD2A-mediated neuroprotection and impaired glycolytic metabolism, indicating its critical role in this pathway. The combined intervention also suppressed systemic inflammation and oxidative stress by decreasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and restoring antioxidant enzyme activities (GSH-Px), while reducing lipid peroxidation (MDA). These findings suggest that MFSD2A facilitates DHA's neuroprotective effects by enhancing glycolytic metabolism and mitigating neuroinflammation. This study highlights MFSD2A and DHA as promising therapeutic targets in ALS and provides novel insights into overcoming BBB transport limitations for neurodegenerative disease treatment.}, }
@article {pmid41954773, year = {2026}, author = {Zhu, Y and Ma, J}, title = {Concerns Regarding Baseline Balance, Blinding Validity, and Clinical Relevance in Aktan et al.'s Study on Home-Based Inspiratory Muscle Training for Stress Urinary Incontinence.}, journal = {International urogynecology journal}, volume = {}, number = {}, pages = {}, pmid = {41954773}, issn = {1433-3023}, }
@article {pmid41955555, year = {2026}, author = {Katzberg, HD and Bril, V and Zinman, L and Abrahao, A and Cherney, D and Shah, H and Mendoza, MG and Alfaidi, N and Alnajjar, S and Barnett-Tapia, C}, title = {The Muscle Cramp Impact Index: A Patient-Centered Scale for the Assessment of Muscle Cramps.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e214835}, doi = {10.1212/WNL.0000000000214835}, pmid = {41955555}, issn = {1526-632X}, mesh = {Humans ; *Muscle Cramp/diagnosis/psychology ; Female ; Male ; Middle Aged ; Adult ; Reproducibility of Results ; *Patient Reported Outcome Measures ; Aged ; Prospective Studies ; Psychometrics ; }, abstract = {BACKGROUND AND OBJECTIVES: Muscle cramps are common, variably disabling, and lack a comprehensive validated tool to assess their multidimensional effect. Previous cramp studies have relied primarily on cramp frequency and intensity, despite qualitative work demonstrating that sleep disturbance, daytime functioning, and mental health are also important to patients. Guided by these findings, the aim of this study was to develop and validate a patient-reported outcome measure, the Muscle Cramp Impact Index (MCII), to assess the effect of muscle cramps across diverse etiologies and clinical settings.<br><br>METHODS: This was a multisite, prospective scale-development and validation study conducted in neuromuscular, amyotrophic lateral sclerosis, hepatology, and kidney clinics at the University Health Network/Mount Sinai Hospital and Sunnybrook Health Sciences Centre (2018-2022). MCII item generation was based on a previous qualitative study, literature review, and cognitive interviews with affected patients. Content validity was assessed through review by 27 international neuromuscular and muscle cramp experts. Adult patients experiencing muscle cramps within the preceding 2 weeks were enrolled. Draft items were evaluated for missing data, floor/ceiling effects, and exploratory factor analysis (EFA). Test-retest reliability was assessed in clinically stable patients over a 2-week interval using weighted &#x3ba; and intraclass correlation coefficients (ICCs). Construct validity was examined through predefined hypotheses correlating MCII scores with established measures of sleep disturbance, mood, pain, stiffness, and quality of life.<br><br>RESULTS: A total of 105 patients (40% female individuals; mean age 60.0 &#xb1; 14.2 years) completed the field testing. Eighteen draft items were refined to 16 after patient and expert review. All items demonstrated low missingness (<6%). EFA identified 3 domains-cramp frequency/distribution, sleep interference, and interference with daily life-and 2 items were removed for floor effects or low factor loadings, yielding a final 14-item measure (score range 0-42). The MCII demonstrated moderate correlations with EuroQol 5 Dimension, Epworth Sleepiness Scale, Beck Depression Inventory, and Sleep Disturbance scores. Test-retest reliability was excellent (n = 57; ICC 0.83, 95% CI 0.72-0.89), confirming strong measurement stability.<br><br>DISCUSSION: The MCII is a patient-centered, psychometrically robust measure capturing the multidimensional effect of muscle cramps. Limitations include reliance on self-reported clinical stability and inability to verify respondent identity for mailed questionnaires. Further evaluation of responsiveness and validation in additional cramp populations is warranted to support broader implementation.}, }
@article {pmid41955837, year = {2026}, author = {Song, Y and Zhao, Z and Dai, Y and Li, C and He, X and Wang, Y and Xu, ZD and Yang, Y}, title = {The m7G modification: An emerging player in neurological diseases.}, journal = {Pathology, research and practice}, volume = {282}, number = {}, pages = {156465}, doi = {10.1016/j.prp.2026.156465}, pmid = {41955837}, issn = {1618-0631}, abstract = {With the growing researches on RNA epigenetics, the importance of 7-methylguanosine (m7G) modification is increasingly recognized. The m7G modification is known as a kind of post-transcriptional modifications of RNA and present in many types of RNAs, including mRNAs, microRNAs, ribosomal RNA, and transfer RNAs. Increasing evidence indicates that m7G modifications are involved in a variety of critical biological processes through affecting the stability of RNA, nucleoplasmic transfer and translation efficiency. In the central nervous system (CNS), m7G modification is catalyzed by three major methyltransferase complexes: METTL1/WDR4, RNMT/RAM, and WBSCR22/TRMT112. Dysregulation of this modification is tightly associated with the pathogenesis of various neurological diseases, such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), epilepsy, glioblastoma, ischemic stroke (IS), etc. Here, we review the current knowledge regarding the latest findings on the distribution, regulatory factors, detection techniques and prediction methods of m7G. We further highlight critical knowledge gaps, especially the limited understanding of m7G "readers," the absence of validated "erasers," and the scarcity of cell-type-resolved profiling in the brain. In addition, we also discuss the translational opportunities and challenges, including biomarker discovery, therapeutic targeting of m7G regulators, and specificity concerns in precision neurological medicine.}, }
@article {pmid41956140, year = {2026}, author = {Wang, P}, title = {Response to Tahir et al.'s commentary on our BSRS causal framework for longitudinal well-being data.}, journal = {Journal of biomedical informatics}, volume = {}, number = {}, pages = {105037}, doi = {10.1016/j.jbi.2026.105037}, pmid = {41956140}, issn = {1532-0480}, abstract = {We thank Tahir et al. for their respectful and constructive commentary on our article proposing the Behaviour Self-Regulation Score (BSRS) and a causally-informed workflow for longitudinal self-report well-being data (Wang et al., 2026). We clarify that (i) the completeness threshold was established a priori to support stable estimation, and we reported included-versus-excluded baseline comparisons showing no statistically significant differences on key measured variables; (ii) while treatment- and outcome-related items were collected via an evening daily questionnaire, we defined day-level temporal ordering and stated identification assumptions; and (iii) our causal interpretation is conditional on standard assumptions, which we complemented with exposure-specific backdoor adjustment and three refutation checks (random common cause, placebo permutation, and data-subset stability), while transparently noting remaining limitations including self-report bias and potential time-varying confounding. We welcome the opportunity to clarify these points in response to the Letter to the Editor.}, }
@article {pmid41956387, year = {2026}, author = {Klemmer Chandía, S and Wellge, B and Barzen, G and Aghamiry, H and Manini, C and Bauer, M and Ivantsits, M and Walczak, L and Hahn, K and Hennemuth, A and Spethmann, S and Tzschätzsch, H and Sack, I and Meyer, T}, title = {Cardiac Multifrequency Time-harmonic Elastography: In Silico Validation and In Vivo Application.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2852-6188}, pmid = {41956387}, issn = {1438-8782}, abstract = {PURPOSE: To introduce and validate optimized multifrequency cardiac time-harmonic elastography (THE) with portable drivers and multiple-heartbeat acquisitions for detecting abnormal diastolic stiffness using in silico testing and investigating participants with confirmed cardiac wild-type transthyretin amyloidosis (ATTRwt), a model disease for myocardial stiffness, compared to healthy controls.<br><br>MATERIALS AND METHODS: Cardiac THE was performed using continuous vibrations of 60, 70, and 80 Hz induced by a portable driver. Shear wave speed (SWS) maps, as a proxy for myocardial stiffness, were acquired over 4 seconds in a parasternal long axis view. Cardiac ultrasound simulations with CT-data-based anatomies were used for in silico validation and parameter optimization. Diagnostic performance was assessed using the area under the ROC curve (AUC) with 95% confidence interval (95%-CI).<br><br>RESULTS: Healthy controls (N=10; median age: 32 years [range: 27-56]; five men) and participants with ATTRwt (N=11; median age: 83 years [range: 64-86]; ten men) were investigated, resulting in accurate amyloidosis detection (AUC: 1.00; 95%-CI: 0.94-1.00). In-silico-estimated SWS agreed with ground-truth values (r&#xb2;=0.94; median error: 5.6% [range: -26.2-19.7]) across various stiffnesses [range: 1.3-4.0 m s[-1]] and thicknesses [range: 10-20 mm]. A trend towards underestimation was only observed in the unlikely scenario of thin and very stiff septa.<br><br>CONCLUSION: For the first time, the accuracy of cardiac THE was quantified both in silico and in vivo, specifically in a cohort including patients with ATTRwt. Multifrequency shear waves induced by portable drivers and encoded in standard ultrasound provide a rapid, low-cost echocardiographic contrast that aids the detection of cardiomyopathies such as amyloidosis. Ziel: Vorstellung und Validierung einer optimierten multifrequenten kardialen zeit-harmonischen Elastographie (THE) mit tragbaren Schwingungstreibern und Mehrfach-Herzschlag-Akquisitionen zur Detektion abnormer diastolischer Steifigkeit. Dies erfolgte durch in-silico-Tests sowie durch Untersuchungen an Probanden mit best&#xe4;tigter kardialer Wildtyp-Transthyretin-Amyloidose (ATTRwt) -einer Modellerkrankung f&#xfc;r myokardiale Steifigkeit- im Vergleich zu gesunden Kontrollpersonen.<br><br>MATERIAL UND METHODEN: Kardiale THE wurde unter Verwendung kontinuierlicher Vibrationen von 60, 70 und 80 Hz durchgef&#xfc;hrt, die durch einen tragbaren Schwingungstreiber erzeugt wurden. Scherwellengeschwindigkeits-(SWS)-Karten als Stellvertreterma&#xdf; f&#xfc;r die myokardiale Steifigkeit wurden &#xfc;ber 4 Sekunden in einer parasternalen L&#xe4;ngsachsendarstellung akquiriert. Ultraschallsimulationen des Herzens basierend auf CT-Daten anatomischer Modelle wurden f&#xfc;r die in-silico-Validierung und Parameteroptimierung eingesetzt. Die diagnostische Leistungsf&#xe4;higkeit wurde anhand der Fl&#xe4;che unter der ROC-Kurve (AUC) mit 95%-Konfidenzintervall (95%-CI) bewertet. Ergebnisse: Gesunde Kontrollpersonen (N=10; Medianalter: 32 Jahre [Bereich: 27-56]; f&#xfc;nf M&#xe4;nner) und Teilnehmende mit ATTRwt (N=11; Medianalter: 83 Jahre [Bereich: 64-86]; zehn M&#xe4;nner) wurden untersucht. Dies f&#xfc;hrte zu einer pr&#xe4;zisen Detektion der Amyloidose (AUC: 0.99; 95%-CI: 0.93-1.00). Die in-silico gesch&#xe4;tzten SWS-Werte stimmten gut mit den Referenzwerten &#xfc;berein (r&#xb2;=0,94; Medianfehler: 5,6% [Bereich: -26.2-19.7]) &#xfc;ber verschiedene Steifigkeiten [Bereich: 1.3-4.0 m s[-1]] und Wanddicken [Bereich: 10-20 mm]. Eine Tendenz zur Untersch&#xe4;tzung zeigte sich nur im unwahrscheinlichen Fall d&#xfc;nner und sehr steifer Septen. Schlussfolgerungen: Zum ersten Mal wurde die Genauigkeit der kardialen THE sowohl in silico als auch in vivo quantifiziert -insbesondere in einer Kohorte, die Patientinnen und Patienten mit ATTRwt einschlie&#xdf;t. Multifrequente Scherwellen, die durch tragbare Schwingungstreiber induziert und in Standard-Ultraschall codiert werden, erm&#xf6;glichen einen schnellen, kosteng&#xfc;nstigen echokardiographischen Kontrast, der die Detektion von Kardiomyopathien wie Amyloidose unterst&#xfc;tz.}, }
@article {pmid41636971, year = {2026}, author = {Bignami, EG and Russo, M}, title = {From promising prototypes to "instructions for use": embedding LLMs safely in perioperative and intensive care.}, journal = {Journal of clinical monitoring and computing}, volume = {40}, number = {2}, pages = {301-304}, pmid = {41636971}, issn = {1573-2614}, abstract = {Large language models (LLMs) show promise for supporting clinical decision‑making in perioperative and intensive care settings. The recent study by Xu et al. on pre‑trained language models for preoperative anesthesia triage demonstrates that such models can effectively integrate structured and unstructured clinical data to support triage decisions. However, the translation of these tools from research prototypes to routine clinical use requires more than technical validation; it demands explicit, operationalised “instructions for use” analogous to those required for pharmaceuticals and medical devices. We argue that responsible deployment of LLMs in ICU and perioperative workflows must clarify: (1) intended clinical scope and non‑indications; (2) role in the decision‑making hierarchy and when clinicians should override model recommendations; and (3) mechanisms for transparency, governance, and staff training. Drawing on Xu et al.‘s methodological rigor and Bignami et al.‘s AI policy checklist framework, we outline a concise, practice‑oriented approach to embedding LLMs safely in critical care. We emphasise that without explicit instructions for use, clear governance structures, and comprehensive training, there is a risk of introducing inscrutable systems into the heart of critical care. The time to define these safeguards is now, before ad hoc, ungoverned adoption becomes the norm.}, }
@article {pmid41945266, year = {2026}, author = {Pouliquen, O}, title = {Non-local rheology in granular media: a perspective on the 2015 EPJE Paper by Bouzid et al.}, journal = {The European physical journal. E, Soft matter}, volume = {49}, number = {4}, pages = {}, pmid = {41945266}, issn = {1292-895X}, support = {101097842//HORIZON EUROPE European Research Council/ ; }, abstract = {The study "Non-local rheology in dense granular flows: Revisiting the concept of fluidity," published in 2015 in The European Physical Journal E (vol. 38) by Mehdi Bouzid and collaborators, stands as an important contribution to the rheology of granular materials. In their work, the authors critically discuss the differences between proposed non-local models and provide clear pathways to discriminate between them. This perspective paper revisits the state of the art at the time of the Bouzid et al's publication, highlighting its role in inspiring subsequent research. We then explore recent advancements since 2015, which, while significant, have not yet fully resolve the questions originally raised by Bouzid et al.}, }
@article {pmid41945652, year = {2026}, author = {Schmidt, J and Lampe, D and Poppe, A and Meyer, I and Söling, S and Köberlein-Neu, J and Grandt, D and Düvel, L and Greiner, W and , }, title = {Enhancing Continuous Medication Safety Through e-Prescription and Clinical Decision Support Systems in Outpatient Practices and Pharmacies: Protocol for a Multiperspective Study (eRIKA Study).}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e87277}, pmid = {41945652}, issn = {1929-0748}, mesh = {Humans ; *Decision Support Systems, Clinical ; *Electronic Prescribing/standards ; *Pharmacies ; Polypharmacy ; Outpatients ; }, abstract = {BACKGROUND: Increased life expectancy is associated with increasing multimorbidity and polypharmacy, leading to a heightened risk of drug-drug interactions and adverse events, especially when multiple health care providers are involved. To address the urgent need for safer medication management in this population, tools such as medication plans (MP), electronic prescriptions (e-prescriptions), and clinical decision support systems (CDSS) offer valuable support. These instruments have the potential to enhance medication safety by providing physicians and pharmacists with a comprehensive overview of a patient's overall medication regimen and by assisting health care professionals in making informed prescribing decisions.<br><br>OBJECTIVE: This study aims to improve medication therapy safety by combining e-prescriptions, the use of claims data, MPs, CDSS, and interprofessional communication. To comprehensively evaluate this complex intervention, a holistic multiphase study will be conducted, examining (1) the effectiveness of the intervention and (2) health-economic and (3) implementation-related aspects.<br><br>METHODS: A multiphase study design is used. In the first phase, the intervention is implemented in selected outpatient practices (n=10) and pharmacies (n=10) in 2 regions in Germany as part of a cluster-randomized controlled trial to assess process-related outcomes. The primary outcome is the congruence between the MP and claims data. In phase 2, the intervention is scaled up in 3 regions and evaluated in a quasi-experimental study. The required sample size for the intervention group is 3528 patients, with a synthetic control group matched from existing claims data. The primary outcome is a combined end point of all-cause mortality and hospitalization within 3 months of an index prescription. Quantitative methods (descriptive, regression-based methods using claims data, calculation of the incremental cost-effectiveness ratio, and survey-based analyses of implementation-related aspects) and qualitative methods (interviews and focus groups to capture experiences of health care professionals and patients) are used.<br><br>RESULTS: In phase 1, a total of 187 patients were recruited (74 in the intervention group and 113 in the control group) by June 2025. Phase 2 is currently ongoing, with data collection continuing through December 31, 2025. Final analyses are planned by March 2027.<br><br>CONCLUSIONS: Medication safety in polypharmacy remains a critical challenge in Germany. This study provides multiperspective evidence supporting the nationwide implementation of the eRIKA (e-prescription as an element of interprofessional care pathways for continuous medication therapy management [eRezept als Element interprofessioneller Versorgungspfade f&#xfc;r kontinuierliche AMTS]) intervention.}, }
@article {pmid41945799, year = {2026}, author = {Barnwal, N and Dubey, S and Tiwari, P}, title = {Benzimidazole as a Versatile Scaffold for Developing Neurotherapeutics Against Neurodegenerative Diseases.}, journal = {ChemMedChem}, volume = {21}, number = {7}, pages = {e202500869}, doi = {10.1002/cmdc.202500869}, pmid = {41945799}, issn = {1860-7187}, mesh = {Humans ; *Benzimidazoles/chemistry/pharmacology/therapeutic use/chemical synthesis ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Animals ; Molecular Structure ; Structure-Activity Relationship ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss, leading to severe cognitive and motor dysfunction. Benzimidazole, a privileged heterocyclic scaffold, has emerged as a promising pharmacophore in modulating key pathological targets across these disorders. In AD, benzimidazole derivatives inhibit cholinesterases, glycogen synthase kinase-3β (GSK-3β), and glutaminyl cyclase (QC), thereby addressing cholinergic dysfunction, tau phosphorylation, and amyloid aggregation. In PD and HD, they act as monoamine oxidase-B (MAO-B) inhibitors, dopamine D1/D2 receptor modulators, and N-methyl D-aspartate receptor antagonists, improving dopaminergic signalling and reducing excitotoxicity. In ALS, benzimidazoles regulate acetylcholine dysfunction and inhibit receptor-interacting protein kinase 1 (RIPK1), limiting neuroinflammation and cell death. Preclinical studies demonstrate potent enzyme inhibition, often with IC50 values in the nanomolar to micromolar range, alongside favourable ADMET properties enabling blood-brain barrier penetration. Clinically, the glutaminyl cyclase inhibitor Varoglutamstat has advanced to Phase II trials for AD, while Riluzole remains the only food and drug administration (FDA)-approved benzimidazole drug for ALS. The structural versatility of benzimidazoles supports their development as multi-target-directed ligands, addressing overlapping mechanisms such as protein aggregation, oxidative stress, and neuroinflammation. Emerging strategies including hybrid molecules, nanocarrier delivery, and AI-driven design may accelerate their clinical translation.}, }
@article {pmid41947254, year = {2026}, author = {Passmore, JS and Nieves Delgado, A and Happel, AU}, title = {Ethical design as a prerequisite for translational microbiome science.}, journal = {Microbiome}, volume = {14}, number = {1}, pages = {}, pmid = {41947254}, issn = {2049-2618}, support = {INV-037612/GATES/Gates Foundation/United States ; VI.Vidi.221F.014//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; K43TW012864/NH/NIH HHS/United States ; }, mesh = {Humans ; *Microbiota ; *Translational Research, Biomedical/ethics ; *Translational Science, Biomedical/ethics ; Research Design ; }, abstract = {Human microbiome research is expanding globally, yet remains dominated by samples, institutions, and leadership from the Global North. This imbalance undermines scientific validity, as microbiomes are shaped by socio-ecological context and temporal dynamics, and risks producing diagnostics and therapeutics that are not applicable across diverse populations. In this comment, we engage with van Daele et al.'s framework of co-laboration and argue for ethical, interdisciplinary, and locally led research models that center community participation, context-rich metadata, and equitable authorship. We outline structural requirements-governance tools, funding mechanisms, and accountability systems-needed to ensure these frameworks are implemented and advance both scientific integrity and global health equity. Video Abstract.}, }
@article {pmid41947659, year = {2026}, author = {Vaudroz, V and Hübers, A and Kiliaridis, S and Antonarakis, GS}, title = {The Repercussions of Amyotrophic Lateral Sclerosis on the Orofacial Sphere: A One-Year Prospective Longitudinal Study.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {46}, number = {2}, pages = {e70170}, doi = {10.1111/scd.70170}, pmid = {41947659}, issn = {1754-4505}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Longitudinal Studies ; Female ; Middle Aged ; Prospective Studies ; Disease Progression ; *Malocclusion/etiology ; Aged ; *Oral Health ; Adult ; }, abstract = {AIM: The aim of this longitudinal study was to evaluate the repercussions of amyotrophic lateral sclerosis (ALS) on orofacial function, dental health, and the development of malocclusions, in order to assess whether disease progression influences oral and craniofacial outcomes.<br><br>SUBJECTS AND METHODS: Thirteen patients diagnosed with ALS according to the Gold Coast criteria were enrolled to be examined at two time points (T1 and T2), with a one-year interval. The ALS Functional Rating Scale-Revised (ALS-FRS-R), the Nordic Orofacial Test Screening (NOT-S), the Decayed Missing and Filled Teeth (DMFT) index, Plaque Index, and standard orthodontic assessments were used to quantify changes in disease progression, orofacial function, dental health, and occlusal parameters, respectively. Statistical evaluation: Paired sample t-tests were performed to evaluate differences between T1 and T2 for continuous variables. Chi-square and Fisher's exact tests were used for categorical data. Multiple linear regression analyses were carried out to assess potential associations between general disease progression, ALS type, and orofacial functional or dental health decline. A significance level of p < 0.05 was adopted for all analyses.<br><br>RESULTS: Thirteen patients were examined at T1, 10 of whom completed both evaluations. A significant deterioration in the general disease condition was observed (ALS-FRS-R: mean difference -6.0 &#xb1; 6.98; p = 0.024). Orofacial function worsened significantly as reflected by an increase in NOT-S total score (+2.3; p = 0.001). Dental health also declined, with a significant increase in DMFT (+1.8; p = 0.014) and Plaque Index (+0.4; p = 0.004). However, occlusal parameters remained stable over the 12-month period, with no significant changes in overjet (p = 0.860) or overbite (p = 0.347). The bulbar type of ALS seems to show worse deterioration of orofacial function over time, and individuals with more significant general disease progression also showed worse orofacial functional decline.<br><br>CONCLUSIONS: ALS has a significant impact on orofacial function and dental health, characterized by neuromuscular deterioration, increased plaque accumulation, and a higher number of affected teeth. Despite this decline, dental occlusion appears to remain stable in the short term. These findings highlight the need for interdisciplinary and preventive oral care strategies in the management of patients with ALS, aiming to preserve oral function and quality of life in a progressively disabling disease.}, }
@article {pmid41949165, year = {2026}, author = {Xu, X and Xu, J and Xue, F and Li, W and Liu, H and Zhang, Z and Chen, S}, title = {Isoform-specific function underlies differential herbicide resistance of the W574L mutation in peanut AhALS isozymes.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.70798}, pmid = {41949165}, issn = {1526-4998}, support = {//S&amp;T Program of Hebei/ ; //Shijiazhuang City Modern Agricultural Innovation Special Project of the Key R &amp; D and Small and medium-sized enterprises Innovation Program/ ; //National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Peanut (Arachis hypogaea) is an important cash crop with high oil yield per unit area; it is considered an excellent source for producing premium edible oil and a variety of processed foods. Weed infestation poses a critical challenge to peanut cultivation. Although the acetolactate synthase (ALS)-inhibiting herbicide imazethapyr is extensively applied for weed control in peanut fields, it also causes significant phytotoxicity to the crop. The development of herbicide-resistant varieties through gene editing represents a promising sustainable solution; however, the identification of efficient gene-editing targets for conferring high herbicide resistance in peanut remains limited. Plant resistance to imazethapyr arises primarily from mutations in the target gene ALS.<br><br>RESULTS: In this study, a total of four AhALS genes (AhALS1a, AhALS1b, AhALS2a and AhALS2b) with high homology were identified in cultivated peanut. Importantly, we demonstrated for the first time that all four AhALS proteins localize to the chloroplast. Using site-directed mutagenesis, we introduced mutations at position 574 (W574L) in AhALS1a, AhALS2a, AhALS1b and AhALS2b. Both petri-dish and whole-plant bioassays revealed that transgenic Arabidopsis thaliana expressing AhALS2b-W574L remained susceptible to imazethapyr. By contrast, lines expressing AhALS1a-W574L, AhALS2a-W574L or AhALS1b-W574L exhibited high herbicide resistance. The reduced binding ability of resistance AhALS isoforms to imazethapyr was mainly responsible for transgenic lines resistance to imazethapyr. Furthermore, enzymatic and molecular interaction analyses critically showed that the W574L mutation in AhALS2b, unlike its paralog AhALS1b, did not reduce binding affinity to imazethapyr and thus conferred no resistance.<br><br>CONCLUSIONS: This demonstrates marked functional divergence among peanut ALS isozymes, where an identical mutation yields different phenotypic outcomes depending on the protein structure. Consequently, position 574 in AhALS2b is an ineffective editing target, underscoring the need for isozyme-specific screening to develop herbicide-resistant peanut varieties. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid41950410, year = {2026}, author = {Koyya, R and O'Brien, C and Drennan, IR and Cheskes, S and von Vopelius-Feldt, J}, title = {Paramedics' decisions to withhold resuscitation in traumatic cardiac arrest: accuracy of paramedic assessments compared with autopsy findings.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/10903127.2026.2655289}, pmid = {41950410}, issn = {1545-0066}, abstract = {OBJECTIVES: Trauma remains the leading cause of death among Canadians under 45, with over 70% of these deaths occurring in the prehospital setting. In Ontario, Canada, paramedics' decision to initiate or withhold resuscitation in traumatic cardiac arrest (TCA) is governed by basic life support (BLS) and advanced life support (ALS) patient care standards. This study explores paramedics' decisions to withhold cardiopulmonary resuscitation (CPR) in cases of prehospital TCA.<br><br>METHODS: We conducted a retrospective review of case files relating to coroner investigations of prehospital TCA across two emergency medical services (EMS) covering a mixed urban/suburban region in Ontario, Canada, with a population of approximately 4.3 million people, from January 2018 to July 2022. We reviewed all deaths where EMS records were available in the death investigation files and where paramedics did not provide CPR. Paramedics' documentation of reasons to withhold CPR was reviewed and compared to post-mortem findings. Descriptive statistics were used to describe the findings.<br><br>RESULTS: We identified 90 cases of prehospital TCA where no CPR was provided by paramedics. Of these, 55 cases (61%) had documented, injuries incompatible with life (decapitation, open head or torso wounds with visible outpouring of brain or abdominal contents) or signs of irreversible death (rigor mortis, lividity, decomposition). Post-mortem examination confirmed paramedics' findings of injuries incompatible with life in 29 cases (89%). For the remaining 35 cases (39%), CPR was withheld due to a combination of prolonged time from TCA to EMS contact, severity of injuries deemed non-survivable, significant external blood loss, and following remote physician agreement in 31 (89%) cases. Of these, 29 (83%) had post-mortem findings demonstrating anatomical injuries that made the TCA irreversible.<br><br>CONCLUSIONS: The majority of decisions to withhold CPR in prehospital TCA cases are based on signs that are clearly incompatible with life, identified by paramedics with high specificity. In the absence of such findings, paramedics consider factors like prolonged time intervals, overall injury severity, and seek guidance through remote physician supervision before deciding whether to withhold resuscitation efforts.}, }
@article {pmid41950600, year = {2026}, author = {Yoo, HE and Issenberg, SB and Roh, YS}, title = {Effects of distinct prebriefing and debriefing on learning outcomes in advanced life support training for ward nurses: A randomized controlled trial.}, journal = {Nurse education today}, volume = {163}, number = {}, pages = {107094}, doi = {10.1016/j.nedt.2026.107094}, pmid = {41950600}, issn = {1532-2793}, abstract = {BACKGROUND: Effective training in advanced life support (ALS) is crucial for improving ward nurses' ALS performance and patient outcomes during in-hospital cardiac arrest. However, the comparative effects of prebriefing and debriefing strategies in ALS education remain unclear.<br><br>OBJECTIVE: This study aimed to determine whether differences in prebriefing and debriefing strategies in ALS training result in significant variations in metacognition, self-efficacy, ALS performance, and learning satisfaction among novice ward nurses.<br><br>METHODS: In this randomized controlled trial, 205 novice ward nurses were assigned to four ALS training groups. Groups 1 and 2 received prebriefing with a role-modeling video, whereas Groups 3 and 4 received prebriefing with self-directed learning. Instructor-led (Groups 1 and 3) or peer-led (Groups 2 and 4) debriefings followed the prebriefing methods. Participants completed baseline and post-intervention assessments that measured metacognition, self-efficacy. ALS performance and learning satisfaction was measured only at the posttest.<br><br>RESULTS: All groups demonstrated improved self-efficacy following ALS training. However, Groups 1 and 2, who received prebriefing with a role-modeling video, achieved greater gains in both metacognition and self-efficacy than Groups 3 and 4, regardless of the debriefing method. Among all groups, Group 1 showed the highest ALS performance and learning satisfaction, followed by Group 2.<br><br>CONCLUSION: This study highlights the effectiveness of structured prebriefing using a role-modeling video for enhancing critical ALS competencies among novice ward nurses. These findings provide evidence to inform the design of more effective simulation-based resuscitation training programs in clinical settings.}, }
@article {pmid41941997, year = {2026}, author = {Cai, ZW and Zhuang, SP and Huang, ZY and Shi, JY and Huang, NX and Chen, S and Zou, ZY and Chen, HJ}, title = {Abnormal cortical hierarchy revealed by gradient dysfunction in patients with definite amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {111850}, doi = {10.1016/j.brainresbull.2026.111850}, pmid = {41941997}, issn = {1873-2747}, abstract = {PURPOSE: Cortical multisystem dysfunction in amyotrophic lateral sclerosis (ALS) has been investigated, but disruptions in unimodal-to-transmodal cortical hierarchy remained unexplored. We identified cortical hierarchy abnormalities using functional connectivity gradient (FCG) analysis and evaluated their clinical relevance in ALS.<br><br>METHODS: Resting-state functional MRI images were acquired from 17 definite ALS patients and 29 healthy controls. Unimodal-to-transmodal cortical gradient values were derived from functional connectivity matrices using diffusion map embedding, a nonlinear dimensionality reduction method. Intergroup differences were examined with two-sample t tests at the voxel and network levels.<br><br>RESULTS: Gradients primarily in transmodal areas (including the bilateral frontal and parietal cortex and anterior cingulate gyrus) decreased, and gradients primarily in unimodal areas (including the bilateral precentral and postcentral gyrus and occipital cortex) increased in ALS patients (false discovery rate (FDR)-corrected P < 0.05). Network-level gradients in ALS were elevated in the sensorimotor (SMN) and visual networks (VN) but reduced in the frontoparietal (FPN) and limbic networks (FDR-corrected P < 0.05). Among ALS patients, the gradient values in SMN (r = 0.506; P = 0.038), VN (r = 0.534; P = 0.027) and FPN (r = -0.792; P < 0.001) correlated with disease duration, and the gradient value in FPN correlated with disease severity (r = 0.532; P = 0.028). Gradient measures demonstrated moderate accuracy for diagnosing ALS (AUC = 0.712-0.866).<br><br>CONCLUSION: Aberrant cortical hierarchy may elucidate pathophysiological mechanisms of multisystem dysfunction in ALS. FCG analysis may provide biomarkers related to hierarchical functional systems for assessing ALS progression and diagnosis.}, }
@article {pmid41942009, year = {2026}, author = {Song, L and Li, W and Li, H and Zhang, L}, title = {Comment on Gao et al.'s "Eggshell Fragments as a High-Yield Diagnostic Target in Microscopic Examination of Scabies: A Retrospective Study.".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.01.105}, pmid = {41942009}, issn = {1097-6787}, }
@article {pmid41942654, year = {2026}, author = {Muhr, P}, title = {Seeing Oneself Seize: A Case Study on the Affordances of a Video-Based Diagnostic Encounter for a Patient with Functional Seizures.}, journal = {Culture, medicine and psychiatry}, volume = {50}, number = {2}, pages = {}, pmid = {41942654}, issn = {1573-076X}, mesh = {Humans ; Adolescent ; *Video Recording ; *Seizures/diagnosis/psychology ; Male ; Female ; *Physician-Patient Relations ; }, abstract = {This paper examines how integrating clinical video recordings into the diagnostic encounter shapes a patient's experience of functional seizures, a contested neurological condition historically known as hysterical attacks. Drawing on James Gibson's theory of affordances and de Haan et al.'s account of how individuals perceive affordances based on their needs and concerns, the study analyzes a single in-depth interview with an 18-year-old patient recently diagnosed with functional seizures. It explores what viewing seizure videos with a doctor offers the patient-in clinical, epistemic, emotional, and experiential terms. The interview was subjected to a close reading, attending to how video-mediated communication of diagnosis intersects with the patient's prior illness history, sociocultural context, and understanding of self. The analysis identified three positive (epistemic insight, diagnostic validation, trauma recollection) and three negative affordances (shame, vulnerability, resignation). These affordances emerged not only from what the videos showed but also from how they were viewed, framed, and interpreted during the diagnostic encounter. The study concludes that the videos' affordances cannot be separated from an individual patient's interpretive resources and biography. Clinical video viewing can generate meaningful diagnostic insights, but it also risks harm unless embedded within a carefully structured dialogical process that attends to the patient's specificities.}, }
@article {pmid41943205, year = {2026}, author = {Beers, DR and Lin, YY and Thonhoff, JR and Thome, AD and Faridar, A and Zhao, W and Wen, S and Appel, SH}, title = {Longitudinal Assessment of Biomarkers in ALS: Discriminative Biomarkers for Disease Progression and Survival.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70381}, pmid = {41943205}, issn = {2328-9503}, abstract = {OBJECTIVE: To assess the association and discriminative performance of serum biomarkers with clinical disease progression and survival in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: This retrospective study, conducted at Houston Methodist Hospital, Houston, TX, used longitudinal serum samples collected between January 2018 and December 2022. A cohort of 100 patients with sporadic or familial ALS was randomly selected and assayed by ELISAs for biomarkers 4-hydroxy-2-nonenal (4-HNE), lipopolysaccharide binding protein (LBP), and neurofilament light chain (NfL) levels.<br><br>RESULTS: Each biomarker was increased in patients. 4-HNE and LBP were increased at diagnosis and continued to increase as the disease progressed; both correlated with progression rates and survival. NfL was increased at diagnosis, then plateaued relatively. LBP correlated with ALSFRS-R at diagnosis; NfL did not correlate. 4-HNE and LBP were increased in bulbar onset patients who survived a shorter period of time; NfL levels for bulbar/limb onsets were not different. Receiver operating characteristic analyses with apparent and optimism-adjusted area-under-the-curve (AUC) demonstrated that 4-HNE and LBP discriminated rapid progression and survival, whereas NfL showed modest discrimination for rapid progression. The combination of biomarkers yielded improved AUCs as depicted in Venn diagrams across individual and combined biomarkers.<br><br>INTERPRETATION: 4-HNE, LBP, and NfL are biomarkers of lipid peroxidation, systemic inflammation, and axonal integrity. 4-HNE and LBP correlated with disease burden, disease progression, and survival. In the bulbar onset, survival was shortened and associated with increased 4-HNE and LBP. This exploratory longitudinal study suggests the utility of combining biomarkers to discriminate disease progression and survival and monitor clinical trial outcomes.}, }
@article {pmid41943580, year = {2026}, author = {Ye, Y and Zhang, Z and Xiao, Y and Zhu, C and Wright, N and Asbury, J and Huang, Y and Wang, W and Gomez-Isaza, L and Troncoso, JC and He, C and Sun, S}, title = {DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2026.01.018}, pmid = {41943580}, issn = {1097-4199}, abstract = {The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping scavenger enzyme (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation via dysregulating the properties and activity of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Loss of TDP-43 hyperactivates P-bodies, increasing mRNA association and RNA decay. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.}, }
@article {pmid41943810, year = {2026}, author = {Khandelwal, N and Geremakis, C and Riaz, F and Ryan, G and Saundankar, V and Sheer, R and Suehs, B}, title = {Epidemiology, Patient Characteristics, Real-World Treatment Patterns, and Healthcare Utilization and Spending for Patients with Multifocal Motor Neuropathy: A US Claims-Based Analysis.}, journal = {Journal of health economics and outcomes research}, volume = {13}, number = {1}, pages = {111-119}, pmid = {41943810}, issn = {2327-2236}, abstract = {BACKGROUND: Multifocal motor neuropathy (MMN) is a rare, progressive neurological disease characterized by asymmetrical limb weakness. The real-world healthcare burden of MMN is not well established.<br><br>OBJECTIVES: To characterize the epidemiology, diagnostic procedures, treatment patterns, healthcare resource utilization (HCRU), and healthcare spending associated with MMN in patients in the US.<br><br>METHODS: This retrospective, observational claims study extracted data from the Humana Healthcare Research Database, comprising US Medicare Advantage plan members. Eligible patients were aged 18-89 years, had &#x2265;2 nondiagnostic medical claims (the first being the index date) associated with an MMN diagnosis code (January 1, 2017-June 30, 2022), and continuous enrollment for 12 months pre-index (baseline) and post-index (follow-up). Patients with amyotrophic lateral sclerosis, chronic inflammatory demyelinating neuropathy, or immunosuppressant use were excluded. Outcomes were assessed during the baseline and follow-up periods.<br><br>RESULTS: Deidentified data were extracted for 248 patients with MMN. Median (Q1, Q3) age at index was 70.0 (62.0, 77.0) years; most patients were male (53.6%) and White (78.2%). Diagnostic procedures included (baseline/follow-up periods) spinal magnetic resonance imaging (21.4%/18.1%), nerve conduction studies (19.8%/14.5%), and electromyography (17.7%/15.3%). Anticonvulsants, pain medications, corticosteroids, and central muscle relaxants were the most commonly used medications. Overall, 5.2% of patients had intravenous immunoglobulin (IVIG) during follow-up. Mean (standard deviation [SD]) time from index to IVIG initiation was 63.1 (52.2) days, with 6.5 (5.4) administrations, 28.7 (22.9) days between administrations, and 147.5 (133.9) days of total treatment. For all-cause HCRU, 23.8% of patients had &#x2265;1 inpatient stay in the baseline period, with mean (SD) length of stay of 12.7 (14.5) days; during follow-up, 27.8% of patients had &#x2265;1 inpatient stay (length of stay, 13.4 [16.2] days). During the baseline/follow-up periods, 43.1%/46.8% of patients had &#x2265;1 emergency department visit, and 18.5%/28.6% used telehealth services. Median all-cause spending (baseline/follow-up) was 11 &#x2009; 299 / 16&#x2009;074 for total healthcare, 6745 / 10&#x2009;630 for medical resources, and 1374 / 1701 for pharmacy.<br><br>DISCUSSION: Further studies are needed to enhance our understanding of the real-world diagnostic and treatment patterns associated with MMN and to determine long-term clinical outcomes.<br><br>CONCLUSION: These real-world data highlighted the considerable burden associated with MMN on the healthcare system and patients.}, }
@article {pmid41943905, year = {2026}, author = {Gera, P and Temkar, S and Deb, AK and Sahi, A}, title = {Letter to the Editor: Comment on Upadhyaya et al.'s "Intravitreal Clindamycin as an Adjuvant Therapy in Congenital Toxoplasma Retinochoroiditis in a Neonate - A Case Report".}, journal = {Ocular immunology and inflammation}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/09273948.2025.2497485}, pmid = {41943905}, issn = {1744-5078}, abstract = {The novel work by Upadhyaya et al. suggests a potential use of intravitreal clindamycin for treating congenital toxoplasma retinochoroiditis. We share our clinical experience of encountering a sudden spike in intraocular pressure (IOP) after administering intravitreal clindamycin (5 mg/0.5 mL) in a neonate. Intravitreal injections are known to cause an increase in IOP immediately, which reduces in a few minutes. However, a smaller vitreous volume in neonates can cause an exponential increase in IOP immediately post-injection, posing a risk of optic nerve damage and compromise in retinal perfusion. We suggest modifying the intravitreal preparation of clindamycin to 0.5 mg/0.025 mL when used in neonates to reduce this risk while maintaining therapeutic efficacy.}, }
@article {pmid41944768, year = {2026}, author = {Pang, XY and Wang, HF and Bai, JM and Huang, XS}, title = {Integration of Single-cell RNA Sequencing and Mendelian Randomization Analysis for Identifying Potential Immune Therapeutic Targets in Amyotrophic Lateral Sclerosis.}, journal = {Biomedical and environmental sciences : BES}, volume = {39}, number = {3}, pages = {327-341}, doi = {10.3967/bes2026.011}, pmid = {41944768}, issn = {2214-0190}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/genetics/therapy ; Humans ; *Mendelian Randomization Analysis ; Sequence Analysis, RNA ; Single-Cell Analysis ; Male ; Middle Aged ; Female ; Genome-Wide Association Study ; CD4-Positive T-Lymphocytes/immunology ; Leukocytes, Mononuclear ; }, abstract = {OBJECTIVE: Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+ cytotoxic T cell-related genes and ALS risk.<br><br>METHODS: Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from patients with ALS and healthy controls (HC) was used to identify differentially expressed genes (DEGs) in CD4+ cytotoxic T cells. Comprehensive analyses of CD4+ cytotoxic T cells, including pseudotemporal trajectory, intercellular communication, and metabolic pathway analysis, were performed. Mendelian randomization (MR) analysis evaluated the causal effects of DEGs on ALS risk, with validation using independent genome-wide association study (GWAS) data. Expression patterns of the causal genes were further verified using scRNA-seq, bulk-seq, and clinical samples.<br><br>RESULTS: CD4+ cytotoxic T cells were significantly expanded in patients with ALS. The upregulated genes S100A6, SERPINB6, SMAD7, and TPST2 were positively correlated with ALS susceptibility, whereas DIP2A showed a protective association.<br><br>CONCLUSION: S100A6, SERPINB6, SMAD7, TPST2, and DIP2A were identified as causal genes and potential therapeutic targets in ALS, implicating CD4+ cytotoxic T cells in the disease mechanisms. Further studies targeting these genes and neuroinflammatory pathways are warranted.}, }
@article {pmid41945020, year = {2026}, author = {Qin, K and Xu, Y and Liang, W}, title = {Letter to the editor regarding "Comparison of the therapeutic effects of modified 15-mm incision minimally invasive approach with the conventional approach in the treatment of AO 23-B3 distal radius fractures".}, journal = {Injury}, volume = {}, number = {}, pages = {113224}, doi = {10.1016/j.injury.2026.113224}, pmid = {41945020}, issn = {1879-0267}, abstract = {This letter comments on Liu et al.'s study comparing a modified 15 mm mini-incision volar plating approach to conventional ORIF for AO 23-B3 distal radius fractures. While endorsing the reported cosmetic and recovery benefits of MIPO, we highlight the need for longitudinal functional data during early rehabilitation and detailed classification of postoperative complications. Addressing these gaps would enhance the understanding of the early recovery trajectory and safety profile of this minimally invasive technique.}, }
@article {pmid41935163, year = {2026}, author = {Sheikhpour, Z and Seyedalipour, B and Ataei, F and Baziyar, P and Akhlaghi, M and Hosseinkhani, S}, title = {Inhibitory effect of epigallocatechin-3-gallate as a potent anti-amyloidogenic agent against the G138E mutant of SOD1.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-42742-2}, pmid = {41935163}, issn = {2045-2322}, abstract = {SOD1 misfolding leads to protein aggregation, which is a common feature of neurodegenerative diseases such as ALS. The effect of epigallocatechin gallate (EGCG) as a potent anti-amyloidogenic polyphenol on the G138E-SOD1 mutant was investigated using computational/experimental approaches. MD simulation results (RMSD, RMSF, Rg, SASA, PCA, and FEL) showed that EGCG binding stabilizes the mutant in a structure closer to the native structure, which was consistent with the FTIR and DSSP results. Intrinsic fluorescence spectroscopy calculated Ksv and Kq values as 1.8 × 10[4] M[-1] and 5.8 × 10[12] M[-1]s[-1], respectively, indicating the participation of a static quenching mechanism. TEM images provide compelling evidence for the potential inhibitory effect of EGCG on protein aggregates in the G138E mutant, confirming the results of the ThT assay. DLS results showed a reduction in the size of aggregated particles in the presence of 80 μM EGCG, confirming the inhibition of amyloid aggregation by this compound. Finally, MTT assay on SH-SY5Y cells showed that cell survival in the presence of SOD1-G138E aggregates was approximately 40%, which increased to 60% with the addition of 80 μM EGCG. Taken together, this study suggests that EGCG may inhibit amyloid aggregation and reduce cytotoxicity by affecting nucleation and structural stabilization, making it a promising compound for ALS therapeutic strategies.}, }
@article {pmid41936785, year = {2026}, author = {Bao, A and Liu, J and Bian, B and Gao, T and Zhou, H}, title = {U-Mamba-Spectra: A novel generative and explainable framework for camel milk adulteration detection using near-infrared spectral learning.}, journal = {Food chemistry}, volume = {514}, number = {}, pages = {149054}, doi = {10.1016/j.foodchem.2026.149054}, pmid = {41936785}, issn = {1873-7072}, abstract = {Camel milk is vulnerable to adulteration due to its high value and limited supply. This study proposes an interpretable framework, U-Mamba-Spectra, for qualitative and quantitative detection of camel milk adulteration using near-infrared (NIR) spectroscopy. A total of 460 samples (0-100% adulteration) were analyzed within 780-1830 nm. The proposed U-Mamba classifier, integrating U-Net and Mamba modules to capture local and global spectral dependencies, achieved superior classification performance compared with conventional machine learning and deep learning models. SHAP analysis identified chemically meaningful bands associated with water, protein, and fat. For quantitative analysis, a two-stage MCR-ALS-RF model enabled accurate and chemically interpretable concentration prediction, with validation according to ICH Q2 (R1) demonstrating recoveries of 96.8-99.5%, RSD < 5%, and detection limits of 0.025-0.060 g/100 g. To improve robustness under limited sample conditions, a hybrid generative model (CVAE-CWGAN-GP-SAM) was introduced for spectral augmentation, increasing classification accuracy from 95.21% to 98.60%.}, }
@article {pmid41937028, year = {2026}, author = {Spindler, A and Maas, D and Zappi, I and Shapiro, J and Lo Sicco, KI}, title = {Response to Lampert et al.'s "Hormonal versus Copper Intrauterine Devices: A Retrospective Analysis of Association with Androgen-related Dermatologic Disorders using the TriNetX Database".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.01.104}, pmid = {41937028}, issn = {1097-6787}, }
@article {pmid41937301, year = {2026}, author = {Laine, M and Raitanen, J and Auvinen, A}, title = {Mortality From Amyotrophic Lateral Sclerosis in Finland 1987-2022.}, journal = {European journal of neurology}, volume = {33}, number = {4}, pages = {e70586}, doi = {10.1111/ene.70586}, pmid = {41937301}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality ; Finland/epidemiology ; Female ; Male ; Aged ; Middle Aged ; Adult ; Aged, 80 and over ; Mortality/trends ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We assessed changes in the mortality from ALS in Finland from 1987 to 2022.<br><br>METHODS: Numbers of deaths caused by ALS (ICD-10 code G12.2) and population sizes by sex, age group, and year were obtained from Statistics Finland. Crude and age-standardized mortality rates were calculated. The annual percentage change was estimated using Poisson regression, and joinpoint regression was used to identify changes in trend during the study period.<br><br>RESULTS: Mortality from ALS increased in Finland from 1987 to 2022. The age-standardized ALS mortality in the entire population was 2.24/100,000 in 1987 and 4.21/100,000 in 2022. The male: female ratio in mortality was 1.18. The age-standardized mortality increased on average by 1.7% (95% CI 1.5%-2.0%) annually. In men, the age-standardized mortality increased on average by 1.2% (95% CI 0.9%-1.6%) annually and in women by 2.0% (95% CI 1.6%-2.3%). The largest increase occurred in the oldest age group (70+ years), with an average annual increase of 2.4% (95% CI 2.0%-2.8%). In joinpoint regression, no changes in trend were identified overall or in men, but in women, the annual percentage change (APC) was 5.5% (95% CI 3.0%-8.0%) in 1987-1997 and 1.0% (95% CI 0.5%-1.4%) during 1997-2022.<br><br>CONCLUSION: Similar to some other countries, mortality from ALS has increased in Finland, nearly doubling in 35&#x2009;years. Further research on possible reasons is needed.}, }
@article {pmid41938070, year = {2026}, author = {Samokhina, E and Buskila, Y}, title = {Astrocytic K[+] regulation during neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1782460}, pmid = {41938070}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na[+], Ca[2+], K[+]) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.}, }
@article {pmid41939038, year = {2026}, author = {Chow, CJ and Curtis, S and Chen, M and Purdy, JC and Stanfield, GM and Rojas, E and Wadsworth, R and Sisler, S and Simonetti, J}, title = {"It Honestly Took Me About Two Years": Minoritized Students' Experiences in Navigating Pathways Between High School, College, and Health Science Graduate Programs.}, journal = {Medical science educator}, volume = {36}, number = {1}, pages = {295-304}, pmid = {41939038}, issn = {2156-8650}, abstract = {INTRODUCTION: This study explores the resources needed by minoritized students-particularly students of color and first-generation college students-to succeed in the pathway toward advanced health sciences degrees. Using Teemant et al.'s equity framework, we investigated how partnerships among key stakeholders-including students, parents, school leaders, and community members-contribute to these students' academic success in the health sciences.<br><br>METHODS: We conducted four focus groups (total&#x2009;=&#x2009;31 participants) with the following groups: (1) parents of first-generation college students, (2) community college students, (3) graduate students in health sciences, and (4) academic advisors. An additional four participants provided perspectives through individual interviews. Focus groups and interviews were transcribed verbatim and coded inductively by a subset of the authors.<br><br>RESULTS: Using Teemant et al.'s framework, our analysis illustrated three overarching themes: barriers, supports, and capacities. Key barriers included limited access to information about applying to higher-education programs and facing skepticism from teachers and advisors regarding the potential to succeed in health sciences. Supportive factors included university-based diversity programs and bridge programs that provided target guidance, resources, and information to both students and their families. Data also indicated that higher-education systems often fall short in ensuring that resources are truly accessible and relevant to diverse student populations.<br><br>CONCLUSIONS: Our study illuminates how the success of minoritized individuals in advanced health sciences hinges on bolstering both students' and their parents' navigational capital, while addressing the complex interplay of structural barriers and targeted supports that shape their educational journeys.}, }
@article {pmid41940896, year = {2026}, author = {Tang, Z and Lei, Y and Huang, J and He, R and Wu, Y and Li, M and Ye, Z and He, X and Heng, H and Zha, Y and Wei, J}, title = {Accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {273}, number = {4}, pages = {}, pmid = {41940896}, issn = {1432-1459}, support = {2020ZYYD024//Local Development Project of Science and Technology guided by the Central Commission/ ; EWT201947//Hubei Province Leading Medical Talents and Hubei Province Famous Doctor Studio Program/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis/complications ; Humans ; *Fasciculation/diagnostic imaging/etiology ; Ultrasonography/standards/methods ; *Muscle, Skeletal/diagnostic imaging ; Sensitivity and Specificity ; }, abstract = {PURPOSE: This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Following PRISMA-DTA guidelines, we systematically searched PubMed, Embase, Cochrane Library, Ovid Medline, Sinomed, Web of Science, CNKI and VIP for studies published up to July 8, 2025 that evaluated muscle ultrasonography to detect fasciculations for ALS diagnosis. The study protocol was registered in PROSPERO (CRD420251057866). Studies were screened using predefined inclusion and exclusion criteria and data were extracted. Risk of bias was assessed with QUADAS-2. Statistical analyses (Stata 16.0 and R 4.5.1 with the "midas," "metandi," and "mada" packages) were used to calculate pooled sensitivity (Sen), specificity (Spe), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR). We constructed forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, summary ROC (SROC) curves and calculated the area under the SROC curve (AUC). Univariate meta-regression and subgroup analyses explored sources of heterogeneity. Publication bias was assessed using Deeks' funnel plot asymmetry test. Fagan nomograms were also used to illustrate the changes from pre-test to post-test probability and to enhance clinical interpretability.<br><br>RESULTS: Thirteen studies involving 1176 participants met the inclusion criteria. Muscle ultrasonography for fasciculation detection in ALS yielded a pooled sensitivity of 0.87 (95% CI 0.83-0.91) and specificity of 0.91 (95% CI 0.86-0.94). The pooled LR+ was 9.81 (95% CI 6.25-15.40) and LR- was 0.14 (95% CI 0.10-0.19), with a DOR of 70.03 (95% CI 41.72-117.56). The area under the SROC curve was 0.94 (95% CI 0.91-0.95). Meta-regression identified scan duration as a primary factor influencing diagnostic accuracy, with scan durations&#x2009;&#x2265;&#x2009;30&#xa0;s associated with higher sensitivity but relatively lower specificity. Deeks' funnel plot showed no significant asymmetry (p&#x2009;=&#x2009;0.61), indicating no notable publication bias. Fagan nomograms showed that, at a pre-test probability of 30%, the post-test probability increased to 81% after a positive MUS result and decreased to 6% after a negative result.<br><br>CONCLUSION: Muscle ultrasonography demonstrates good pooled diagnostic accuracy for detecting fasciculations in ALS and may serve as a useful adjunct to electrodiagnostic evaluation. Scan duration appears to significantly affect the diagnostic performance, with longer scanning improving sensitivity at the cost of reduced specificity. We speculate that prolonged scanning may be more useful in clinical scenarios where fasciculations are subtle or atypical, whereas shorter scanning may be sufficient when fasciculations are already readily apparent. Nevertheless, further large-scale prospective studies are needed to validate standardized scanning protocols and to better define the clinical role of MUS in ALS diagnostic pathways.}, }
@article {pmid41941281, year = {2026}, author = {Subramanian, I and Surajambika, RR and Sekar, D and Natarajan, R and Nagarajan, NC}, title = {A Systematic Review on Isoquinoline Derivatives as Emerging Multi-target Agents in Alzheimer's and Parkinson's Disorder Therapy.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249401454260108062419}, pmid = {41941281}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by progressive neuronal loss driven by damage or apoptosis. Although their precise etiologies remain unclear, neuronal degeneration is a common pathological hallmark.<br><br>METHODS: This review compiles and critically evaluates studies investigating the potential of isoquinoline derivatives to mitigate neurodegeneration. Particular attention is given to their inhibitory effects on key enzymes implicated in these disorders and structural modifications aimed at improving potency and reducing toxicity.<br><br>RESULTS: Experimental findings demonstrate that isoquinoline derivatives exhibit significant inhibitory activity against several neurodegeneration-related enzymes. These compounds show promise in attenuating disease progression in preclinical models, supporting their potential as therapeutic leads.<br><br>DISCUSSION: Isoquinoline derivatives display multitarget properties, and structural optimization has enhanced their efficacy and safety profiles. Their multifunctional nature could offer advantages over current single-target therapies by improving efficacy and reducing adverse effects.<br><br>CONCLUSION: Isoquinoline derivatives represent promising scaffolds for developing novel therapeutics targeting neurodegenerative disorders. However, most data are limited to in vitro and earlystage preclinical studies. Comprehensive mechanistic investigations, standardized in vivo evaluations, and early-phase clinical trials are required to establish their pharmacokinetics, blood-brain barrier permeability, safety, and therapeutic potential.}, }
@article {pmid41941533, year = {2026}, author = {Zhuolin, D and Chun, H and Su, X}, title = {Association between allostatic load and thyroid function in U.S. adults: a cross-sectional study based on NHANES data.}, journal = {Stress (Amsterdam, Netherlands)}, volume = {29}, number = {1}, pages = {2653858}, doi = {10.1080/10253890.2026.2653858}, pmid = {41941533}, issn = {1607-8888}, mesh = {Humans ; Female ; Male ; *Allostasis/physiology ; Cross-Sectional Studies ; Middle Aged ; Adult ; Nutrition Surveys ; United States ; *Thyroid Gland/physiopathology/physiology ; Thyrotropin/blood ; Aged ; Thyroid Function Tests ; Thyroxine/blood ; Biomarkers/blood ; *Thyroid Diseases/physiopathology ; Triiodothyronine/blood ; *Stress, Psychological/physiopathology ; }, abstract = {Chronic stress may contribute to endocrine dysregulation. The allostatic load (AL), an indicator of cumulative physiological burden across multiple systems, has unclear associations with thyroid function. We analyzed 5525 adults (2678 men and 2847 women) from NHANES 2007-2010. The participants were categorized into allostatic load score (ALS) quartiles: Q1 (n = 2582), Q2 (n = 1394), Q3 (n = 1003), and Q4 (n = 546). The ALS was constructed from eight cardiovascular, metabolic, and inflammatory biomarkers. Thyroid function was assessed (TSH, FT3, FT4, TgAb, and TPOAb) and categorized as thyroid dysfunction. Survey-weighted multivariable linear and logistic models estimated associations; trend tests and restricted cubic splines (RCS) assessed linearity. Subgroup and interaction analyses examined effect modification, and sensitivity analyses evaluated robustness. ALS was positively associated with higher TSH (β = 0.038, 95% CI: 0.019-0.057, p = 0.001) and FT3 (β = 0.005, 95% CI: 0.003-0.008, p < 0.001). No significant associations were observed for FT4, TPOAb, or TgAb. TSH increased linearly across ALS quartiles (p-trend < 0.001). Restricted cubic splines indicated no overall departure from linearity; in sex-stratified analyses, the association was linear in women and nonlinear in men. Significant interactions with age and race (p < 0.05) indicate that the ALS-TSH association differs by demographics. The results were consistent across the subgroup and sensitivity analyses. Our study suggested a significant positive association between AL and TSH levels. Further research is needed to clarify the mechanisms linking stress and thyroid function.}, }
@article {pmid41931746, year = {2026}, author = {Chalitsios, CV and Rudolf, O and Gao, J and Turner, MR and Thompson, AG}, title = {Long-Term Exposure to Ambient Air Pollution and Incident Amyotrophic Lateral Sclerosis: A Prospective Cohort Analysis of the UK Biobank.}, journal = {Neurology}, volume = {106}, number = {8}, pages = {e214858}, doi = {10.1212/WNL.0000000000214858}, pmid = {41931746}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/etiology ; Middle Aged ; Female ; Male ; United Kingdom/epidemiology ; *Air Pollution/adverse effects ; Aged ; Prospective Studies ; Adult ; Biological Specimen Banks ; *Environmental Exposure/adverse effects ; Incidence ; Particulate Matter/adverse effects ; Gene-Environment Interaction ; *Air Pollutants/adverse effects ; Cohort Studies ; Nitrogen Oxides ; C9orf72 Protein/genetics ; UK Biobank ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex etiology. Although a range of genetic and lifestyle factors have been implicated, the potential role of environmental airborne pollution exposure is uncertain. This study examined the association between long-term ambient exposure to air pollutants and the incidence of ALS in UK Biobank participants.<br><br>METHODS: This prospective cohort study was based on the UK Biobank participants aged 40-69 years. The analytical sample comprised participants free of ALS at baseline and had complete data on air pollution exposure. Long-term exposure (2006-2021) to nitrogen dioxide (NO2), nitrogen oxides (NOX), fine particulate matter (PM2.5; <2.5 &#xb5;m), and coarse particulate matter (PM10; <10 &#xb5;m) was assessed using data from the UK Department for Environment, Food and Rural Affairs at a spatial resolution of 1 &#xd7; 1 km. To evaluate the association between these pollutants and ALS risk, we used multivariable time-varying Cox proportional hazards models. Several sensitivity analyses were conducted to assess the robustness of the results. We also examined for gene-environment interaction stratified by C9orf72 status and UNC13A genotype.<br><br>RESULTS: Among the 501,308 participants with a mean age of 56.5 (SD 8.1) years at baseline, 272,764 (54.4%) were female. Over a median follow-up of 8.4 years, 687 individuals developed ALS. We did not observe any associations for any of the examined pollutants and ALS risk. Specifically, the hazard ratios per SD increment for PM10, PM2.5, NOX, and NO2 were 1.03 (95% CI 0.92-1.15), 1.00 (95% CI 0.88-1.14), 1.01 (95% CI 0.90-1.13), and 1.00 (95% CI 0.89-1.12), respectively. Individuals living in areas with the highest tertile of air pollutant exposure, compared with those in the lowest tertile, did not show a higher risk of ALS across any of the pollutants examined (p for trend >0.05). Restricted cubic spline analyses revealed no nonlinear associations between air pollution and ALS risk (all p for nonlinearity >0.05). These results remained robust in various subgroup and sensitivity analyses. No evidence of gene-environment interaction was found.<br><br>DISCUSSION: In this large population-based study with high statistical power, ambient air pollution was not a risk factor for the development of ALS.}, }
@article {pmid41932459, year = {2026}, author = {Biscardi, T and Pepe, R and Cortini, E and Luongo, D and Notariale, R and Sharbafshaaer, M and Trojsi, F and Bergamo, P}, title = {Supplementation with Conjugated Linoleic Acid ameliorates the level of some Nrf2-activated systemic markers in patients with amyotrophic lateral sclerosis: a proof-of-principle study.}, journal = {Free radical biology &amp; medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2026.03.067}, pmid = {41932459}, issn = {1873-4596}, }
@article {pmid41932651, year = {2026}, author = {Scaricamazza, S and Nesci, V and Fenili, G and Tiberi, M and Percio, A and Rosina, M and Salvatori, I and Riggio, F and Candelise, N and Pieroni, L and Greco, V and Chiurchiù, V and Ferri, A and Valle, C}, title = {The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.}, journal = {Molecular metabolism}, volume = {}, number = {}, pages = {102360}, doi = {10.1016/j.molmet.2026.102360}, pmid = {41932651}, issn = {2212-8778}, abstract = {BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear.<br><br>METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival.<br><br>FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival.<br><br>INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.}, }
@article {pmid41934600, year = {2026}, author = {Landers, SE and Sun, Y and Tolegenova, A and McNabb, K and Zhao, Y and Kuskulov, A and Nyblade, L and Tucker, JD and Balabekova, O and Gryazev, D and Mergenova, G and Davis, A and , }, title = {A Content Analysis of Digital Crowdsourced Messages to Reduce HIV Stigma and Promote Testing Among Adolescents and Young Adults in Kazakhstan.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {41934600}, issn = {1573-3254}, support = {R21TW012017//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; 2T32 MH078788/MH/NIMH NIH HHS/United States ; K01DA044853/DA/NIDA NIH HHS/United States ; K24AI143471//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {In Kazakhstan, almost a quarter of HIV infections are estimated to be among adolescents and young adults (AYA). However, AYA have low testing rates, partially due to stigma. A nationwide digital crowdsourcing open call invited AYA ages 13-29 years old to create media content that could reduce HIV stigma in order to promote testing among peers. This study examines the format and content of entries to the open call, exploring whether AYA address key points about stigma and testing identified by public health professionals. The content analysis framework was informed by Nyblade et al.'s concept of immediately actionable drivers of stigma: awareness of stigma, fear of HIV acquisition, attitudes, and institutional environment. Additional codes examined content type, tone, AYA-specific appeal, social support, and testing messages. The open call received 96 entries, representing almost all provinces in Kazakhstan. AYA submitted more videos/images (67%) compared to other types of content. Most content was emotive in tone (60%) and included features with AYA-specific appeal (80%). Nearly a third of entries referenced the impact of social support. Eighty-eight percent included at least one driver of stigma; most addressed them in a positive way, but some perpetuated stigmatizing ideas. Finally, 60% explained the importance of HIV testing, mainly focusing on health implications. Findings suggest AYA are willing to submit to open calls and can produce creative, relevant content to address HIV stigma and promote testing. A minority of entries included potentially stigmatizing content, highlighting the importance of a structured, multi-phase judging process in crowdsourcing.}, }
@article {pmid41741537, year = {2026}, author = {Aouabed, Z and Therrien, V and Bouaoune, MA and Bakhtyari, M and Hijri, M and Makarenkov, V}, title = {Soil microbiome prediction using traditional machine learning and deep learning models.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41741537}, issn = {2045-2322}, abstract = {The accuracy of macrobiological community predictions largely depends on the taxonomic scale considered. Nowadays, the applicability of such predictions remains an important challenge when extended to microbial soil communities. This is not only due to the lack of reliable benchmark data, but also to a greater diversity of the soil microorganisms compared to other environments. In this study, we use six traditional machine learning regression models and one deep learning regressor to predict relative frequencies of bacterial and fungal communities within the soil microbiome based on environmental factors. We analyze the data from two publicly available soil microbiome datasets: (1) Data collected by Averill and co-authors and analyzed in a recent Nature Ecology and Evolution article, and (2) Data extracted from the NEON database, to estimate the composition of bacterial and fungal communities at the functional (i.e. functional group level) and taxonomic scales (i.e. phylum, class, order, family, and genus levels). Our findings suggest the presence of a general pattern across the observed taxonomic scales according to which the predictability of the soil microbiome increases with taxonomic scale. However, a notable exception occurs when machine learning models are applied to predict bacterial communities at the functional group level for Averill et al.’s data when all of them fail to provide accurate predictions results. The best overall results obtained include the value of the coefficient of determination [Formula: see text]=0.57 at the phylum taxonomic level, provided by the Gradient boosting model for the bacterial dataset collected by Averill et al., and the value of [Formula: see text]=0.45 at the functional group level, provided by both the Random forest and Gradient boosting models for the fungal dataset extracted from NEON. The best overall predictions were obtained using the Random forest and k-NN models. Random forest yielded the best average results on the phylim, class, and order taxonomic levels, while k-NN was particularly effective on lower taxonomic levels, including family and genus. Moreover, both of these traditional machine learning models usually outperformed the deep learning-based Multilayer perceptron regressor. This is probably due to a relatively limited number of samples available for model training in the two public datasets analyzed in our study. The data and code allowing one to reproduce the presented results can be accessed using our GitHub repository at: https://github.com/Vincent-Therrien/micropyome.}, }
@article {pmid41925964, year = {2026}, author = {Oriquat, G and H, M and Maharana, L and Dhyani, A and Al-Hasnaawei, S and Singh-Chauhan, A and Arora, V and Sharma, J and Sadeghi-Samarjan, R}, title = {The Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41925964}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons and a median survival of 2 to 3 years after symptom onset. Despite advances in genetics, particularly the identification of mutations in C9ORF72, SOD1, and TDP 43, substantial variability in disease onset and progression remains unexplained. Mounting evidence points to the gut microbiome as a potential modifier of ALS biology. Microbial communities within the intestine influence systemic and central immune responses, energy metabolism, and the bioavailability of nutrients and therapeutic agents. Animal studies reveal that dysbiosis contributes to intestinal barrier dysfunction, immune activation, and altered metabolite production, while supplementation with beneficial metabolites such as butyrate or nicotinamide can delay disease progression and extend survival. Human studies, though inconsistent in their findings, consistently identify microbial imbalances and loss of diversity in subsets of patients. The gut-brain axis provides a plausible framework for these effects, as microbial products can signal through endocrine, neural, and immune pathways to influence central nervous system function. Beyond motor decline, microbiota alterations may also contribute to non-motor symptoms such as depression, anxiety, and gastrointestinal dysfunction, further shaping quality of life. While methodological variability complicates interpretation, integration of microbiome research with host genomics and metabolomics offers a path toward precision medicine. Targeting microbial composition and function may ultimately represent a novel therapeutic approach capable of modifying both disease biology and patient outcomes in ALS.}, }
@article {pmid41926450, year = {2026}, author = {Christoforidou, E and Rowe, JS and Simoes, FA and Cassel, R and Dupuis, L and Leigh, PN and Hafezparast, M}, title = {Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346246}, pmid = {41926450}, issn = {1932-6203}, mesh = {Animals ; *Interneurons/metabolism/pathology ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Spinal Cord/metabolism/pathology ; Disease Models, Animal ; Male ; Cell Survival ; *Dyneins/metabolism/genetics ; *Cytoplasmic Dyneins/metabolism/genetics ; }, abstract = {Impaired cytoplasmic dynein function has been implicated in amyotrophic lateral sclerosis (ALS) pathogenesis, yet the contributions of spinal interneurons to disease phenotypes remain unclear. We tested the hypothesis that hypomorphic dynein function in cholinergic neurons disrupts the development, survival, or positioning of inhibitory interneuron populations in the lumbar spinal cord. Using ChAT-Cre recombination, we generated four mouse genotypes with graded reductions in dynein activity in ChAT+ cells: Dync1h1+/+ (wildtype), Dync1h1-/+ (hemizygous wildtype), Dync1h1+/Loa (heterozygous Loa mutation), and Dync1h1-/Loa (hemizygous Loa). At 52 weeks of age, lumbar spinal cords (L3-L6) were harvested, cryosectioned, and immunostained for ChAT, GAD-67, Parvalbumin, and Calbindin. Cell counts were performed on confocal images from eight sections per mouse (N = 3 male mice/genotype), and radial distances from the central canal were normalised to gray matter width. Angular distributions were analysed via circular statistics. There were no significant genotype-dependent differences in the numbers of ChAT+, GAD-67+, Parvalbumin+, or Calbindin+ cells, nor in ChAT+ subpopulations (motor neurons versus interneurons) or double-positive interneuron subsets (e.g., ChAT+-GAD-67+, Parvalbumin+-GAD-67+, Parvalbumin+-Calbindin+). Radial positioning relative to the central canal was similarly preserved across all markers and genotypes. Circular-median tests revealed statistically significant shifts in mean angle for ChAT+, GAD-67+, and certain double-positive cells, but these amounted to only 5-10° displacements, translating to lateral shifts of ~10-20 µm, well within single laminar bands, and are unlikely to impact circuit connectivity. Despite substantial motor deficits and hallmark TDP-43 pathology previously seen in these models, impaired dynein function does not precipitate interneuron loss or gross migratory defects in the lumbar spinal cord. Instead, our findings suggest that the primary contributions of dynein to ALS-like phenotypes likely arise from functional disruptions in axonal transport, synaptic maintenance, and neuronal physiology rather than from structural alterations or loss of interneuron populations.}, }
@article {pmid41926608, year = {2026}, author = {Mori, F and Kon, T and Itazawa, R and Akatsu, A and Miki, Y and Arai, A and Kurotaki, H and Tomiyama, M and Wakabayashi, K}, title = {Relationship between promyelocytic leukemia protein nuclear bodies and TAR DNA-binding protein-43 aggregation in spinal anterior horn cells in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlag029}, pmid = {41926608}, issn = {1554-6578}, support = {23K06802 (F.M.), 25K10784 (T.K.), 24K10654 (Y.M.), and 23K24209 (K.W.)//JSPS KAKENHI Grant/ ; }, abstract = {Promyelocytic leukemia protein nuclear bodies (PML-NBs) and stress granules serve as deposition sites for stress-induced, aggregation-prone proteins. We previously reported that TAR DNA-binding protein 43 (TDP-43) colocalizes with stress granules during early aggregation in sporadic amyotrophic lateral sclerosis (ALS), and recent studies have noted PML-NB loss in familial ALS. To explore the role of PML-NBs in TDP-43 inclusion maturation, we analyzed spinal cord specimens from 12 patients with sporadic ALS and 5 controls using immunostaining for PML and TDP-43. PML-NB counts in anterior horn cells (AHCs) were significantly lower in patients with ALS than in controls (P < 0.05), especially in AHCs with TDP-43 inclusions (P < 0.01). Average numbers of PML-NB decreased progressively with inclusion type (3.1 in diffuse punctate cytoplasmic staining, 2.3 in round inclusions, and 0.8 in skein-like inclusions); all of these were significantly lower than those in inclusion-free AHCs (controls: 4.6; ALS: 5.5; P < 0.01). AHCs in ALS without inclusions showed higher PML-NB counts than in controls (P < 0.05), suggesting an early protective response. In contrast, reduced PML-NBs in mature inclusions may reflect diminished cellular defense. These findings implicate PML-NBs in the pathogenesis of sporadic ALS.}, }
@article {pmid41928488, year = {2026}, author = {Andersen, B and Krarup, C}, title = {Reappraisal of the Diagnostic Significance of Transcranial Magnetic Stimulation and Triple Stimulation in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {33}, number = {4}, pages = {e70560}, doi = {10.1111/ene.70560}, pmid = {41928488}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Transcranial Magnetic Stimulation/methods ; Male ; Middle Aged ; Female ; Evoked Potentials, Motor/physiology ; Aged ; Electromyography ; Adult ; Prospective Studies ; Neural Conduction/physiology ; Motor Neurons/physiology ; }, abstract = {OBJECTIVE: To reassess the importance of transcranial magnetic stimulation (TMS), including the triple stimulation technique (TST), to detect upper motor neuron (UMN) involvement in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In this single-center prospective study, 144 consecutive patients suspected of having motor neuron disease were included over 5&#x2009;years at the time of diagnosis. All patients were examined clinically and with EMG to assess UMN and lower motor neuron (LMN) involvement, and survival was ascertained 2&#x2009;years after inclusion of the last patient. Our TMS protocol consisted of TST in both arms and conventional motor evoked potentials (MEP) in arms and legs to assess central motor conduction time (CMCT).<br><br>RESULTS: The TST could be performed in 142 patients who showed central conduction failure in 63%, which was often markedly asymmetrical, and 50% had prolonged CMCT in the legs. Combining TST in the arms and conventional MEP in the legs showed central abnormalities in 77%. In 62 patients with only signs of LMN involvement at clinical and EMG assessment, the TST amplitude ratio was reduced in 45%, and combined TST to the arms and conventional MEP to the legs disclosed a central abnormality in 61%.<br><br>CONCLUSION: The main clinical significance was the subclinical corticospinal involvement at TMS with TST in a large proportion of patients without clinical UMN involvement. TMS with TST is a sensitive, non-invasive electrophysiological method to detect corticospinal dysfunction in ALS.}, }
@article {pmid41928634, year = {2026}, author = {Dahshan, A and Khalil, MIM and Deraz, HADA}, title = {From theory to practice: physicians' knowledge, attitudes, and practices regarding amyotrophic lateral sclerosis in Egypt - a cross-sectional study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2652326}, pmid = {41928634}, issn = {2167-9223}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with heterogeneous presentations that often mimic other conditions, leading to frequent misdiagnosis and delayed recognition. Physician awareness and diagnostic confidence are critical for early detection, yet little is known about these factors in the Middle East and North Africa (MENA) region, where ALS services and specialized centers remain limited.<br><br>METHODS: We conducted a nationwide cross-sectional survey of 1,320 physicians in Egypt. A validated online questionnaire assessed demographics, knowledge, attitudes, and practice patterns regarding ALS. Data were analyzed using appropriate statistics, with multivariate regression to identify predictors of knowledge, attitudes, and practices.<br><br>RESULTS: Overall, 41.0% of physicians demonstrated poor knowledge of ALS, while only 8.8% achieved good knowledge. Nearly half (46.5%) reported little or no diagnostic confidence, and 93.7% expressed a strong need for additional educational programs. Most respondents identified MRI (78.3%) as the main diagnostic test, whereas only 2.0% selected electrophysiological studies. Nevertheless, practice scores were higher: 65.7% reported good practice levels and 48.4% indicated they would directly refer suspected cases to specialists. Knowledge strongly correlated with attitudes (r&#x2009;=&#x2009;0.610, p&#x2009;<&#x2009;0.001) and both were moderately correlated with practice. Multivariate analysis identified neurology specialty, postgraduate ALS training, and urban practice as independent predictors of better knowledge and attitudes, while greater experience predicted improved practice.<br><br>CONCLUSION: Egyptian physicians show limited ALS knowledge and low diagnostic confidence despite reasonable practice behaviors. Training and structured referral pathways are urgently needed to improve ALS preparedness in Egypt and the wider MENA region.}, }
@article {pmid41928799, year = {2026}, author = {Ouyang, Z and Walmsley, K and Luo, S and Tippett, D and Wyse-Sookoo, K and Fifer, M and Vansteensel, MJ and Angrick, M and Ramsey, N and Crone, NE}, title = {Stable speech BCI performance during slow progression of ALS: A longitudinal ECoG study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-9156039/v1}, pmid = {41928799}, issn = {2693-5015}, abstract = {Background Electrocorticographic (ECoG) speech brain-computer interfaces (BCIs) show promise for restoring communication in amyotrophic lateral sclerosis (ALS), but the long-term stability of speech-related neural signals and decoding performance during disease progression remains unclear. We tracked signal characteristics and decoding over 25 months in a participant with ALS to determine how high-gamma (HG, 70-170 Hz) activity changes over time and whether these changes affect offline speech decoding. Methods We implanted two 8×8 subdural ECoG grids over left sensorimotor cortex (SMC) in a participant with slowly progressive bulbar variant ALS. Across 25 months, the participant performed an overt syllable-repetition task (12 consonant-vowel tokens) during simultaneous ECoG and audio recording. We quantified HG activation ratio (ActR), spectral signal-to-noise ratio (SNR; HG/HF, where HF = 300-499 Hz), and peak z-scored HG responses. Speech acoustics were evaluated using first/second formants (F1/F2) and the triangular vowel space area (tVSA). Offline EEGNet-based decoders were assessed in two stages: models trained on post-implant months 1-6 were tested on months 7-25, while models trained on stabilized data (months 7-11) were tested on the remaining period (months 12-25). Electrode-level saliency assessed spatial contributions to decoding. Results Acoustic analyses showed a significant reduction in tVSA over two years (-44.6 Hz[2]/day; P < 10 [-] [7]), consistent with mild intelligibility decline. Neural metrics (ActR and SNR) followed a biphasic trajectory: increasing during the first 6 months, after which ActR stabilized (0.041%/day; P = 0.13), and SNR declined gradually (-0.46%/day, P < 10 [- 4]). The model trained on months 1-6 achieved 55.7% accuracy (chance: 8.33%), but performance declined over time (-0.019%/day; P = 2.1×10 [-] [4]). Conversely, the model trained on months 7-11 achieved higher accuracy (65.9%) on subsequent data with no significant temporal decline (P = 0.23). Conclusions Speech-related HG features exhibited an initial unstable period followed by a long-term gradual SNR reduction, potentially reflecting disease progression. Models trained after signal stabilization generalized robustly to data recorded over a year later. These findings confirm that despite reduced absolute HG power and mild acoustic degradation of speech, cortical features remain stable enough to support durable ECoG speech BCIs without frequent recalibration. These findings will motivate future adaptive calibration algorithms that account for slow signal changes while leveraging stable spatial representations in ventral SMC. ClinicalTrials.gov Identifier NCT03567213.}, }
@article {pmid41928938, year = {2026}, author = {Michels, S and Chen, C and Ruf, WP and Garcia Garcia, MM and Arnold, FJ and Wu, Z and Bennett, CL and Shams, D and Thompson, LM and Walker, AC and Dickson, DW and Petrucelli, L and Dorst, J and Prudencio, M and Li, W and La Spada, AR}, title = {Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.20.711195}, pmid = {41928938}, issn = {2692-8205}, abstract = {The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid-biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 non-disease controls. Following targeted enzymatic methyl-sequencing (EM-seq) of ∼4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of ∼70% of ALS patients with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.}, }
@article {pmid41929081, year = {2026}, author = {Fodder, K and Murthy, M and de Silva, R and Raj, T and Farrell, K and Humphrey, J and Bettencourt, C}, title = {Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.25.714147}, pmid = {41929081}, issn = {2692-8205}, abstract = {Myelin oligodendrocyte basic protein (MOBP) is an abundant oligodendrocyte gene implicated in multiple neurodegenerative diseases. Genetic variation at the MOBP locus has been associated with risk for progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), corticobasal degeneration (CBD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Creutzfeldt-Jakob disease (CJD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. Here, we investigated whether shared or disease-specific genetic mechanisms at MOBP converge on altered DNA methylation and expression across neurodegenerative disorders. We analysed MOBP variants using summary statistics from recent GWAS for ALS, PSP, FTD, LBD, PD, MSA, AD, and CJD. Colocalisation (COLOC and SuSiE-coloc) was used to test whether disease-associated variants overlapped between diseases, and with oligodendrocyte expression quantitative trait loci (eQTLs) and bulk brain methylation quantitative trait loci (mQTLs). To further investigate mQTL effects at this locus, rs1768208, a variant previously associated with PSP, was genotyped in an overlapping brain methylation cohort, allowing direct testing of genotype-methylation associations in frontal white matter tissue. ALS and PSP GWAS demonstrated strong association at MOBP , with most strongly associated SNPs (e.g. rs631312, rs616147, rs1768208) shared between both disorders. Colocalisation analyses indicated high posterior probability that ALS and PSP share the same causal variant, with weaker overlap with FTD. mQTL colocalisation highlighted cg15069948, located near an exon junction within MOBP , as strongly colocalising with the ALS/PSP risk variants. In complementary tissue analyses, rs1768208-T carriers showed hypomethylation at cg15069948 in PSP brains. No genotype-methylation effects were detected in MSA or Parkinson's disease. Together with prior evidence of promoter hypermethylation and reduced expression in MSA, our findings identify cg15069948 as a regulatory methylation site linking ALS/PSP risk variants to altered MOBP methylation, and support MOBP dysregulation as a shared feature of neurodegeneration. However, the underlying mechanisms appear disease-specific, highlighting the complexity of involvement of this gene across neurodegenerative disorders.}, }
@article {pmid41929167, year = {2026}, author = {Mahrous, AA and Heit, BS and Heckman, CJ}, title = {Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.23.713695}, pmid = {41929167}, issn = {2692-8205}, abstract = {Riluzole is the most commonly prescribed among the limited approved therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motoneuron loss and paralysis. It is thought to act by suppressing motoneuron excitability and glutamate release, but its clinical benefits are modest and often diminish over time. We previously showed that homeostatic mechanisms in the SOD1 [G93A] (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that chronic riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results suggest that hyperactive homeostatic mechanisms in ALS counteract the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, consistent with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, indicating normalization of cell size and potentially reduction in metabolic demand. Together, these findings help explain the limited clinical efficacy of riluzole while revealing a previously unrecognized neuroprotective mechanism of the drug in ALS.}, }
@article {pmid41929296, year = {2026}, author = {Sebogo, MA and Frans, MC and Paulose, H and Rodriguez, CL and Hsiung, GY and Cashman, NR and Ly, CV and Leavens, MJ}, title = {Longitudinal Analysis of Superoxide Dismutase 1 Seeding Activity in Amyotrophic Lateral Sclerosis Cerebrospinal Fluid.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.20.26348753}, pmid = {41929296}, abstract = {Twenty percent of familial amyotrophic lateral sclerosis (fALS) cases are linked to mutations in the Superoxide Dismutase 1 (SOD1) gene and accumulation of misfolded SOD1 aggregates. SOD1 misfolding from the broader ALS population without SOD1 mutations is less clear. Here, we report SOD1 seeding activity in antemortem cerebrospinal fluid (CSF) from ALS participants with and without SOD1 mutations during ALS progression. Antemortem CSF from controls, SOD1- ALS, and sporadic ALS (sALS) patients was subjected to SOD1 seed amplification real-time quaking induced conversion (RT-QuIC) assays. SOD1 -ALS CSF exhibited shorter lag phase and increased ThioflavinT (ThT) fluorescence amplitude compared to healthy controls and those with spinal muscular atrophy. CSF from sALS participants, who had no mutations in SOD1 or nine other ALS risk genes, also displayed SOD1 seeding activity, indicating wild-type SOD1 is aggregate-prone in the broader ALS population. Longitudinal CSF data indicated that SOD1 seeding activity correlates with ALS progression via the ALS Functional Rating Scale Revised (ALSFRS-R) slope decline and CSF neurofilament light. Our sALS CSF cohort primarily comprised of participants less than 2 years from symptom onset, suggesting that SOD1 seeding activity is an early biomarker that may enable inclusion in clinical trials. With the FDA-approval of tofersen (Qalsody), a SOD1-lowering antisense oligonucleotide, new SOD1 diagnostic, prognostic and pharmacodynamic biomarkers may enable SOD1-targeting strategies that could benefit the broader ALS population.}, }
@article {pmid41929582, year = {2026}, author = {Poyan Mehr, A and Sundang, A and Drasin, T and Bhalla, N and Zheng, S and Pravoverov, L}, title = {Comparison of peritoneal dialysis catheter placement outcomes: image-guided percutaneous technique versus advanced laparoscopic surgical technique.}, journal = {Clinical kidney journal}, volume = {19}, number = {4}, pages = {sfag048}, pmid = {41929582}, issn = {2048-8505}, abstract = {BACKGROUND: Peritoneal dialysis (PD) is an increasingly emphasized modality in nephrology care, due to patient autonomy, reduced healthcare cost and alignment with value-based care initiatives. A critical factor influencing successful PD uptake is the timely placement of peritoneal dialysis catheters (PDCs). Traditional advanced laparoscopic surgical (ALS) methods are effective but constrained by the need for general anesthesia and operating room access. The image-guided percutaneous (IGP) approach has emerged as a potentially safer and more accessible alternative.<br><br>METHODS: We conducted a retrospective study of adult patients who underwent PDC placement within Kaiser Permanente Northern California (KPNC) from 1 January 2018 to 31 December 2022. Patient characteristics, procedural variables, post-procedure length of stay, 90- and 180-day catheter intervention rates, 30-day readmission and mortality rates were compared between IGP and ALS techniques.<br><br>RESULTS: Among 3062 patients, 835 (27%) received PDCs via IGP and 2227 (73%) via ALS. While there were differences in patient characteristics due to selection biases, with the IGP group having higher prevalence of heart failure, and lower body mass index (BMI), estimated glomerular filtration rate, hemoglobin and albumin levels, IGP was associated with significantly shorter post-procedure length of stay among admitted outpatients (1.8 vs 3.1 days, P&#xa0;=&#xa0;.01) and lower catheter intervention rates at 90 days (1% vs 2.5%, P&#xa0;=&#xa0;.006) and 180 days (1.3% vs 4%, P&#xa0;<&#xa0;.0001). After adjustment for patient gender, race, BMI and polycystic kidney disease status, the ALS technique remained significantly associated with higher odds of catheter re-intervention compared with IGP at both 90 days [adjusted odds ratio (OR) 2.76, 95% confidence interval (CI) 1.30-5.85, P&#xa0;=&#xa0;.008] and 180 days (adjusted OR 3.16, 95% CI 1.67-5.96, P < .0004). Overweight BMI was independently associated with increased intervention risk.<br><br>CONCLUSIONS: Despite being applied to a potentially sicker patient cohort, IGP was associated with favorable short- and intermediate-term outcomes compared with ALS, including reduced catheter interventions, without compromising safety outcomes.}, }
@article {pmid41929709, year = {2026}, author = {Gazwi, K and Zaza, T and Mitwally, H and Davda, N and Ganaw, A}, title = {Botulinum toxin injection induced autoimmune thyroiditis and myxedema coma: A case report.}, journal = {SAGE open medical case reports}, volume = {14}, number = {}, pages = {2050313X261430649}, pmid = {41929709}, issn = {2050-313X}, abstract = {This case describes a 28-year-old female with amyotrophic lateral sclerosis and recurrent urinary tract infections who developed myxedema coma following a botulinum toxin type-A (Btx) injection for muscle spasticity. On intensive care unit admission, she presented with hypothermia, bradycardia, and reduced consciousness. Laboratory evaluation revealed markedly elevated thyroid-stimulating hormone levels, confirming myxedema coma. Prompt treatment with intravenous levothyroxine and hydrocortisone resulted in rapid improvement in temperature and mental status. Further investigation showed elevated antithyroid peroxidase antibodies, suggesting drug-induced autoimmune thyroiditis triggered by Btx. This case highlights the potential link between Btx injection and thyroid autoimmunity, emphasizing the importance of early recognition and monitoring of thyroid function to prevent life-threatening complications in at-risk patients.}, }
@article {pmid41930586, year = {2026}, author = {Pavithra, N and Begum, RF and Ashwini, ST and Nirenjen, S and Singh, A and Manisha, M and Sridevi, S and Singh, SA}, title = {AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273436955260126215111}, pmid = {41930586}, issn = {1996-3181}, abstract = {Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are examples of neurodegenerative disorders (NDDs) that share overlapping neuropathological processes and largely affect motor coordination. For early diagnosis, illness monitoring, and treatment targeting, it is essential to find trustworthy biomarkers that represent motor circuit dysfunction. The purpose of this study is to summarize the state of the art regarding molecular, neurochemical, and imaging biomarkers that are pertinent to motor impairment and to investigate the function of artificial intelligence (AI) in their identification and verification Methods: With an emphasis on biomarker discovery, validation, and AI/ML applications in PD, HD, ALS, and SCAs, a thorough literature search was carried out in the PubMed, Scopus, and Google Scholar databases for research published between 2015 and 2025. The motor-specific correlations of key molecular (α-synuclein, tau, neurofilament light chain, TDP-43, mutant huntingtin), neuroimaging, and digital biomarkers were carefully examined Results: AI-driven methods, such as deep learning and machine learning, have shown great promise in combining multimodal data from digital, fluid, and imaging sources. These techniques enhanced the detection of disease-specific biomarker signatures, especially those associated with deficiencies in motor coordination Discussion: Data heterogeneity, biomarker standardization, model interpretability, and limited cross-disease validation are still issues despite encouraging developments. Improving the clinical reliability of AI-based biomarker models requires filling in these gaps Conclusion: An effective foundation for deciphering intricate motor neurological pathways is provided by AI-assisted biomarker discovery. Transparent algorithms, multicenter data integration, and ethical frameworks should be given top priority in future research to guarantee clinical translation and better patient stratification.}, }
@article {pmid41930760, year = {2026}, author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK}, title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X385491251208144807}, pmid = {41930760}, issn = {1875-6190}, abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.}, }
@article {pmid41920737, year = {2026}, author = {Jude, JJ and Haro, S and Levi-Aharoni, H and Hashimoto, H and Acosta, AJ and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Williams, ZM and Cash, SS and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {Decoding intended speech with an intracortical brain-computer interface in a person with long-standing anarthria and locked-in syndrome.}, journal = {Cell reports}, volume = {45}, number = {4}, pages = {117162}, doi = {10.1016/j.celrep.2026.117162}, pmid = {41920737}, issn = {2211-1247}, abstract = {Intracortical brain-computer interfaces (iBCIs) for decoding intended speech have provided individuals with ALS and severe dysarthria an intuitive method for high-throughput communication. These advances have been demonstrated in individuals who are still able to vocalize and move speech articulators. Here, we decoded intended speech from an individual with long-standing anarthria, locked-in syndrome, and ventilator dependence due to advanced symptoms of ALS. We found that phonemes, words, and higher order language units could be decoded well above chance. While sentence decoding accuracy was below that of demonstrations in participants with dysarthria, we attained an extensive characterization of neural signals underlying speech in a person with locked-in syndrome and identify directions for future improvement. These include closed-loop speech imagery training and decoding linguistic (rather than phonemic) units from neural signals in middle precentral gyrus to augment decoding at the sentence level. These results demonstrate that usable speech decoding from motor cortex may be feasible in people with anarthria and ventilator dependence.}, }
@article {pmid41921453, year = {2026}, author = {Preuilh, A and Lackmy-Vallée, A and Béranger, B and Galléa, C and Bede, P and Querin, G and Pradat, PF and Pélégrini-Issac, M and Marchand-Pauvert, V}, title = {Impaired kinesthesia and cerebral integration during tendon vibration in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {187}, number = {}, pages = {2111864}, doi = {10.1016/j.clinph.2026.2111864}, pmid = {41921453}, issn = {1872-8952}, abstract = {OBJECTIVE: This study investigates the cortical processing of spindle input in patients with amyotrophic lateral sclerosis (ALS), hypothesizing that functional MRI (fMRI) activation elicited by muscle-tendon vibration would reveal specific disruptions in the integration of this sensory pathway.<br><br>METHODS: A block-designed fMRI protocol was used, consisting of 20-second periods of focal muscle-tendon vibrations (&#x223c;70-Hz frequency) applied to the first dorsal interosseous tendon, alternating with rest periods. Parametric brain activation maps were examined in 22 patients with ALS without clinically overt sensory deficits and in an age- and sex-matched group of 23 healthy controls. The relationship between task-related brain activations and clinical scores was assessed in patients reporting vibration-induced kinesthetic sensations.<br><br>RESULTS: Muscle-tendon vibration elicited activation of the precentral gyrus contralateral to the vibration site, in both ALS patients and healthy controls. Compared to controls, ALS patients exhibited reduced activation in prefrontal and cerebellar lobule VI regions. Notably, a greater proportion of ALS patients (41%) failed to perceive kinesthetic stimuli compared to controls (13%). Furthermore, activations in contralateral prefrontal and cerebellar areas were associated with hand motor disability and cognitive impairment.<br><br>CONCLUSION: It suggests that motor impairment in ALS is accompanied by disrupted perception of movement, and concomitant altered brain integration of proprioceptive inputs.<br><br>SIGNIFICANCE: ALS-related motor impairment extends beyond motor output, underscoring the need for assessing movement (body) awareness in clinical practice.}, }
@article {pmid41921847, year = {2026}, author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D}, title = {Unveiling the UFMylation Pathway: Implications in neurodegenerative diseases.}, journal = {Journal of molecular biology}, volume = {}, number = {}, pages = {169772}, doi = {10.1016/j.jmb.2026.169772}, pmid = {41921847}, issn = {1089-8638}, abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.}, }
@article {pmid41924615, year = {2026}, author = {Almalki, S and Salama, M and Taylor, MJ and Ahmed, Z and Tuxworth, RI}, title = {TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1671909}, pmid = {41924615}, issn = {1662-5099}, abstract = {Mislocalization and aggregation of the DNA/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while TDP-43-depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities.}, }
@article {pmid41924700, year = {2026}, author = {McMackin, R and Tadjine, Y and Suleyman, N and Woods, E and Plaitano, S and Fasano, A and Awiszus, F and Hardiman, O and Carson, RG}, title = {Long-interval intracortical inhibition is similar in people with and without amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag091}, pmid = {41924700}, issn = {2632-1297}, abstract = {Long-interval intracortical inhibition, measured using transcranial magnetic stimulation, provides a non-invasive measure of spinal inhibition at interstimulus intervals below 100 ms and of GABA-B-mediated motor cortical inhibition at interstimulus intervals of 100-200 ms. To date, only a few small studies have investigated if long-interval intracortical inhibition is affected in amyotrophic lateral sclerosis. None have employed threshold tracking protocols or investigated multiple induced current directions. In this study, we aimed to determine if long-interval intracortical inhibition (i) differs between people with amyotrophic lateral sclerosis and healthy controls; (ii) relates to motor symptom severity, disease duration or survival time in those with amyotrophic lateral sclerosis; or (iii) relates to intracortical facilitation or short-interval intracortical inhibition. Employing automated threshold tracking during paired-pulse transcranial magnetic stimulation of the precentral gyrus, long-interval intracortical inhibition was recorded in 30 people with amyotrophic lateral sclerosis [9 female, 21 male, median (range) age: 63.5 (41-79) years] and 45 healthy controls [16 female, 29 male, median (range) age: 57 (34-76) years]. Long-interval intracortical inhibition was recorded with interstimulus intervals of 50, 100, 150 and 200 ms using posterior-to-anterior induced current (LICIPA), and with interstimulus intervals of 150 and 200 ms using anterior-to-posterior induced current (LICIAP). In subcohorts of both healthy controls and people with amyotrophic lateral sclerosis, short-interval intracortical inhibition was recorded with interstimulus intervals of 1 and 3 ms using posterior-to-anterior induced current and 3 ms using anterior-to-posterior current. Intracortical facilitation was recorded with an interstimulus interval of 10 ms using posterior-to-anterior induced current. No differences were found between those with and without amyotrophic lateral sclerosis in long-interval intracortical inhibition magnitude (P ≥ 0.44, Hedge's g ≤ 0.14) or in the interstimulus interval at which maximal long-interval intracortical inhibition occurs (P = 0.68, χ2 = 1.5). In those with amyotrophic lateral sclerosis, no statistically significant correlations were identified between long-interval intracortical inhibition measures and disease duration or functional rating scale scores. Statistically significant positive correlations were observed between LICIPA recorded with 100 and 150 ms interstimulus intervals, and between LICIPA recorded with 150 and 200 ms interstimulus intervals, but not between LICIPA and LICIAP measures or between long-interval intracortical inhibition and short-interval intracortical inhibition or intracortical facilitation. Our findings indicate that disinhibition manifested in this disease is primarily not mediated via changes in the cortical GABA-Bergic or spinal circuitry which underpins long-interval intracortical inhibition measures. As LICIPA and LICIAP measures show minimal covariation, it is possible that these measures are underpinned by distinct aspects of motor cortical inhibition.}, }
@article {pmid41925063, year = {2026}, author = {Shtilbans, A and Lang, AE}, title = {Combination Disease-Modifying Therapy for Neurodegenerative Diseases Using Repurposed Drugs.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78190}, pmid = {41925063}, issn = {1531-8249}, abstract = {We review the positive effects of several existing drugs from different classes, such as chemical chaperones, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), iron chelators, and cluster-Abelson tyrosine kinase inhibitors (c-Abl TKIs), in preclinical disease models and in available published human data following use of these drugs in individuals with common neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). A concept of combinatory neuroprotective therapy using a drug-repurposing approach is then discussed. Finally, we propose a strategy to design an ideal combination of drugs able to address multiple pathogenic processes involved in neurodegeneration to achieve clinically meaningful results. ANN NEUROL 2026 ANN NEUROL 2026.}, }
@article {pmid41925076, year = {2026}, author = {Krajewski, T and Koch, G}, title = {Randomization-Based Covariance Analysis for Confidence Intervals of Treatment Comparisons Based on Restricted Mean Survival Time With Categorized Time-to-Event Data.}, journal = {Statistics in medicine}, volume = {45}, number = {8-9}, pages = {e70422}, doi = {10.1002/sim.70422}, pmid = {41925076}, issn = {1097-0258}, support = {T32 ES007018/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics &amp; numerical data ; Confidence Intervals ; Survival Analysis ; Analysis of Variance ; Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Models, Statistical ; Double-Blind Method ; Computer Simulation ; Data Interpretation, Statistical ; Random Allocation ; }, abstract = {This paper introduces a randomization-based method for covariate-adjusted comparisons of restricted mean survival time (RMST) between treatment arms in randomized controlled trials. Existing approaches for covariate-adjusted RMST analysis have model-based assumptions that may not be compatible with the complexity of survival data. We estimate the treatment difference in RMST using randomization-based analysis of covariance (RB-ANCOVA) for categorized time-to-event data by constraining the covariate mean differences between treatment groups to zero. Accordingly, we provide corresponding confidence intervals that offer greater precision than those based on unadjusted RMST differences. The methodology is detailed for comparing two treatment groups for a single or multiple time intervals, as well as for multiple treatment groups over a single interval. We demonstrate the application of these methods using data from a randomized, double-blind, placebo-controlled clinical trial evaluating three doses of a test treatment for ALS.}, }
@article {pmid41925483, year = {2026}, author = {Kleinerova, J and Tahedl, M and Finegan, E and Siah, WF and Hengeveld, JC and Doherty, MA and Hardiman, O and McLaughlin, RL and Hutchinson, S and Tan, EL and Bede, P}, title = {Neuroimaging confirms selective cerebral involvement in primary lateral sclerosis and predilection to brain regions with high metabolic activity.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2026.03.003}, pmid = {41925483}, issn = {0035-3787}, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a low incidence motor neuron disease manifesting in progressive limb spasticity, gait impairment, bulbar dysfunction and often in pseudobulbar affect. Varying degree of frontotemporal involvement has also been recently confirmed. Postmortem data is scarce in PLS and disease burden patterns are best characterised in vivo by purpose-designed neuroimaging protocols.<br><br>METHODS: A large prospective neuroimaging study has been undertaken to explore cerebral involvement patterns in PLS using a both structural T1-weighted data and diffusion MRI data. Neuroimaging data were complemented by genetic screening and comprehensive clinical profiling. Brain involvement patterns have been first characterised by standard morphometric and diffusivity analyses. Resulting disease burden maps were then correlated to physiological mitochondrial density (MitoD) maps. In an additional, region-of-interest analysis, brain regions with significant topological associations between neurodegeneration and MitoD were ranked based on their r-values.<br><br>RESULTS: Grey matter degeneration in PLS is not limited to the motor cortex, but also encompasses frontotemporal, caudate, thalamic, cerebellar and cingulate regions. Voxelwise statistics confirm topological associations between atrophy and physiological mitochondrial density. The most significant associations between neurodegeneration and MitoD were detected in the cerebellum, superior temporal lobe, precentral gyrus, inferior operculum, and orbitofrontal gyrus. Similarly, white matter degeneration is not limited to the corticospinal tracts, but includes the corpus callosum, frontotemporal association fibres, the cingulum, cerebellar peduncles, and the fornix. Anatomical associations were also detected between diffusivity alterations and focal MitoD.<br><br>DISCUSSION: PLS is associated with a selective disease burden pattern, and our data suggest that brain regions with high baseline metabolic activity are more likely to succumb to neurodegeneration. Cerebral areas showing the most significant anatomical associations between atrophy and mitochondrial density (precentral gyrus, cerebellum, frontotemporal regions) are pathognomonic brain regions of PLS driving its core clinical manifestations.}, }
@article {pmid41731540, year = {2026}, author = {Sarigiovannis, P and Foster, NE and Jowett, S and Saunders, B}, title = {Development of an evidence-based framework to guide delegation of clinical tasks to physiotherapy support workers in musculoskeletal outpatient physiotherapy services.}, journal = {BMC health services research}, volume = {26}, number = {1}, pages = {}, pmid = {41731540}, issn = {1472-6963}, support = {Clinical Doctoral Research Fellowship NIHR301550//National Institute for Health and Care Research/ ; Investigator grant (ID: 2018182)//Australian National Health and Medical Research Council/ ; }, abstract = {BACKGROUND: Delegation of clinical tasks to physiotherapy support workers (PSWs) is a key strategy in musculoskeletal (MSK) outpatient physiotherapy services to meet rising demand and optimise workforce use. However, delegation practices remain inconsistent, due to variability in training, role definition, supervision and patient communication. This paper presents the final phase of a mixed-methods research program. In this phase, findings from earlier phases were triangulated to inform the development of a practical, evidence-based framework to support safe and consistent delegation in MSK outpatient physiotherapy services.<br><br>METHODS: This final phase of the research program used a triangulation approach to integrate findings from three earlier phases: (1) a focused ethnography of real-world delegation practices; (2) a consensus study using nominal group technique to identify best practice components of a delegation framework; and (3) a discrete choice experiment capturing patient preferences. Triangulation followed Farmer et al.&#x2019;s convergence coding matrix to assess agreement, partial agreement, silence, or dissonance across data sources. A component was included if supported by at least two phases.<br><br>RESULTS: Triangulation revealed strong convergence across professional and patient perspectives. Seven core components were identified for inclusion in the final framework: (1) training and development, (2) a clear delegation process, (3) defined roles, (4) a supportive team culture, (5) embedded safety mechanisms, (6) patient awareness and communication, and (7) implementation and evaluation strategies. The framework was developed with input from a clinical advisory group and public contributors to ensure relevance and applicability to real-world practice.<br><br>CONCLUSIONS: This final phase of the research program synthesised diverse findings to produce a framework for improving delegation to PSWs in MSK physiotherapy services. The framework offers structured, practical guidance to support consistent delegation in clinical teams. The principles may be transferable to other healthcare settings. Further research should explore implementation and evaluate impact in routine practice.}, }
@article {pmid41917198, year = {2026}, author = {Yin, H and Ren, Z and Zhang, Y and Wang, Y and Sun, Y and Fu, X and Yan, W and Zhang, F and Zeng, L}, title = {Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-09930-2}, pmid = {41917198}, issn = {2399-3642}, support = {20250206017ZP//Department of Science and Technology of Jilin Province (Jilin Province Science and Technology Department)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves disrupted lipid metabolism. Bax inhibitor 1 (BI1), an endoplasmic reticulum protein downregulated in ALS neuroprotective, represents a therapeutic target, but its metabolic regulatory mechanisms are incompletely understood. Using transcriptomics in skeletal muscle of ALS mice pre- and post-BI1 treatment, we identified BI1-regulated pathways. Structure-based virtual screening of FDA-approved compounds nominated lisinopril as a BI1 activator. Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and protecting against SOD1[G93A]-induced apoptosis in NSC34 cells. Concurrently, it regulated TGF-β1/mTOR-dependent autophagy, maintained NMJ integrity, and reshaped triglyceride/sphingolipid/glycerophospholipid metabolism to attenuate spinal cord pathology in ALS mice, promoting energy metabolism shift toward glucose oxidation. Additionally, lisinopril inhibited the TGF-β1/Smad2/3 pathway to alleviate muscle fibrosis, downregulate Acp5/FN expression, and reduce type I collagen deposition. In conclusion, this study provides evidence that pharmacological activation of BI1 by lisinopril suppresses TGF-β1, modulates lipid metabolism, and ameliorates ALS pathology, demonstrating promising therapeutic repurposing potential.}, }
@article {pmid41917433, year = {2026}, author = {Hop, PJ and Kooyman, M and Kenna, BJ and Zwamborn, RAJ and van Eijk, KR and Wang, Y and van Dijk, CH and Bekema, E and van Rheenen, W and Beele, P and van Vugt, JJFA and ,  and ,  and ,  and ,  and Khleifat, AA and Iacoangeli, A and Cooper-Knock, J and Smith, BN and Topp, S and van der Kooi, AJ and Fominykh, V and Drory, V and Lerner, Y and Shovman, Y and Rowe, DB and Williams, KL and McLaughlin, RL and Hurt, J and Huang, Y and Chen, CY and Tsai, E and Runz, H and Aronica, E and Groen, EJN and van Es, MA and Pasterkamp, RJ and Farhan, SMK and Garton, FC and McRae, AF and McCombe, PA and Henderson, RD and Fan, D and Šlachtová, L and Høyer, H and Nishimura, AL and Cauchi, RJ and Brylev, L and Rogelj, B and Koritnik, B and Zidar, J and Salas, T and Mora Pardina, JS and Gotkine, M and Povedano, M and Corcia, P and Vourc'h, P and Couratier, P and Weber, M and Kiernan, MC and Pamphlett, R and Blair, IP and de Carvalho, M and Başak, NA and Ingre, C and Andersen, PM and Zinman, L and Rogaeva, E and MacKenzie, IR and Dupre, N and Rouleau, GA and Traynor, BJ and Ticozzi, N and Chiò, A and Silani, V and Hardiman, O and Phatnani, H and Harms, MB and Dalgard, CL and Glass, JD and Landers, JE and Van Damme, P and Morrison, KE and Shaw, PJ and Shaw, CE and Al-Chalabi, A and van den Berg, LH and Kenna, KP and Veldink, JH}, title = {Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {41917433}, issn = {1546-1718}, support = {19-SI-459//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; ZonMW-VIDI 91719350//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; ZonMW-VIDI 91719350//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.}, }
@article {pmid41917466, year = {2026}, author = {Liu, Y and Song, M and Wan, L and Guo, P and Han, D}, title = {Condensate protein aggregation in ALS/FTD is regulated by GGGGCC-repeat RNA scaffolds.}, journal = {Nature structural &amp; molecular biology}, volume = {}, number = {}, pages = {}, pmid = {41917466}, issn = {1545-9985}, abstract = {Biomolecular condensates regulate essential biological processes relevant to health and disease. However, the mechanisms driving pathogenic condensate formation and their therapeutic targeting have not been fully elucidated. In amyotrophic lateral sclerosis and frontotemporal dementia caused by C9orf72 GGGGCC repeat expansions (c9ALS/FTD), the expanded repeat RNA and repeat-associated non-AUG translation products are key pathogenic factors. Here, we show that the GGGGCC-repeat RNA and poly(GR) form cocondensates in vitro and in cellulo. The G-quadruplex and hairpin structures of GGGGCC-repeat RNA act as scaffolds to accelerate liquid-to-solid phase transition and aggregation of poly(GR), with the hairpin structure promoting amorphous solid-like condensates in vitro and reducing poly(GR) mobility. The cocondensation of GGGGCC-repeat RNA and poly(GR) exacerbates nucleolar stress and cellular toxicity. Targeting both G-quadruplex and hairpin structures of GGGGCC-repeat RNA with small molecules diminishes poly(GR) aggregation and ameliorates cellular dysfunction. These findings expand our understanding of poly(GR) aggregation in c9ALS/FTD, highlight the importance of RNA structure in regulating protein aggregation and suggest that targeting the RNA scaffold may expand the druggable space of pathogenic condensates.}, }
@article {pmid41917768, year = {2026}, author = {Jiang, Z and Ren, YL and Gu, XJ and Su, WM and Duan, QQ and Yin, KF and Cao, B and Li, JY and Yan, B and Chen, YP}, title = {Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {16}, number = {4}, pages = {e71366}, doi = {10.1002/brb3.71366}, pmid = {41917768}, issn = {2162-3279}, support = {2022YFC2703101//National Key Research and Development Program of China/ ; 82371422//National Natural Science Fund of China/ ; 81971188//National Natural Science Fund of China/ ; 2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; //the National Natural Science Fund of China/ ; //the Science and Technology Bureau Fund of Sichuan Province/ ; //the National Natural Science Fund of Sichuan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Mendelian Randomization Analysis/methods ; *Autophagy/genetics ; DNA Methylation/genetics ; Quantitative Trait Loci/genetics ; Genetic Predisposition to Disease/genetics ; Multiomics ; }, abstract = {BACKGROUND: Autophagy dysregulation has been implicated in the toxic protein aggregates of amyotrophic lateral sclerosis (ALS). However, the causal relationship between impaired autophagy and ALS remains ambiguous, necessitating further elucidation.<br><br>METHODS: This Mendelian randomization (MR) study employs a two-sample design, utilizing genetic instruments to proxy autophagy dysregulation as the exposure and ALS as the outcome. It incorporates summary statistics of ALS (27,205 cases, 110,881 controls), along with data on DNA methylation, RNA splicing, gene expression, and protein abundance quantitative trait loci (QTLs) in both blood and brain tissues (mQTL, sQTL, eQTL, and pQTL, respectively) sourced from European cohorts. Cis-variants situated proximal to or within the 604 autophagy-related genes, exhibiting robust associations with molecular alterations in autophagy, are employed as instrumental variables. Their causal links with ALS are assessed via summary-data-based MR (SMR) analyses, followed by Bayesian colocalization, sensitivity analyses, brain cell-specific MR analyses, protein-protein interaction (PPI), and druggable analyses.<br><br>RESULTS: Consistent evidence supported the causal effects of two lysosome genes (FNBP1 and IDUA), one autophagy core gene (C9orf72), and one mitophagy gene (USP35) on ALS risk. Specifically, brain FNBP1 splicing level (OR = 1.18, p = 3.38E-5) and blood USP35 expression level (OR = 1.17, p = 5.94E-5) were positively associated with higher ALS risk. In contrast, we found strong causal evidence of brain IDUA methylation level (OR = 0.96, p = 8.36E-6) and blood C9orf72 methylation level (OR = 0.55, p = 7.59E-12) with lower ALS risk. Cell-type-specific MR analyses, PPI, and druggable analyses further nominated the key brain cell type (astrocytes), potential interaction with known causative genes (SQSTM1 and PFN1), and promising druggability for FNBP1 in ALS.<br><br>CONCLUSIONS: This multi-omics MR study identified causal associations between the regulation of four autophagy-related genes and ALS risk, shedding light on autophagy-mediated mechanisms and offering early evidence of novel therapeutic targets for ALS.}, }
@article {pmid41917957, year = {2026}, author = {Desnuelle, C and Couratier, P and Corcia, P and Arcelin, T and Nevoret, C and Duburcq, A and Baffert, S and Turgeman, S}, title = {The economic burden of amyotrophic lateral sclerosis for patients and families: a survey on out-of-pocket expenses and income loss in France.}, journal = {Orphanet journal of rare diseases}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13023-026-04326-1}, pmid = {41917957}, issn = {1750-1172}, support = {Association for Research on Amyotrophic Lateral Sclerosis and other Motor Neurone Diseases//Association for Research on Amyotrophic Lateral Sclerosis and other Motor Neurone Diseases/ ; }, }
@article {pmid41919222, year = {2026}, author = {Spatafora, MG and Dubin, J and Domi, T and Lombardi, R and Cabras, P and Dalla Bella, E and Consonni, M and Quattrini, A and Verri, M and Lauria, G and Van Damme, P and Poesen, K and Riva, N and Peviani, M}, title = {Increased CSF levels of soluble AXL at diagnosis correlate with poor prognosis in patients affected by amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag086}, pmid = {41919222}, issn = {2632-1297}, abstract = {AXL, a receptor tyrosine kinase expressed in neurons and glial cells, involved in neuronal survival, myelination, and regulation of immune responses, can undergo shedding due to the activation of metalloproteases in neuroinflammatory conditions. Indeed, CSF and serum levels of soluble AXL (sAXL) have been correlated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). Based on these observations, we explored whether sAXL is implicated in amyotrophic lateral sclerosis (ALS). sAXL levels were measured in biofluids (CSF and serum) from two biorepositories, totalling 107 ALS patients, 76 healthy controls, 25 AD patients, 22 patients with multiple sclerosis and 51 patients with ALS disease mimicking disorders (i.e. patients that displayed symptoms resembling ALS, in whom eventually ALS was excluded after a thorough clinical examination). Gender and age were considered as covariate in the statistical analyses. Our results provide the first evidence of sAXL alterations in the CSF and serum of ALS patients at diagnosis and demonstrate a significant association between CSF sAXL levels and disease progression, as well as its prognostic value in ALS. While these observations require validation through multicentre studies, they suggest the involvement of the AXL pathway in ALS pathology and pave the way for leveraging CSF sAXL levels as a biomarker to aid ALS disease stratification.}, }
@article {pmid41919473, year = {2026}, author = {Cheng, Y and Qiu, M and Yu, Z and Tang, X and Zhang, J}, title = {Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.}, journal = {Biomolecules &amp; biomedicine}, volume = {}, number = {}, pages = {}, doi = {10.17305/bb.2026.13978}, pmid = {41919473}, issn = {2831-090X}, abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are age-related disorders characterized by progressive neuronal loss, cognitive decline, and limited options for disease-modifying treatments. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in neurodevelopment, neuronal homeostasis, and disease progression; however, their involvement in shared pathogenic pathways and clinical applications remains inadequately defined. This review consolidates recent experimental, transcriptomic, bioinformatic, and emerging clinical findings regarding the role of lncRNAs in NDDs. We examine how lncRNAs modulate common disease mechanisms, including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, ferroptosis, synaptic failure, and aging-related neurodegenerative processes. These regulatory functions occur through various mechanisms, including epigenetic modifications, transcriptional regulation, post-transcriptional processes, and RNA-protein interactions, as well as novel mechanisms such as liquid-liquid phase separation (LLPS), peptide coding, and exosome-mediated intercellular communication. Current evidence supports the potential of lncRNAs as minimally invasive liquid biopsy biomarkers, detectable in blood, cerebrospinal fluid (CSF), and extracellular vesicles. Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms. Overall, lncRNAs have emerged as central molecular regulators and promising candidates for translation in NDDs. Nonetheless, challenges related to specificity, validation, delivery across the blood-brain barrier, and clinical standardization must be addressed before their routine application in precision neurology.}, }
@article {pmid41919495, year = {2026}, author = {De Tito, S and Tooze, SA}, title = {Lysosomal homeostasis at the crossroads of neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {7}, pages = {}, doi = {10.1172/JCI199845}, pmid = {41919495}, issn = {1558-8238}, mesh = {Humans ; *Lysosomes/metabolism/pathology/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; *Homeostasis ; Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; *Neurons/metabolism/pathology ; }, abstract = {Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.}, }
@article {pmid41919981, year = {2026}, author = {Liampas, I and Kimiskidis, VK and Zouvelou, V and Veltsista, D and Moscholouri, A and Triantafyllou, E and Daponte, A and Xirou, S and Sterpi, AE and Salakou, S and Poulidou, V and Arnaoutoglou, M and Tsouris, Z and Ralli, S and Dardiotis, E and Papagiannopoulos, S and Zampetakis, A and Zaganas, &#x399; and Mitsias, P and Giannakis, A and Konitsiotis, S and Kefalas, F and Alexiou, E and Stoiloudis, P and Parissis, D and Kiamelidis, S and Terzoudi, A and Tsivgoulis, G and Rentzos, M and Chroni, E}, title = {Clinical parameters affecting the course of amyotrophic lateral sclerosis: a longitudinal analysis of the Greek registry for amyotrophic lateral sclerosis (ALS-GR).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2648293}, pmid = {41919981}, issn = {2167-9223}, abstract = {BACKGROUND: Reliable prognostic factors are essential for both clinical and research purposes in amyotrophic lateral sclerosis (ALS). The current study aimed to investigate the prognostic properties of clinical parameters regarding the course of ALS.<br><br>METHODS: A mixed retrospective-prospective cohort study was conducted in 11 specialized centers in Greece. Participants with ALS were assessed on the ALS functional rating scale-revised (ALSFRS-R) at baseline and follow-up (on 6-9-12-18-24&#x2009;months). In case of dropouts, we elucidated whether death had occurred. Adjusted survival analyses were used to explore associations with mortality; adjusted generalized estimating equations were used to examine associations with the rate of functional decline.<br><br>RESULTS: A total of 165 individuals with an average follow-up of 12.6&#x2009;&#xb1;&#x2009;6.3&#x2009;months were included in the current longitudinal analysis. Baseline ALSFRS-R was the strongest determinant of survival [Hazard-ratio; HR = 0.949 (0.921-0.977)], followed by age at diagnosis [HR = 1.043 (1.011-1.075)] and restrictive respiratory pattern [HR = 2.321(1.193-4.515)], while cramps [HR = 0.485 (0.249-0.946)] and pain [HR = 2.007 (1.041-3.868)] were the least influential. Regarding functional decline rates, the strongest predictor was dysphagia [&#x3b2;=&#x2009;-0.633 (-0.992, -0.274)], followed by pseudobulbar syndrome [&#x3b2;=&#x2009;-0.460 (-0.832, -0.088)], depression [&#x3b2;=&#x2009;-0.375 (-0.688, -0.062)], pain [&#x3b2;=-0.362 (-0.627, -0.096)]. fatigue [&#x3b2;=&#x2009;-0.338 (-0.644, -0.033)], spasticity [&#x3b2;=&#x2009;-0.362 (-0.644, -0.081)] and the interval between diagnosis and baseline visit to a specialized unit in months [&#x3b2;&#x2009;=&#x2009;0.031 (0.013, 0.048)].<br><br>CONCLUSIONS: Lower baseline ALSFRS-R scores, older age at diagnosis, restrictive respiratory pattern, pain and absence of cramps were linked to shorter survival in ALS. Dysphagia, pseudobulbar syndrome, depression, pain, fatigue, spasticity and shorter intervals between diagnosis and baseline visit to specialized units were related to steeper functional decline.}, }
@article {pmid41546073, year = {2026}, author = {Dewan, MF and Rayani, AM and Hannan, J}, title = {Improving nursing students' clinical experience with genetics: the influence of prior knowledge and leadership support through the Donabedian Model.}, journal = {BMC nursing}, volume = {25}, number = {1}, pages = {}, pmid = {41546073}, issn = {1472-6955}, abstract = {BACKGROUND: As advancements in genetics and genomics continue to evolve, nursing students need to be equipped with prior knowledge and academic leadership support (ALS) to interpret genetic information, educate patients, and participate in clinical decision-making. ALS is actions or behaviors by leaders to support, guide, and empower their students. The incorporation of genetics/genomics into the nursing curriculum has been recognized on a global scale.<br><br>AIM: To evaluate the impact of nursing students&#x2019; prior knowledge of genetics/Genomics and genomics and academic leadership support on their clinical experience.<br><br>METHOD AND DESIGN: A cross-sectional study was conducted among nursing students at xxxxx University College of Nursing, Saudi Arabia, between December 2024 and February 2025 (IRB# KSU-HE-24-1055). A total of 169 participants completed an online survey.<br><br>RESULTS: Most participants were in their fourth year, internship year, or enrolled in postgraduate programs (BSN&#x2009;=&#x2009;118; Master&#x2019;s&#x2009;=&#x2009;46; PhD&#x2009;=&#x2009;3). The average age was 26.6 years (SD&#x2009;=&#x2009;5.8), and more participants were female (58.5%) than male (41.5%). Male participants reported receiving higher levels of leadership support than their female counterparts did. ALS on clinical experience (p&#x2009;<&#x2009;0.01); and prior knowledge (p&#x2009;<&#x2009;0.008); R[2]&#x2009;=&#x2009;0.440 with large effect size&#x2009;=&#x2009;0.78.<br><br>CONCLUSIONS: Integrating genetics and genomics education into the nursing curriculum is needed to meet today&#x2019;s healthcare standards. Academic nursing leaders in educational settings play a key role in advancing nursing students&#x2019; curriculum thereby increasing their knowledge and preparedness for clinical practice.<br><br>Educational settings that integrate nursing genetics and genomics courses into curricula and provide leadership support to students will improve their clinical experience and enhance patients&#x2019; care.<br><br>IMPACT: What problem did the study address? ALS is a key driver of improving students&#x2019; clinical experience. What were the main findings? Male nursing students reported higher levels of leadership support than female nursing students highlighting the need for strategies that support equity and prevent disparities in educational settings on the basis of gender. Who will benefit? Nurse educators and nurse leaders could utilize these findings to improve educational environments. Nurses with up-to-date knowledge will benefit their patients&#x2019; outcomes by being better informed.<br><br>REPORTING METHOD: We adhered to the STROBE guidelines for cross-sectional research.}, }
@article {pmid41912662, year = {2026}, author = {Liu, Y and Huang, Z and Hsu, YW and Deme, P and Frankenfield, AM and Wu, S and Zhao, X and Liu, H and Zhang, T and Alexander, EJ and Liu, M and Zhang, Y and Wang, H and Zhou, Y and Monteiro, MJ and Hao, L and Haughey, NJ and Wang, J}, title = {UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {41912662}, issn = {1546-1726}, support = {NS089616//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS110098//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS074324//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS128494//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS098243//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; FS-2023-SBF-S6//Target ALS (Target ALS Foundation)/ ; }, abstract = {Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.}, }
@article {pmid41912988, year = {2026}, author = {Zheng, H and Yu, S and Zhou, T and Fu, S and Zhang, J and Zhang, N and Liu, Y and Huang, Y and He, Z and Zhang, J and Liu, P and Gong, M and Zhou, C}, title = {Distinct amino acid metabolic subtypes predict prognosis and stratify treatment response in acute-on-chronic liver failure: a multicenter prospective study.}, journal = {Hepatology international}, volume = {}, number = {}, pages = {}, pmid = {41912988}, issn = {1936-0541}, support = {82305067//National Natural Science Foundation of China/ ; 2018ZX10725506-002//National Science and Technology Major Project of China during the 13th Five-Year Plan Period/ ; }, abstract = {BACKGROUND: Acute-on-chronic liver failure (ACLF) exhibits high mortality and heterogeneity, demanding precise risk stratification. We aimed to identify metabolic subtypes and explore their association with prognosis and real-world artificial liver support (ALS) responsiveness.<br><br>METHODS: This prospective, multicenter, observational cohort study enrolled 142 ACLF patients. Serum was collected at baseline, prior to ALS initiation. Patients were subtyped via metabolomics clustering. ALS exposure was analyzed using inverse probability of treatment weighting (IPTW) and Cox models to test for heterogeneity of treatment effect.<br><br>RESULTS: Two subtypes were identified (Cluster 1/2). Cluster 2 showed significantly higher 90&#xa0;day mortality (p&#x2009;=&#x2009;0.032) and severe amino acid metabolic reprogramming, particularly in branched-chain amino acid and glutamine pathways. Exploratory analysis suggested a differential association between ALS and survival across subtypes (interaction p&#x2009;=&#x2009;0.12). ALS showed a weaker survival association in Cluster 2 after IPTW adjustment.<br><br>CONCLUSION: ACLF patients possess distinct amino acid-based metabolic subtypes that are potent prognostic indicators. Baseline metabolic profiling can serve as a stratification tool to identify patients who may derive the greatest clinical benefit from ALS therapy, guiding personalized treatment strategies.}, }
@article {pmid41913878, year = {2026}, author = {Elfadil, U and Al-Majmuei, A and Alatoom, M and Juma, S and Shukralla, A}, title = {The Impact of Preoperative Nutritional Status on the Incidence of Anastomotic Leaks in Colorectal Surgery.}, journal = {Cureus}, volume = {18}, number = {2}, pages = {e104329}, pmid = {41913878}, issn = {2168-8184}, abstract = {Anastomotic leaks (ALs) are among the most serious complications following colorectal surgery, contributing to significant morbidity, reoperation, and prolonged hospitalisation. Poor preoperative nutritional status has been proposed as a modifiable risk factor; however, evidence from studies remains inconsistent. This systematic review, conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251034523), synthesised findings from 32 eligible studies, including randomised controlled trials, cohort studies, and case-control designs, published between 2005 and 2025. Across 474 initially identified articles, nutritional status was assessed using serum albumin, body mass index (BMI), Subjective Global Assessment (SGA), Nutritional Risk Index (NRI), or Prognostic Nutritional Index (PNI). AL incidence ranged from 2.8% to 11.3%, with hypoalbuminaemia and low nutritional indices consistently associated with increased risk. Several studies have suggested that nutritional optimisation, particularly immunonutrition and enteral support initiated 7-14 days preoperatively, improves secondary outcomes, such as wound infection rates, hospital stay, and overall morbidity. However, reductions in leak incidence are less consistent. The certainty of evidence linking poor nutritional status to leak risk was rated as moderate, while the evidence for nutritional interventions was rated as low due to heterogeneity and small sample sizes. Perioperative factors, including operative time, intraoperative blood loss, transfusion, and steroid use, were also significant contributors to leak risk. Overall, nutritional status is a key, modifiable predictor of AL; however, integration with surgical and perioperative optimisation is essential. High-quality multicentre trials are needed to define optimal nutritional strategies and establish standardised risk assessment tools for clinical practice.}, }
@article {pmid41914380, year = {2026}, author = {Chen, L and Chen, EW and Chen, BW and Wang, D}, title = {Retinol Taking a Detour Promotes Neural Stem Cell Self-Renewal In Vivo Accompanied by Down-Regulation of Some Retinoic Acid Receptors.}, journal = {Stem cells and development}, volume = {}, number = {}, pages = {15473287261436286}, doi = {10.1177/15473287261436286}, pmid = {41914380}, issn = {1557-8534}, abstract = {Since our previous studies have indicated retinol promotes self-renewal of embryonic stem cells in vitro culture, we speculate that retinol may be directly involved in regulating adult stem cell self-renewal or developmental function in vivo. Vitamin A or retinoic acid (RA) solution was first injected into the abdominal cavities of mice, and then self-renewal and development marker gene expressions were investigated. The in vivo effects of retinol and RA on RA receptor expressions were further examined. The results showed that retinol not only significantly promotes self-renewal of neural stem cells in vivo but also induces orientational development of neural stem cells in vivo and significantly downregulates the expression of some RA receptor gene expression in the brain. This study provides experimental and theoretical bases for elucidating the regulation mechanism of retinol-mediated cell development in vivo, especially in brain, and the development of therapeutic drugs for neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, and Huntington's disease.}, }
@article {pmid41915953, year = {2026}, author = {Zhang, Y}, title = {Letter to the editor: "Evolution of triglyceride and total cholesterol levels after critical illness: Preliminary insights into post-ICU metabolic sequelae".}, journal = {Journal of critical care}, volume = {94}, number = {}, pages = {155557}, doi = {10.1016/j.jcrc.2026.155557}, pmid = {41915953}, issn = {1557-8615}, abstract = {This letter evaluates Rousseau et al.'s recent study on post-intensive care unit dyslipidemia. While commending their focus on metabolic sequelae, we propose three clinical refinements. First, defining "de novo" hypertriglyceridemia using acute-phase ICU lipid troughs risks overestimating its true incidence, as these values represent pathological stress rather than physiological baselines. Second, profound post-discharge lifestyle transitions, particularly severe physical inactivity and ad libitum diets, must be considered alongside systemic inflammation as primary drivers. Finally, stratifying the cohort's diverse admission etiologies is essential to avoid diluting distinct metabolic phenotypes and improve targeted post-ICU care.}, }
@article {pmid41916013, year = {2026}, author = {Phan, PQ and Nagata, JM and Le, TP}, title = {Queer Asian American men's self-objectification: A test of racially relevant factors.}, journal = {Body image}, volume = {57}, number = {}, pages = {102079}, doi = {10.1016/j.bodyim.2026.102079}, pmid = {41916013}, issn = {1873-6807}, abstract = {Queer Asian American men face pervasive experiences of racial discrimination within the queer community and the broader society, which may critically impact their body image outcomes. While some studies have documented how racially relevant factors may shape body image attitudes among queer Asian American men, no studies have investigated the racialized experience of self-objectification among this under-researched subgroup. Hence, the present study adopts Cheng et al.'s (2017) racially expanded model of objectification theory among Asian American college women and applies a strengths-based approach to examine the associations between resistance and empowerment against racism (REAR), internalized racism, pride in Asian features, and self-objectification. Thus, among a sample of 265 queer Asian American men, analyses of indirect effects revealed that REAR was indirectly associated with lower self-objectification via greater pride in Asian features, whereas internalized racism was not indirectly associated with self-objectification via pride in Asian features. Furthermore, internalized racism was directly associated with greater self-objectification and lower pride in Asian features. Our findings contribute to the limited yet growing literature on the racialized experience of body image among queer Asian American men, underscoring the nuanced ways in which resistance against racism and internalization of racial oppression are associated with self-objectification. Social justice-informed implications are discussed, including efforts to deconstruct the internalization of White supremacist ideologies and empower queer Asian American men to engage in resistance through future research, clinical interventions, and prevention programs.}, }
@article {pmid41916622, year = {2026}, author = {Addington, C and Davies, N and Howell, P and Cruickshank, S and Hainsworth, E}, title = {Lived experiences of cancer care for people living with HIV who are treated for anal cancer: a scoping review.}, journal = {BMJ open}, volume = {16}, number = {3}, pages = {e114180}, doi = {10.1136/bmjopen-2025-114180}, pmid = {41916622}, issn = {2044-6055}, mesh = {Humans ; *Anus Neoplasms/therapy/psychology/complications ; *HIV Infections/complications/psychology ; *Quality of Life ; }, abstract = {OBJECTIVE: This scoping review aims to identify existing evidence on the lived experiences of people living with HIV and treated for anal cancer, and to identify what aspects of health and well-being are addressed in clinical guidance.<br><br>DESIGN: A preregistered protocol (Open Science Framework, 2025) guided the review. We followed the Arksey and O'Malley framework, incorporating Levac et al's refinements around stakeholder consultation. Joanna Briggs Institute (JBI) guidance informed eligibility and data for charting, and reporting adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines.<br><br>DATA SOURCES: Systematic searches were performed across multiple databases, including CINAHL, MEDLINE, PsycINFO and Embase, using EBSCOhost and Ovid, supplemented handsearching reference lists. Two search strategies were used: one for research studies and one for clinical guidelines.<br><br>ELIGIBILITY CRITERIA: Sources included people living with HIV treated for anal cancer, capturing lived experiences directly through qualitative studies or indirectly via quantitative patient-reported outcomes and/or health-related quality of life. Guidelines addressing HIV or anal cancer were also included.<br><br>DATA CHARTING AND SUMMARIES: Data were charted to capture patient experiences and outcomes on living with and beyond cancer, and how these are addressed in clinical management and guidance, including biomedical, psychosocial, sexual and functional aspects, and patient-reported outcomes.<br><br>RESULTS: Of 945 records, three studies and four guidelines met criteria. No study focused exclusively on people living with HIV; findings reflect broader anal cancer populations with HIV-positive subsets. Studies addressed aspects of health-related quality of life which we mapped into physical, psychosocial and sexual domains. Clinical guidance prioritised treatment dosage and survival, with limited attention to broader effects. Stakeholders highlighted that existing research and guidance miss important nuances of lived experience and care needs.<br><br>CONCLUSIONS: No identified research solely explored the lived experiences of people living with HIV treated for anal cancer, leaving guidance non-specific and biomedical. The identified domains offer a starting point for future research; however, to inform patient-centred care, stakeholders emphasised the need to understand how living with HIV and anal cancer shapes health needs.}, }
@article {pmid41916881, year = {2026}, author = {Calma, AD and Pavey, N and Silva, CS and Tsuji, Y and Ghapar, AA and Morris, K and Kiernan, MC and Farrar, MA and Menon, P and Vucic, S}, title = {Utility of Far-Field Potentials as a Biomarker of Neurodegeneration in Spinal Muscular Atrophy.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70231}, pmid = {41916881}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluated the utility of ulnar nerve FFP as a robust research biomarker of lower motor neuron degeneration in spinal muscular atrophy (SMA).<br><br>METHODS: Peripheral neurophysiological assessments were performed in 13 participants with SMA, 19 with amyotrophic lateral sclerosis (ALS), and 19 healthy controls. The ulnar nerve was stimulated at the wrist, and motor responses were recorded over the abductor digiti minimi (ADM) muscle. Recorded measures included compound muscle action potential (CMAP), FFP and near-field potential (NFP) amplitudes, and motor unit number index (MUNIX).<br><br>RESULTS: The FFP amplitude was significantly lower in SMA participants compared to healthy volunteers (p&#x2009;<&#x2009;0.001), but comparable to ALS (p&#x2009;=&#x2009;0.11). The FFP amplitude showed strong correlations with the Revised Upper Limb Module (RULM) (&#x3c1;&#x2009;=&#x2009;0.92), ALS Functional Rating Score-Revised (&#x3c1;&#x2009;=&#x2009;0.85), upper limb MRC score (&#x3c1;&#x2009;=&#x2009;0.89), CMAP amplitude (&#x3c1;&#x2009;=&#x2009;0.97), NFP amplitude (&#x3c1;&#x2009;=&#x2009;0.88), and MUNIX values (&#x3c1;&#x2009;=&#x2009;0.84), all of which were highly statistically significant. Multiple linear regression indicated that FFP amplitude was an independent predictor of RULM (p&#x2009;<&#x2009;0.001).<br><br>DISCUSSION: FFP amplitude appears to be a promising neurophysiological biomarker for SMA, with potential utility for monitoring disease progression, particularly in a clinical trial setting.}, }
@article {pmid41917183, year = {2026}, author = {Eom, E and Kim, J and Kim, J and Kang, SJ}, title = {STING is the scaffold protein for stress granule pre-condensation at the ER.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {41917183}, issn = {1476-5403}, support = {RS-2024-00339685//National Research Foundation of Korea (NRF)/ ; RS-2024-00339685//National Research Foundation of Korea (NRF)/ ; }, abstract = {Stress granules (SGs) are dynamic, membraneless ribonucleoprotein condensates that assemble in response to cellular stress and coordinate diverse cellular stress responses and diseases. Although SG have been reported to associate with the endoplasmic reticulum (ER), how ER-localized stress granule assembly is organized and regulated remains unclear. STING (stimulator of interferon genes) is a central innate immune adaptor that has recently been implicated in diverse non-canonical cellular functions, yet its potential link to SG regulation has not been established. Independent of its canonical functions in innate immune signaling, we identified a novel role of STING as a regulator of SG formation. We found that prior to stress stimulation, STING interacts with key SG core components G3BP1 and UBAP2L via its C-terminal domain (CTD) at the ER, forming a pre-condensation complex that facilitates SG maturation in response to stress. Loss of STING reduces SG formation and increases stress-induced cell death, whereas ER-anchored STING CTD is sufficient to reverse them. Mechanistically, STING enhances basal interactions between G3BP1 and UBAP2L, lowering the threshold for SG maturation upon stress. In addition, STING promotes the pathologic effects of TDP-43 mutations associated with amyotrophic lateral sclerosis. Our findings implicate STING as an ER-resident regulator of SG dynamics that contributes to neurodegenerative pathology, highlighting it as a potential therapeutic target in diseases associated with aberrant SG assembly.}, }
@article {pmid41906032, year = {2026}, author = {Abdelaal, Z and Boya, BR and Lee, JH and Lee, J}, title = {Targeting Als3 adhesin of clinically relevant Candida species using natural carotenoids: an in-silico study.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {41906032}, issn = {1573-501X}, support = {RS-2025-00513239//the National Research Foundation of Korea (NRF)/ ; }, abstract = {Candidemia, caused by the opportunistic Candida spp., poses a severe global health threat, characterized by mortality rates reaching 75% and the increasing prevalence of multidrug-resistant biofilms. In this study, we targeted the Agglutinin-Like Sequence 3 (Als3) adhesin protein, the primary mediator of Candida species attachment, as a non-lethal strategy to inhibit biofilm formation. Using molecular docking, we screened a library of 1570 natural carotenoids against the conserved N-terminal domain of Als3 of Candida albicans and compared to five positive controls. Our virtual screening identified five compounds (mangicrocin, MODU, α-zeacarotene-3,17'-diol, BTTB, and (15Z)-zeaxanthin-3'-rhamnoside), with the best binding pose and the least binding energy. Among them, mangicrocin showed best binding affinity (docking score - 7.18 kcal/mol, ΔGbind - 35.23 kcal/mol) against C. albicans Als3, compared to the in vitro and in silico positive control, rutin (docking score - 5.772 kcal/mol, ΔGbind - 30.59). It consistently achieved the best docking scores across C. albicans Als family proteins (Als1 and Als5) and Als3 proteins of other species in the Candida genus like C. auris, C. tropicalis, C. parapsilosis, and C. dubliniensis. Molecular electrostatic potential (MESP) mapping analysis further clarified that the hydrophobic polyene backbone and the negative electrostatic potential of the OH groups on the aromatic rings aid in anchorage to the key cadherin-binding residues-Lys59 and Ser170 in the Als3 binding pocket. Density Functional Theory (DFT) analysis shows high electrophilicity and a narrow energy gap contributes to mangicrocin's interactions and chemical reactivity. Molecular dynamics simulations suggested stable retention of mangicrocin within the Als3 binding pocket, supported by stable structural parameters and favorable interaction energy profiles. In silico ADMET profiling concludes these top five hits had limited toxicity and are druggable. As this study is entirely computational, these findings are predictive and require future in vitro validation to confirm biological efficacy.}, }
@article {pmid41906147, year = {2026}, author = {Zhou, X and Yu, P and Shen, X}, title = {m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.}, journal = {Molecular brain}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13041-026-01297-z}, pmid = {41906147}, issn = {1756-6606}, support = {82471208 and 82171184//National Natural Science Foundation of China/ ; }, abstract = {m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its spatial organization across neurons and glial cells, highlighting established roles in brain development, synapse formation, and axon growth. We then focus on experience-dependent plasticity, synthesizing evidence that neuronal activity and environmental inputs dynamically reshape m6A to regulate immediate-early transcription and local translation at synapses across sensory, cognitive, emotional, and motor domains. With aging, m6A programs are reconfigured in a cell-type-specific manner, a shift associated with reduced plasticity and increased vulnerability. We further survey disease-associated alterations in m6A across Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke-related cognitive impairment, ALS and FTD, as well as metal or toxin exposure, emphasizing convergent effects on dopaminergic and glutamatergic signaling, synaptic integrity, inflammation, and cellular stress responses. Finally, we discuss emerging opportunities and conceptual challenges in targeting m6A enzymes or reader proteins, and outline priorities for future work, including cell-type- and subcellular-resolved mapping, causal perturbation in defined circuits and life stages, and the development of biomarkers and selective modulators. Together, these observations position m6A as a molecular interface linking experience-dependent plasticity, brain aging, and neurodegenerative vulnerability.}, }
@article {pmid41906403, year = {2026}, author = {Correale, J}, title = {Glial Plasticity and Dysfunction: Mechanistic Insights and Therapeutic Opportunities in Neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {170}, number = {4}, pages = {e70414}, doi = {10.1111/jnc.70414}, pmid = {41906403}, issn = {1471-4159}, mesh = {Humans ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Neurodegenerative Diseases/therapy/metabolism/pathology/physiopathology ; *Neuronal Plasticity/physiology ; *Cell Plasticity/physiology ; }, abstract = {Recent advances, including single-cell transcriptomics, lineage tracing, and in vivo imaging, have unveiled the heterogeneity, plasticity, and functional versatility of astrocytes, microglia, oligodendrocytes, and Schwann cells. These cells respond to metabolic and immune cues, participate in synaptic regulation, and provide metabolic and trophic support to neurons. Their dual roles in neuroprotection and neurodegeneration underscore the complexity of their contributions across CNS disorders. This review examines the diverse physiological and pathological roles of glia, emphasizing their involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Mechanisms including metabolic dysfunction, inflammatory polarization, glial-immune crosstalk, and extracellular vesicle-mediated signaling are critically discussed. Emerging therapeutic strategies, ranging from glial reprogramming and senolytic therapies to the use of engineered extracellular vesicles and metabolic modulators, are evaluated for their potential to harness glial plasticity and mitigate disease progression. The review also outlines current challenges in translating glial biology into clinical interventions, including cellular heterogeneity, delivery barriers, and the need for specific biomarkers. A glia-centered therapeutic paradigm offers promising avenues to restore CNS homeostasis and promote regeneration in neurodegenerative diseases.}, }
@article {pmid41906714, year = {2026}, author = {Schellenberg, KL and Nataraj, R}, title = {Reviewer Comment on Li et al. "Nocturnal Hypoxia and Sleep-Disordered Breathing as Potential Early Biomarkers of Respiratory Progression in Mild ALS".}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1}, doi = {10.1017/cjn.2026.10558}, pmid = {41906714}, issn = {0317-1671}, }
@article {pmid41907197, year = {2026}, author = {Elshony, H and Almuhanna, R and Albazli, KO and Muddassir, R}, title = {Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.}, journal = {eNeurologicalSci}, volume = {43}, number = {}, pages = {100607}, pmid = {41907197}, issn = {2405-6502}, abstract = {BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder that may mimic motor neuron disease (MND), leading to misdiagnosis and delayed access to disease-modifying therapies.<br><br>CASE REPORT: We report the first genetically confirmed case of ATTRv mimicking amyotrophic lateral sclerosis (ALS) in Saudi Arabia. A 47-year-old male presented with progressive right-sided limb weakness (proximal > distal) and dysarthria over 18&#xa0;months. Neurological examination revealed fasciculations, distal atrophy, and brisk reflexes with normal muscle tone and no spasticity. Electrophysiological studies demonstrated a length-dependent sensorimotor axonal neuropathy with widespread denervation changes involving bulbar, cervical, and lumbosacral regions. Brain and spine MRI, along with whole-body CT, excluded structural or paraneoplastic causes. Genetic testing identified a pathogenic heterozygous variant in the TTR gene: NM_000371.4:c.424G&#xa0;>&#xa0;A (p.Val142Ile). Transthoracic echocardiography revealed mild concentric left ventricular hypertrophy. There was no clinical evidence of autonomic, renal, or ocular involvement.<br><br>DISCUSSION: This case underscores the importance of considering ATTRv in patients presenting with atypical MND, particularly when clinically significant sensory symptoms, absent upper motor neuron signs, or unexplained cardiac abnormalities are present. Early diagnosis enables access to targeted therapies such as TTR stabilizers and gene-silencing agents, which can alter disease trajectory.}, }
@article {pmid41907482, year = {2026}, author = {Pham, N and Nguyen, CTH and Van, TT}, title = {Response to Brenaut et al., "Response to Pham et al's 'Sensory symptoms of scalp psoriasis are not sensitive scalp syndrome'".}, journal = {JAAD international}, volume = {25}, number = {}, pages = {139}, pmid = {41907482}, issn = {2666-3287}, }
@article {pmid41907560, year = {2026}, author = {Ozgor, B and Goktas, OF and Baygin, M and Dogan, S and Tuncer, T}, title = {Differential quadruple pattern: A new EEG signal classification framework.}, journal = {IBRO neuroscience reports}, volume = {20}, number = {}, pages = {492-505}, pmid = {41907560}, issn = {2667-2421}, abstract = {EEG signals are the letters of the brain and reflect neural activity. Abnormal EEG patterns indicate brain disorders such as epilepsy. Recently, machine learning has enabled automated EEG interpretation with high accuracy. This study introduces an explainable EEG classification model based on feature engineering. A novel feature extractor, Differential Quadruple Pattern (DiffQuadPat), is proposed. DiffQuadPat computes relations between four channel values using difference-based transformations and combinational transition tables. Feature selection is performed by Cumulative Weight Neighborhood Component Analysis (CWNCA), and classification is achieved with t-algorithm-based k-Nearest Neighbors (tkNN). For interpretability, Directed Lobish (DLOB) is used to produce symbolic explanations. The proposed DiffQuadPat-centric XFE framework was validated on two EEG datasets: Amyotrophic Lateral Sclerosis (ALS) and neonatal epilepsy detection. The model achieved over 98% accuracy under 10-fold cross-validation. Furthermore, cortical and hemispheric connectome diagrams were generated, enabling transparent visualization of brain-level interactions.}, }
@article {pmid41908423, year = {2026}, author = {Girdthep, S and Yodsin, N and Phonprasert, J and Suwanchawalit, C and Swanglap, P}, title = {Sustainable Natural Lake Pigments from Caesalpinia sappan: Improving Stability through Inorganic Support Morphologies for Colored PLA Packaging Films.}, journal = {ACS omega}, volume = {11}, number = {11}, pages = {17948-17966}, pmid = {41908423}, issn = {2470-1343}, abstract = {Red-pink natural lake pigments were prepared from Caesalpinia sappan L. extract colorant powder (S-Alum, without inorganic supports) and as colorant-adsorbed inorganic supports: silica (S-Si) and kaolinite (S-Kaol). Among these, S-Kaol demonstrated the highest stability and color strength (K/S), supported by its superior initial thermal degradation at 450 °C, high pH and UV stability, and consistent hue (H° = 19-22). X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) analyses confirmed the formation of a stable structure in S-Kaol, involving strong electrostatic interactions between brazilein and the kaolinite surface through Al[3+] chelation. The DFT results further revealed an Al adsorption energy of -0.97 eV and a strong orbital hybridization between the Al (s) and the O (p) orbitals. The resulting pigments were incorporated into PLA to produce pinkish-red composite films. PLA/S-Kaol demonstrated superior pigment dispersity, thermal stability, and photostability, showing only a minor hue shift (H° shifting from 33.12° to 32.21°) after 168 h of UV exposure, attributed to the UV-shielding effect of kaolinite layers. In contrast, spherical S-Si particles introduced film defects, while amorphous S-Alum yielded moderate improvements. Overall, the inorganic supports acted as nucleating agents, enhancing PLA crystallization and thermal performance. These findings highlight S-Kaol as a renewable, nontoxic with heavy metal-free alternative to synthetic dyes for biodegradable polymer applications.}, }
@article {pmid41908699, year = {2025}, author = {Barai, P and Leroy, G and Ahmed, A}, title = {Comparative Evaluation of Text and Audio Simplification: A Methodological Replication Study.}, journal = {Communications of the Association for Information Systems}, volume = {57}, number = {}, pages = {1059-1084}, pmid = {41908699}, issn = {1529-3181}, abstract = {This study serves as a methodological replication of Leroy et al.'s (2022) research, which investigated the impact of text simplification on healthcare information comprehension in the evolving multimedia landscape. Building upon the original study's insights, our replication study evaluates audio content, recognizing its increasing importance in disseminating healthcare information in the digital age. Specifically, we explored the influence of text simplification on perceived and actual difficulty when users engage with audio content automatically generated from that text. Our replication involved 44 participants for whom we assessed their comprehension of healthcare information presented as audio created using Leroy et al.'s (2022) original and simplified texts. The findings from our study highlight the effectiveness of text simplification in enhancing perceived understandability and actual comprehension, aligning with the original study's results. Additionally, we examined the role of education level and language proficiency, shedding light on their potential impact on healthcare information access and understanding. This research underscores the practical value of text simplification tools in promoting health literacy. It suggests the need for tailored communication strategies to reach diverse audiences effectively in the healthcare domain.}, }
@article {pmid41909467, year = {2026}, author = {Nagamatsu, Y and Umezu, T and Hong, T and Niijima, T and Ohno, SI and Harada, Y and Kanekura, K and Ochiya, T and Kuroda, M}, title = {Exosome-like nanovesicles from acerola for CRISPR-Cas9 ribonucleoprotein delivery to the central nervous system.}, journal = {Molecular therapy. Nucleic acids}, volume = {37}, number = {2}, pages = {102896}, pmid = {41909467}, issn = {2162-2531}, abstract = {An aberrant six-base repeat in intron 1 of C9orf72 is the most frequent cause of solitary and familial amyotrophic lateral sclerosis and frontotemporal dementia. This mutation is a potential target for CRISPR/Cas9-based genome editing. However, the blood-brain barrier and limitations of current viral or nanoparticle-based delivery systems to neurons significantly restrict the clinical application of CRISPR-Cas9 in the brain. To address these challenges, we developed a drug delivery system using acerola-derived exosome-like nanoparticles (AELNs), which may overcome several limitations associated with human exosomes. AELNs stably form complexes with ribonucleoproteins (RNPs) comprised of Cas9 proteins and guide RNAs (gRNAs). We improved the delivery efficiency and selectivity of AELN/RNP complexes in GLP2-receptor-expressing neurons by incorporating GLP2 peptides into the AELN/RNP complexes. Intranasal administration of peptide-tagged AELN/RNP complexes in vivo confirmed the successful genome editing of C9orf72, demonstrating the potential of this system for treating neurodegenerative diseases. This study presents a potentially innovative approach for in vivo genome editing using a noninvasive delivery system.}, }
@article {pmid41909487, year = {2026}, author = {Gowdy, J and Ahn, J and Miller, RH and Islam, Y}, title = {Neurovascular dysfunction in the development and progression of neuroinflammatory diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1741928}, pmid = {41909487}, issn = {1662-5102}, abstract = {The neurovascular unit (NVU) is critical for brain homeostasis through its roles in maintenance of an effective blood brain barrier (BBB) and regulation of cerebral blood flow. Perturbation of the NVU is a hallmark of the pathology of multiple neurodegenerative diseases resulting in loss of BBB integrity, neuroinflammation and neuronal dysfunction. The NVU is a complex structure composed of endothelial cells, pericytes, as well as central nervous system (CNS) glial and neuronal components. While the importance of the CNS vasculature in health and disease is well established, the mechanisms underlying vascular pathology and its contributions to neurodegenerative diseases are less well defined. Neuroinflammation and reactive gliosis occurs in the majority of neurodegenerative diseases and recent studies suggest that immune mediated disruption of the BBB contributes to the induction of reactive gliosis and neuronal dysfunction. Potential consequences of NVU disruption include immune-driven vascular inflammation and leukocyte infiltration in Multiple Sclerosis (MS), protease-mediated tight junction degradation in ischemic stroke (IS), α-synuclein-associated endothelial dysfunction in Parkinson's Disease (PD), amyloid-β- and tau-induced pericyte injury in Alzheimer's Disease (AD), and complement-mediated vascular damage in Amyotrophic Lateral Sclerosis (ALS). Here we review the nature of NVU perturbations in these common neurodegenerative diseases, with an emphasis on the contribution of immune modulation of BBB disruption in neuropathology and disease progression.}, }
@article {pmid41909553, year = {2026}, author = {J, MA and C, A}, title = {Gender euphoria reimagined: toward an Extended Theory of Trans-Identity.}, journal = {Frontiers in psychology}, volume = {17}, number = {}, pages = {1738195}, pmid = {41909553}, issn = {1664-1078}, abstract = {INTRODUCTION: The paper focuses on developing an Extended Theory of Trans-Identity integrating Nagoshi et al.'s trans-identity theory with the creative expression of the self to explore gender-euphoric experiences.<br><br>METHOD: Having explored Austin et al.'s research on the artistic expression of trans people, the article attempts to explore the creative manifestation of identity as an important aspect of trans-identity formation, alongside Nagoshi et al.'s trans-identity theory. The synthesis of four aspects, including physical embodiment, self-construction, social construction, and the creative manifestation of the identified gender leading to the attainment of gender-euphoric factors identified by Austin et al. and Leitch et al., culminates in an Extended Theory of Trans-Identity. The theoretical framework is applied to I Am Vidya: A Transgender's Journey (2013), the autobiography of Living Smile Vidya, who is an eminent trans theatre artist and activist from Tamil Nadu, India. Furthermore, the use of a literary text to validate the Extended Theory draws on Schilling's concept of theory extrapolation from literature. The exemplifying textual analysis of the dynamic role of the four aspects of trans-identity in asserting transness and achieving gender euphoria attempts to substantiate the proposed theoretical extension.<br><br>RESULTS: The results indicate that identity construction through the creative aspect, in combination with the biopsychosocial aspects, contributes to the utmost attainment of gender euphoria.<br><br>DISCUSSION: Therefore, the article formulates an extended version of the trans-identity framework, emphasising the inclusion of creativity in the gender-affirmative journeys of trans people.}, }
@article {pmid41910574, year = {2026}, author = {Zhang, W}, title = {The evolving portrait of psychologists: A commentary on Xu et al. (2026).}, journal = {The American psychologist}, volume = {81}, number = {3}, pages = {423-425}, doi = {10.1037/amp0001694}, pmid = {41910574}, issn = {1935-990X}, mesh = {Humans ; *Psychology/trends ; Psychologists ; }, abstract = {Xu et al.'s (2026) portrayal of the evolving portrait of psychologists is valuable, yet several points merit further discussion or refinement. When interpreting the "decline of conscientiousness and rise of openness," additional factors should be considered-such as psychology's growing applied attribute, the public impact of psychoanalysis, transformations in book publishing, and the increasing number of female psychologists. The analysis could also benefit from: A stronger account of psychology's own disciplinary self-positioning, cross-cultural extensions and comparative findings, and comparisons with personality assessments of actual psychologists. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid41910654, year = {2026}, author = {Yu, Z and Li, H and Wang, Y and Li, Y and Shen, F and Wang, Y}, title = {The Microglial Lactate-Lactylation Axis as a Metabolic-Epigenetic Driver of Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1487}, pmid = {41910654}, issn = {2152-5250}, abstract = {The idea of amyloid-β (Aβ) plaques and tau neurofibrillary tangles has long been central to framing an understanding of Alzheimer disease (AD), but emerging and growing evidence now points to bioenergetic failure and metabolic-epigenetic crosstalk as central to AD progression. Hai et al. summarize animal and human biofluid and neuroimaging data to carve out the pathophysiology of AD in relation to the role of disrupted glucose metabolism, lactate build-up and protein lactylation in glucose metabolism, in their comprehensive review "Lactate, Lactylation and Alzheimer Disease". Building on Hai et al.'s key contributions, we offer a complementary perspective. The microglial lactate-lactylation axis may be remodeled across disease stages during chronic neuroinflammation, potentially serving compensatory functions early but shifting toward maladaptive, pro-inflammatory amplification at later stages. In light of emerging evidence for tau lactylation in human AD brain tissue, we propose a testable hypothesis of intercellular metabolic crosstalk: lactate exported from highly glycolytic microglia may alter local lactate availability and provide an additional substrate for neuronal tau lactylation. Although the causal contribution of lactate from distinct cellular sources remains to be established, this framework provides a useful lens for interpreting coupled metabolic and epigenetic mechanisms in AD. Our future efforts should focus particularly on glycolytic flux, lactate, epigenetic writers/erasers, therapeutic approaches, and non-pharmacological approaches to stage- and cell-specific lactylation profiling, biomarker development, and the incorporation of metabolic and epigenetic endpoints into interventional studies.}, }
@article {pmid41910849, year = {2026}, author = {Akram, SW and K, C}, title = {Enhancing Parkinson's Disease Staging: An Integrative Deep Learning Framework for Multimodal Feature Selection.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {41910849}, issn = {1559-1166}, mesh = {Humans ; *Parkinson Disease/diagnostic imaging/genetics/pathology/diagnosis ; *Deep Learning ; Neuroimaging/methods ; Magnetic Resonance Imaging ; Male ; Female ; }, abstract = {Parkinson's disease (PD) affects 10 million globally, with accurate staging essential for personalized treatment planning. Current UPDRS assessments achieve < 93% accuracy due to subjective clinical judgment and unimodal data limitations, failing to capture complex genetic-neuroimaging-clinical interactions driving disease heterogeneity. This study introduces MAFNet, a novel deep learning framework pioneering Iterative Adaptive Vold-Kalman Filter (IAVKF) temporal denoising, Accelerated Binary Particle Swarm Optimization (ABPSO) swarm feature selection, Multilayer Perceptron-Lagrangian Support Vector Machine (MLP-LSVM) classification, and Graph-Attention Based Multimodal Fusion Network (GAMF). Applied to PPMI cohort (200 patients) with genetic SNPs (50), neuroimaging voxels (1,024), and UPDRS-III scores, the end-to-end pipeline delivers 97.6% accuracy, 98.2% precision, 96.8% recall, and 97.3% F1-score-outperforming CNN (92.4%), Autoencoder (90.8%), InceptoFormer (96.6%), and HCT (97.0%). IAVKF boosts SNR + 15.2dB (+ 2.9% accuracy vs. PCA/t-SNE); ABPSO reduces 1,276→340 features (73% reduction); regularization cuts overfitting gap to 0.9% (vs. 4.2% baseline). SHAP interpretability validates clinical plausibility (top predictors: LRRK2 SNPs, UPDRS-III tremor, hippocampal volume). Five-fold CV confirms stability with the Indian cohort external validation. Real-time inference (0.2s/patient, RTX 3090) enables clinical deployment. Future scope includes longitudinal temporal modelling, modality-agnostic fusion, edge deployment, federated learning, and extension to Alzheimer's/ALS. MAFNet transforms PD staging from subjective assessments to objective precision medicine, enabling biomarker discovery, progression forecasting, and personalized therapies across diverse global populations.}, }
@article {pmid41910875, year = {2026}, author = {Rajagopalan, V and Pioro, EP}, title = {Diffusion network model analysis of multimodal neuroimaging reveals differential patterns of brain disease propagation in four subgroups of ALS patients.}, journal = {Brain imaging and behavior}, volume = {20}, number = {2}, pages = {}, pmid = {41910875}, issn = {1931-7565}, }
@article {pmid41911331, year = {2026}, author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP}, title = {Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag115}, pmid = {41911331}, issn = {1460-2156}, abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.}, }
@article {pmid41911483, year = {2026}, author = {Nusir, A and Anthony, SM and Zhou, W and Kabbani, N}, title = {Microglial Adaptations to Chronic Nicotine in the Cerebellum: Proteomic Evidence for Neuroimmune Vulnerability.}, journal = {Journal of proteome research}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jproteome.5c01027}, pmid = {41911483}, issn = {1535-3907}, abstract = {Smoking is a major public health concern with widespread effects on multiple organ systems, including the immune system. Chronic nicotine exposure can alter immune cell function through nicotinic receptors expressed on peripheral macrophages and microglia in the brain. Recent evidence indicates that the cerebellum is impacted by nicotine, contributing to motor and nonmotor outcomes, during drug use. In this study, we investigated the effect of chronic nicotine on microglia proteomes in the adult mouse cerebellum. Microglia were isolated by fluorescence-activated cell sorting (FACS) based on CD11b[high] CD45[low/intermediate] expression from male and female mice (n = 9 per group) exposed to 200 μg/mL nicotine (dissolved in 2% saccharin drinking water) for 30 days. Proteomic analysis was performed using liquid chromatography electrospray ionization (LC-ESI) mass spectrometry (MS) comparing the effect of nicotine relative to vehicle control. Our results reveal a sex-dependent effect of nicotine on microglial proteomes. While both males and females exhibited histone-related genomic responsiveness to nicotine, males demonstrated enrichment in cytoskeletal and metabolic proteins, and females showed complement-protein adaptations. The microglial proteome in male mice displayed nicotine-related adaptations in proteins that can contribute to neurodisorders including Huntington's disease and amyotrophic lateral sclerosis (ALS), of which smoking is a known risk factor. Together, these results highlight an effect of nicotine on the proteome of microglia providing insight into immune pathways that can contribute to smoking-related behavior and disease.}, }
@article {pmid41911992, year = {2026}, author = {Di Napoli, G and Alfurno, L and Fissore, A and Raccuia, E and Olivieri, P and Marengo, M and Oliaro-Bosso, S and Piaz, FD and Catucci, G and Gilardi, G and Velazquez-Campoy, A and Prischi, F and De Simone, A and Spyrakis, F and Di Palma, F and Adinolfi, S}, title = {Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {151719}, doi = {10.1016/j.ijbiomac.2026.151719}, pmid = {41911992}, issn = {1879-0003}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, leading to muscle paralysis and respiratory failure. Genetic mutations, notably in the ANXA11 gene, have been implicated in both familial and sporadic ALS forms. ANXA11 functions as a cellular "tether," orchestrating the transport of RNA-protein complexes and lysosomes through its N-terminal (Nt) and C-terminal (Ct) domains, respectively. This study uncovers a novel calcium-dependent regulatory mechanism governing the intramolecular interaction between these domains. Using biochemical, biophysical, and computational approaches, we suggest that in the absence of calcium, ANXA11 adopts a closed conformation with stable Nt-Ct interactions. Elevated calcium levels induce a conformational shift, disrupting this interaction and exposing binding sites for RNA and membranes. Crucially, we show that the ALS-associated D40G mutation in the Nt domain impairs this calcium-regulated interaction, favoring a persistent open conformation that predisposes to toxic protein aggregation. These findings reveal that calcium acts as a molecular switch modulating ANXA11 conformation and function, providing new insights into its role in ALS pathogenesis and potential therapeutic targets.}, }
@article {pmid41912102, year = {2026}, author = {Li, A and Xiao, X and Liu, G and Li, K and Ling, Y and Deng, S and Xu, C and Cao, SQ and Wen, J and Lu, G and Yang, G and Fang, EF and Qin, D and Su, H}, title = {Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β-TFEB signaling axis.}, journal = {Pharmacological research}, volume = {}, number = {}, pages = {108172}, doi = {10.1016/j.phrs.2026.108172}, pmid = {41912102}, issn = {1096-1186}, abstract = {Lysosomal dysfunction is a core pathological driver of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transcription factor EB (TFEB) serves as a master regulator of lysosomal biogenesis, and its pharmacological activation represents a strategy to restore lysosomal function in disease and aging. Here, using a series of artificial intelligence-powered computational virtual screening workflows, we have identified isoginkgetin (ISO), a small-molecule compound, as a potent TFEB activator that promotes mechanistic target of rapamycin complex 1 (mTORC1)-independent TFEB nuclear translocation to enhance lysosomal biogenesis and function. Mechanistically, ISO functions as an ATP-competitive inhibitor that binds to the key Lys85 residue within the ATP-binding pocket of glycogen synthase kinase 3β (GSK-3β), thereby regulating the GSK-3β-TFEB signaling axis to activate TFEB nuclear translocation. Functionally, ISO improves lysosomal function and protects motor neurons differentiated from induced pluripotent stem cells derived from patients with ALS from degeneration. Collectively, these results support the hypothesis that lysosomal dysfunction is a druggable target for ALS.}, }
@article {pmid41912266, year = {2026}, author = {Pennington, CR and Shaw, DJ and Skubera, M and Rose, AK and Jones, A}, title = {Declining trends in adolescent alcohol consumption and related harms: No room for complacency (an empirical reply to Vieira et al. 2025).}, journal = {Addiction (Abingdon, England)}, volume = {}, number = {}, pages = {}, doi = {10.1111/add.70413}, pmid = {41912266}, issn = {1360-0443}, support = {ES/Y001877/1//Economic &amp; Social Research Council (ESRC)/ ; SBF0010\1109/AMS_/Academy of Medical Sciences/United Kingdom ; }, abstract = {Vieira et al. report that alcohol-related harms among adolescents have generally declined in high-income countries where youth drinking has decreased, but several methodological choices complicate this conclusion. By performing reproducibility analyses on Vieira et al.'s raw data, we show that their findings are more nuanced and complex. Secondary data analyses reveal that 19-24-year-olds have elevated vulnerability to alcohol-related harms. Any discussion of declining trends in adolescent alcohol consumption and related harms should acknowledge that current prevalence rates and harms remain unacceptably high and require continued public health attention.}, }
@article {pmid41912367, year = {2026}, author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E}, title = {Authors' Response to "Comment on 'Improving Care for Amyotrophic Lateral Sclerosis with Artificial Intelligence and Affective Computing'".}, journal = {Journal of the neurological sciences}, volume = {}, number = {}, pages = {125885}, doi = {10.1016/j.jns.2026.125885}, pmid = {41912367}, issn = {1878-5883}, }
@article {pmid41856244, year = {2026}, author = {Behling, E and Bloch, MH}, title = {Editorial: Should Weight Gain Be a Factor in Choosing an Antidepressant?.}, journal = {Journal of the American Academy of Child and Adolescent Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaac.2026.03.008}, pmid = {41856244}, issn = {1527-5418}, abstract = {There is limited evidence to guide clinicians regarding the side effect profiles of antidepressants in youth. Weight gain is a frequent concern raised by patients and their families when starting psychiatric medications. In the current issue of JAACAP, Rifas-Shiman et al.[1] present a retrospective cohort study using electronic health record (EHR) data from 67,039 patients 5 to 19 years of age to investigate the impact of antidepressants on body mass index (BMI) in children and adolescents over the longer term (up to 1 year). The authors found a small, albeit statistically significant, increase in BMI with the most commonly used selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, fluoxetine, sertraline), but not with bupropion.[1] Rifas-Shiman et al.'s findings of slight weight gain associated with SSRIs in youth align with observational studies in adults.[2] Previous smaller prospective cohort studies in youth have suggested possible differences in effect of SSRIs on weight gain, with (es)citalopram being associated with more weight gain than sertraline (fluoxetine was intermediate).[3] The weight changes seen with escitalopram and citalopram are highly variable across patients and potentially associated with slow CYP2C19 metabolizer status.[4] Rifas-Shiman et al. did not replicate these differences in weight change between SSRI agents at 1-year follow-up despite the much larger sample size.}, }
@article {pmid41901170, year = {2026}, author = {Kwaśniewska, K and Fic, W and Polak-Szczybyło, E}, title = {Vitamins as Modulators of Neurodegenerative Disease Pathways: Mechanisms and Therapeutic Perspectives.}, journal = {Nutrients}, volume = {18}, number = {6}, pages = {}, pmid = {41901170}, issn = {2072-6643}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Vitamins/therapeutic use/pharmacology/administration &amp; dosage ; *Neuroprotective Agents/pharmacology ; *Dietary Supplements ; Antioxidants ; Oxidative Stress/drug effects ; Ubiquinone/analogs &amp; derivatives ; Animals ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, currently represent one of the major challenges in contemporary medicine and geriatrics. Progressive degeneration of the nervous system affects not only patients' physical functioning but also their psychosocial well-being, often leading to social isolation and disruption of interpersonal relationships. These processes are most strongly associated with individuals over 65 years of age, in whom metabolic syndrome is frequently diagnosed and constitutes a significant factor predisposing them to the exacerbation of neuropathological changes. This review analyzes the role of selected vitamins in modulating the course of neurodegenerative disorders, with particular emphasis on their neuroprotective potential. Specific attention is given to their involvement in antioxidant defense mechanisms, regulation of inflammatory pathways, prevention of abnormal protein aggregation, participation in neurotransmitter synthesis, and support of mitochondrial function and cellular energy metabolism. The review also considers key interactions between vitamins and coenzyme Q10, which synergistically enhance neuroprotective mechanisms. Deficiencies in certain vitamins may exacerbate oxidative stress, impair synaptic transmission, and intensify neuroinflammatory responses, thereby contributing to disease progression. The study analyzes the available data on therapeutic doses of vitamins and compares them with the recommended dietary intake and the upper tolerable intake levels (UL). The available evidence suggests that personalized vitamin supplementation, when integrated with a well-balanced and nutrient-dense diet, may constitute a valuable adjunctive therapeutic strategy. Such an approach may help attenuate disease progression, support neuronal integrity, and improve functional outcomes. Ultimately, targeted nutritional interventions may enhance overall well-being and quality of life in patients affected by neurodegenerative diseases.}, }
@article {pmid41902308, year = {2026}, author = {Datoo, M and Kadir, S}, title = {Voices from the minority: Understanding the acculturative experiences of British Shia Muslims.}, journal = {Psychology and psychotherapy}, volume = {}, number = {}, pages = {}, doi = {10.1111/papt.70058}, pmid = {41902308}, issn = {2044-8341}, support = {//University of Leicester/ ; }, abstract = {OBJECTIVES: The aim of this research was to understand the acculturative experiences of British Shia Muslims, with hopes for practitioners to better understand how to support this population.<br><br>DESIGN: Qualitative methodology was used, utilising semi-structured interviews. Braun and Clarke's (Thematic analysis: A practical guide, Sage Publications Limited, 2022) reflexive thematic analysis was chosen to analyse the data and identify themes within 15 interview transcripts.<br><br>METHODS: Recruitment took place through mosques, with inclusion criteria involving British Shia Muslim participants over 18&#x2009;years, who had lived in England for a minimum of 5&#x2009;years. First-, second- and third-generation participants were recruited.<br><br>RESULTS: Five themes were identified, sitting under the main overarching theme, 'navigating through multiple worlds', which depicted acculturation as a fluid, complex journey, consistent with Schwartz et&#xa0;al.'s (American Psychologist, 2010, 65, 37) multidimensionality model of acculturation. These themes included: do I belong here, with subthemes of conflicting cultural values and who am I, the emotional toll of acculturation, with subthemes of negotiating authenticity and Muslim therapeutic support, negotiating faith in a secular society, living with layered discrimination, with a subtheme of Shia-specific discrimination and, finally, holding each other up: sources of strength.<br><br>CONCLUSIONS: This research demonstrates the multidimensional and complex journey of acculturation for British Shia Muslims. Through this, there is an emphasis on understanding more about the experiences of minoritised communities to improve their mental health support. The clinical implications to support this are diversifying the workforce, enhancing cultural competence and humility, adopting an intersectional approach and addressing discrimination.}, }
@article {pmid41903716, year = {2026}, author = {Alam, Z and Nguyen, KT and Lauck, KC and Malick, H and Tolkachjov, SN}, title = {Response to Newell et al.'s commentary on DPP4 inhibitor use and skin cancer risk in type 2 diabetes.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.073}, pmid = {41903716}, issn = {1097-6787}, }
@article {pmid41903799, year = {2026}, author = {Chamorro-Muñoz, MI and Afkir-Ortega, MN and Aguilar-Monge, A}, title = {Impact of care by a multidisciplinary team on the assessment of cognitive aspects and decision-making at the end of life in a Spanish population with amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {}, number = {}, pages = {501950}, doi = {10.1016/j.nrleng.2026.501950}, pmid = {41903799}, issn = {2173-5808}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a disease with a fatal course, often associated with unassessed cognitive-behavioural disturbances, and very relevant end-of-life care decisions. The aim of this study is to verify whether multidisciplinary team care for ALS patients in our setting has modified the cognitive assessment and the end-of-life decision making, compared to a model of uncoordinated specialist care.<br><br>METHODS: An observational, longitudinal, retrospective study was conducted on a cohort of patients with probable or definite ALS, in a referral hospital, between 01-01-2000 and 31-12-2022, differentiating whether they were treated before or after the implementation of a multidisciplinary model. We analysed the performance of cognitive assessment, the use of riluzole, gastrostomy, non-invasive ventilation and invasive ventilation, and the recording of patients' decisions regarding the care they wished to receive. Comparisons between variables were performed using the chi-square test or Fisher's exact test.<br><br>RESULTS: We evaluated 47 patients seen by uncoordinated specialists and 146 with a multidisciplinary model. Patients cared for using the multidisciplinary model were more frequently cognitively assessed (55.48% vs 12.8%, p&#x2009;<&#x2009;0.001), diagnosed with dementia (11.6% vs 2.3%, p&#x2009;<&#x2009;0.048) and their advance directives were recorded (56.8% vs 23.4%, p&#x2009;<&#x2009;0.001). We found no differences in the use of advanced interventions, except for invasive ventilation, which was only performed in the context of multidisciplinary care.<br><br>CONCLUSIONS: The multidisciplinary model of care for ALS patients in our setting has improved cognitive assessment, promoted the registration of their advance directives, and thus helped to improve respect for their autonomous decisions and dignity.}, }
@article {pmid41903869, year = {2026}, author = {Yang, Y and Yang, Y and Zhang, X and Ma, H and Ji, S and Zou, F and Yu, X and Du, G and Zhu, X and Tian, J}, title = {Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy.}, journal = {Neuropharmacology}, volume = {}, number = {}, pages = {110940}, doi = {10.1016/j.neuropharm.2026.110940}, pmid = {41903869}, issn = {1873-7064}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress representing core pathological features. Epidemiological studies indicate geographical variations in incidence, and recent multi-omics evidence identifies a hypermetabolic state and mitochondrial dysfunction as key drivers of disease progression. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which regulates antioxidant response and metabolism, represents a promising therapeutic target; however, the exploration of specific activators remains insufficient. This study evaluated the efficacy and mechanism of a novel KEAP1-NRF2 activator, MKL01351, in SOD1 G93A transgenic mice and NSC-34 motor neuron-like ALS models. Behavioral analyses demonstrated that MKL01351 significantly delayed disease onset, improved motor coordination in the rotarod and hanging tests, and extended survival. The compound alleviated oxidative stress by reducing malondialdehyde (MDA) levels and restoring the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, while also ameliorating the energy deficit by modulating glycolytic and mitochondrial functions, as confirmed by Seahorse analysis. Mechanistic investigations revealed that MKL01351 activated the NRF2 pathway, upregulating downstream targets such as NQO1 and HO-1, and specifically enhanced the expression of malic enzyme 1 (ME1). Loss-of-function experiments confirmed that ME1 knockdown abolished the protective effects, indicating that the NRF2-ME1 axis is a central hub for the synergistic regulation of metabolic and oxidative homeostasis. In conclusion, MKL01351 concurrently ameliorates oxidative stress and metabolic dysregulation via the NRF2-ME1 signaling pathway, offering a novel neuroprotective strategy for ALS treatment.}, }
@article {pmid41904003, year = {2026}, author = {Kinger, S and Choudhary, A and Kumar, P and Jagtap, YA and Sharma, V and Dhiman, R and Prasad, A and Verma, R and Chinnathambi, S and Mishra, A}, title = {Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {181-219}, doi = {10.1016/bs.apcsb.2025.10.033}, pmid = {41904003}, issn = {1876-1631}, mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/pathology ; *Molecular Chaperones/metabolism ; Animals ; }, abstract = {Protein homeostasis is a critical aspect of cellular homeostasis as proteins are one of the most diverse biomolecules, responsible for multiple molecular and cellular functions. Protein quality control machinery is essential for maintaining integrity of cellular proteome via regulating its synthesis, structure, function, and degradation. Molecular chaperones are central to the protein quality control apparatus of cells and assist in folding nascent polypeptides, maturation, sequestration, solubilisation, and degradation of proteins. The coordination and cooperation between multiple cellular chaperones and other quality control elements, such as ubiquitin-proteasome system and autophagy, form a network, critical for proteostasis. Disturbed proteostasis and protein aggregation are hallmark features of neurodegenerative diseases. Re-establishing cellular proteostasis and enhancing chaperones' levels and functions can alleviate protein aggregation and associated cytotoxicity. Here, we have explored the potential of abundant cellular chaperone Hsp90, large chaperone Hsp110, small chaperone Hsp27, and anti-oxidant and mitoprotective chaperone DJ-1 in the regulation of proteostasis, with implications for neurodegenerative diseases, Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. We have focused on roles and mechanisms of function of these chaperones in countering disturbed proteostasis in neurodegenerative disorders.}, }
@article {pmid41904009, year = {2026}, author = {Chinnathambi, S and Malik, S}, title = {Cytoskeltal intermediate filaments in Tau pathology and neurodegeneration.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {351-376}, doi = {10.1016/bs.apcsb.2025.10.028}, pmid = {41904009}, issn = {1876-1631}, mesh = {Humans ; *Intermediate Filaments/metabolism/pathology ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Cytoskeleton/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Intermediate Filament Proteins/metabolism ; }, abstract = {Intermediate filaments are cytoskeletal proteins that are vital for proper cell structure formation and functioning. There are six types of these proteins. Type I includes acidic keratins, Type II includes basic and neutral keratins, both of which are present in epithelial cells. Type III includes vimentin, desmin, glial fibrillary acidic protein and peripherin, among which the last two are highly involved in neurodegenerative diseases. Type IV includes three types of neurofilament proteins, NF-L, NF-M and NF-H, where L signifies light, M signifies medium and H signifies heavy. The fourth protein in this category is α-internexin. All of these proteins are highly involved in neurodegenerative diseases, especially the neurofilament proteins. The type V intermediate filament proteins are lamins. The type VI intermediate filaments are nestins. Their involvement in a variety of neurodegenerative diseases has been observed, including Alzheimer's disease, Cerebral Ischemia, Multiple Sclerosis, Alexander Disease, Neuronal IF inclusion disease (NIFID) and Amyotrophic Lateral Sclerosis (ALS). Alzheimer's disease is a neurodegenerative disease in which two proteins are mainly involved, the Tau protein and the Amyloid-β protein. This review discusses the crosstalk of the intermediate filament proteins with the pathological proteins involved in the neurodegenerative diseases. For the case of the Alzheimer's disease, many of the intermediate filament proteins are involved in the disease pathology and are vital markers for the disease. One of the category of proteins involved is neurofilaments, among which NF-L is a marker for the disease. Keratin 9 and the glial fibrillary acidic protein (GFAP) are other intermediate filament proteins that are being explored as markers for the Alzheimer's disease.}, }
@article {pmid41904011, year = {2026}, author = {Selvaraj, C and Desai, D and Sumitha, E}, title = {The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.}, journal = {Advances in protein chemistry and structural biology}, volume = {150}, number = {}, pages = {397-422}, doi = {10.1016/bs.apcsb.2025.10.026}, pmid = {41904011}, issn = {1876-1631}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Cytoskeletal Proteins/metabolism/genetics/antagonists &amp; inhibitors ; Animals ; *Neurons/metabolism/pathology ; Cytoskeleton/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.}, }
@article {pmid41904090, year = {2026}, author = {Haidar, M and Viden, A and Daniel, C and Cuic, B and Wang, T and Rosier, M and Tomas, D and Mills, SA and Govier-Cole, A and Djouma, E and Perera, ND and Luikinga, S and Rytova, V and Barton, SK and Gonsalvez, DG and Palmer, LM and McLean, C and Kiernan, MC and Vucic, S and Turner, BJ}, title = {Corrigendum to "Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice"[Prog. Neurobiol. 252 (2025) 102809].}, journal = {Progress in neurobiology}, volume = {}, number = {}, pages = {102910}, doi = {10.1016/j.pneurobio.2026.102910}, pmid = {41904090}, issn = {1873-5118}, }
@article {pmid41904598, year = {2026}, author = {Amholt, TT and Kurtzhals, M and Melby, P and Bølling, M and Møller, OM and Lise, MK and Stage, A and O'Brien, W and Belton, S and Elsborg, P and Nielsen, G and Bentsen, P}, title = {Feasibility of the Promoting Pupils' Physical Literacy (3PL) intervention: Does it work? Will it work?.}, journal = {Pilot and feasibility studies}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40814-026-01806-w}, pmid = {41904598}, issn = {2055-5784}, support = {153181//TrygFonden/ ; }, abstract = {BACKGROUND: The rise in physical inactivity among children poses serious health risks impacting physical, mental, and social well-being. Physical literacy (PL) has been identified as an effective approach to encourage long-term physical engagement. Schools and communities, particularly through physical education (PE) programs, play a critical role in promoting PL. However, while there are several PL-focused PE interventions worldwide, no such programs have been specifically tailored to Nordic contexts, making feasibility testing essential for effective implementation. This study investigated the feasibility of a Danish adaptation of an Irish PL program, Y-PATH.<br><br>METHODS: The adapted program, the Promoting Pupils' Physical Literacy (3PL) intervention, provided PE teachers with resources, courses, and a website to enhance motivational climates in PE and promote PL among 4th and 5th grade pupils. The study was conducted in accordance with Medical Research Council guidelines and Bowen et al.'s (2009) framework. Feasibility indicators including acceptability, demand, implementation, practicality, adaptation, and integration were investigated using a weekly questionnaire for PE teachers, interviews (n&#x2009;=&#x2009;four teachers and 20 pupils), observations, and field notes. The quantitative data were analyzed descriptively, while the qualitative data were analyzed using thematic analyses.<br><br>RESULTS: 3PL was found to be feasible and acceptable among pupils and teachers (e.g., materials were used in 71% of lessons). While the materials supported implementation for teachers, workload adjustments are needed. Teachers adapted lessons effectively, balancing an inclusive and motivating learning environment. Despite minor challenges, 3PL fostered engagement among pupils and teachers with potential for expansion.<br><br>CONCLUSION: 3PL represents a feasible and promising approach to promote PL in a Danish school setting. Feasibility testing demonstrated the potential for scaling 3PL, while recognizing that large-scale trials are needed to validate its broader impact.<br><br>TRIAL REGISTRATION: A protocol for adaptation of 3PL was published in Open Science Framework, registered in December 2022 (1). The 3PL study was preregistered at ClinicalTrials.gov (ID NCT05822024), April 2023, version 1 (https://classic.<br><br>CLINICALTRIALS: gov/ct2/show/NCT05822024), before enrolment. A study protocol was written before intervention start (August 2023) and hereafter officially published in January 2024 (2).}, }
@article {pmid41905172, year = {2026}, author = {Balaji, R and Joshi, H and Patel, BK}, title = {Elucidating the conformational dynamics of the mitochondrial localization signal, M3, of TDP-43 and accessing potential binders using molecular docking and simulation.}, journal = {Computational biology and chemistry}, volume = {123}, number = {}, pages = {109029}, doi = {10.1016/j.compbiolchem.2026.109029}, pmid = {41905172}, issn = {1476-928X}, abstract = {Aberrant mitochondrial localization of RNA/DNA-binding protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS), which may affect mitochondrial dynamics and contribute to neuronal toxicity. Inhibitors of the cytoplasmic aggregation of TDP-43 were reported previously, but their effect on the mitochondrial mislocalization of TDP-43 remains to be investigated. Three internal peptide sequences from TDP-43, M1, M3, and M5, were found to enable TDP-43's mitochondrial localization. The peptides carrying these sequences thwarted mitochondrial import of TDP-43 and rescued TDP-43-induced cytotoxicity to neurons. In the current study, we aimed to assess the repurposing potential of 2115 FDA-approved small molecules for binding to the M3 region of TDP-43 (aa: 146-150) through virtual screening. The M3 region is present in the RNA-recognition motif-1 (RRM-1); hence, multiple all-atom molecular dynamics (MD) simulations, with two different starting conformations, of the tandem RRM1-2 domains of TDP-43 in explicit solvent water were performed to understand the dynamics of the target M3 region. The analysis of the simulation trajectories suggests that the M3 region is relatively non-flexible and buried relative to the other regions of the tandem RRM1-2 domains. Cholecalciferol (Vitamin D3), as identified through virtual screening, consistently docked with the M3 region across various docking strategies, despite the region's poor accessibility in most conformations. Vitamin D3 also remained stably bound to the M3 region in most frames of four replica MD simulations, each of one microsecond. Taken together, our study proposes vitamin D3 as a potential binder to the M3 region, which may inhibit the pathogenic mitochondrial mislocalization of TDP-43.}, }
@article {pmid41905471, year = {2026}, author = {Kuiper, MM and Cuppers, L and Sewell-Green, A and Kruithof, WJ and Visser-Meily, JMA and Beelen, A}, title = {Criterion validity of equations as alternatives to reference standards for assessing body composition and energy expenditure in amyotrophic lateral sclerosis - a systematic literature review.}, journal = {Clinical nutrition ESPEN}, volume = {}, number = {}, pages = {103262}, doi = {10.1016/j.clnesp.2026.103262}, pmid = {41905471}, issn = {2405-4577}, abstract = {BACKGROUND &amp; AIM: People living with amyotrophic lateral sclerosis (ALS) are at high risk of malnutrition, making it essential to monitor their nutritional status through measurements of body composition and energy expenditure. However, validity of equations, as alternatives to reference standards for assessing these parameters in ALS, is unclear. This systematic review evaluates criterion validity of equations to estimate body composition and energy expenditure in ALS.<br><br>METHODS: Four electronic databases (EMBASE, MEDLINE, CINAHL and Cochrane) were systematically searched from inception until July 7[th], 2025. Studies were included if criterion validity of an instrument or method for estimating body composition or energy expenditure was examined in people diagnosed with ALS. Methodological quality was assessed using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) risk of bias checklist. Criterion validity was rated as sufficient (+), indeterminate (?) or insufficient (-) based on COSMIN criteria for good measurement properties. Results were qualitatively summarised.<br><br>RESULTS: Twelve studies were included: five evaluated the criterion validity of equations to estimate body composition using Bioelectrical Impedance Analysis (BIA) or anthropometry, and seven to estimate resting or total daily energy expenditure. No equation was rated as sufficient for criterion validity across studies.<br><br>CONCLUSION: Equations to estimate body composition and energy expenditure should be applied with caution, as no equation exhibited high criterion validity in ALS. ALS-specific equations require further validation, and ideally, new equations tailored to the unique physiological characteristics of ALS should be developed.<br><br>PROSPERO REGISTRATION NUMBER: CRD42024573509.}, }
@article {pmid41905645, year = {2026}, author = {Martín-Sánchez, FJ and Marcos Sastre, MC and Muñoz de Maya, E and Sánchez-Pinto Pinto, B and Trueba Vicente, &#xc1; and Artero Ortiz, J and Arribas Guerrero, J and Soto Vargas, N and García Sánchez, IM and Marco Martínez, J and , }, title = {Six months of experience at a specialized daytime care center for people with amyotrophic lateral sclerosis (ALS) in the Community of Madrid.}, journal = {Neurologia}, volume = {}, number = {}, pages = {502006}, doi = {10.1016/j.nrleng.2026.502006}, pmid = {41905645}, issn = {2173-5808}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to motor deterioration and a reduced quality of life. In the Community of Madrid, the ALS Network was established to improve patient care. In April 2024, the Specialized Day Care Centre for ALS (CEADELA) was inaugurated, complementing the care provided by the ALS Network. The aim of this study was to describe the experience of CEADELA during its first six months.<br><br>MATERIALS AND METHODS: A retrospective descriptive study was conducted on a cohort of CEADELA patients between April and October 2024. Clinical, functional, and therapeutic data were analyzed, along with overall satisfaction levels.<br><br>RESULTS: A total of 91 patients were included, with a mean age of 65.2 years (SD 11); of these, 59 (64.8%) were men. Most had spinal-onset ALS and were receiving treatment with riluzole. A significant increase was observed in the use of physiotherapy, speech therapy, and occupational therapy after referral to the centre. Functionality significantly declined over six months. The mortality rate was 12.1% (18.2% opted for assisted dying). Overall, 76 patients (83.5%) responded to the survey, with 100% reporting satisfaction or high satisfaction with the centre (80.2% very satisfied and 18.4% satisfied).<br><br>CONCLUSIONS: CEADELA has improved access to specialized therapies with a high level of satisfaction, although disease progression remains a challenge. The need to continue developing integrated, evidence-based care models to optimize ALS management is highlighted.}, }
@article {pmid41895273, year = {2026}, author = {Kim, D and Kondo, T and Inoue, H}, title = {Dissecting microglial contributions to neurodegenerative disease pathophysiology using human pluripotent stem cells.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102866}, doi = {10.1016/j.stemcr.2026.102866}, pmid = {41895273}, issn = {2213-6711}, abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss. Microglia, the brain's resident macrophages, are key contributors to disease pathogenesis, with many genetic risk variants enriched in microglia-specific genes. While rodent models have provided valuable insights, human induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) technologies now enable the generation of human microglia-like cells, offering a physiologically relevant platform to study human microglial biology. This review discusses the developmental origins and functions of microglia, current differentiation approaches, and how these models help elucidate disease-relevant phenotypes and molecular mechanisms in neurodegeneration.}, }
@article {pmid41895675, year = {2026}, author = {Barthes, R and Niérat, MC and Rivals, I and Gatignol, P and Raux, M and Faure, M and Bruneteau, G and Serresse, L and Morélot-Panzini, C and Similowski, T}, title = {Association between dyspnea and cognitive task performance in amyotrophic lateral sclerosis: an exploratory study.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {}, number = {}, pages = {104566}, doi = {10.1016/j.resp.2026.104566}, pmid = {41895675}, issn = {1878-1519}, abstract = {Dyspnea is a major sensory and emotional burden in patients with chronic respiratory insufficiency. While experimentally induced acute dyspnea has been shown to interfere with cognition in healthy participants, interferences between cognition and chronic clinical dyspnea have not been studied. We conducted an exploratory study to examine the association between dyspnea severity and cognitive performance in patients with amyotrophic lateral sclerosis (ALS) and chronic respiratory failure. Twenty patients were studied during unassisted breathing and during non-invasive ventilation (NIV). Dyspnea was assessed using the Multidimensional Dyspnea Profile, and cognitive performance was evaluated using the Paced Auditory Serial Addition Test (PASAT) and the Corsi block-tapping test. Respiratory-related cortical activity was assessed using electroencephalography. Linear mixed-effects models were used to examine associations between dyspnea descriptors and cognitive outcomes, adjusting for age, educational level, and disease severity. NIV markedly relieved dyspnea, anxiety, and respiratory-related cortical activity but was not associated with changes in cognitive performance. Dyspnea unpleasantness was independently associated with longer PASAT response time, whereas no associations were observed with PASAT accuracy measures or Corsi test outcomes. Neither ventilation condition nor respiratory-related cortical activity was associated with cognitive performance. These findings suggest that, in patients with ALS, dyspnea unpleasantness may be associated with slower PASAT response time without detectable relationships with other cognitive measures assessed in this study. Given the exploratory and focal nature of the study, further investigations are warranted to better characterize dyspnea-cognition interactions in this population.}, }
@article {pmid41896845, year = {2026}, author = {Chang, J and Lipscombe, H and Lv, J and McCombe, PA and Henderson, RD and Ngo, ST and Steyn, FJ and Shaw, TB}, title = {White matter changes in reward circuits of amyotrophic lateral sclerosis: a fixel-based study of appetite loss.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04763-6}, pmid = {41896845}, issn = {1741-7015}, support = {UQ Graduate School Scholarship (RTP)//University of Queensland/ ; Scott Sullivan MND Research Fellowship//University of Queensland/ ; Faculty of Medicine//University of Queensland/ ; TU2201//Motor Neurone Disease Research Australia/ ; PDF2112//Motor Neurone Disease Research Australia/ ; Scott Sullivan MND Research Fellowship//Royal Brisbane and Women's Hospital Foundation/ ; Scott Sullivan MND Research Fellowship//MND and Me Foundation/ ; Scott Sullivan MND Research Fellowship//FightMND/ ; Collaborative Initiative Grant//FightMND/ ; 2017-07//Wesley Medical Research/ ; APP2029871//National Health and Medical Research Council/ ; }, abstract = {BACKGROUND: Non-motor symptoms such as appetite loss contribute to weight and fat mass reduction in people living with Amyotrophic Lateral Sclerosis (plwALS), both of which are strong prognostic factors in the disease. Consequently, understanding the neural mechanisms underlying appetite and other non-motor disturbances in ALS is of significant clinical concern. Previous studies highlight widespread grey and white matter involvement beyond the motor system, including hypothalamic volume loss and functional changes in reward-related regions. However, it remains unclear whether structural alterations in white matter tracts implicated in reward processing and behaviour contribute to the multisystem pathology of ALS.<br><br>METHODS: In this case-control study, we employ fixel-based analysis to examine changes in fibre characteristics of non-motor and motor tracts and their associations with clinical, anthropometric, and appetite-related measures within plwALS. Thirty-two plwALS and 24 non-neurodegenerative disease (NND) controls underwent multiband diffusion and structural imaging. Fixel-based analysis was conducted using MRtrix3 to model fibre pathways. For group-level statistical contrasts, fixels were generated in a common template space. We considered case-control differences, appetite, metabolism, body composition, and clinical measures.<br><br>RESULTS: Results reveal reductions in fibre density and cross-section in the corticospinal/corticobulbar and cerebellothalamic tracts. Exploratory analyses identified fibre density cross-section reductions throughout the temporo-ponto-cerebellar tract, the medial forebrain bundle, and the uncinate fasciculus. Though no direct associations were observed between fibre characteristics and measures of appetite or metabolism, we found significant correlation between fibre cross-section of the corticospinal/corticobulbar tracts and fat-free mass in NND controls, but not in plwALS. Furthermore, disease severity was associated with reduced fibre cross-section in the corticospinal/corticobulbar tract, medial forebrain bundle, uncinate fasciculus, and the temporopontine tract.<br><br>CONCLUSIONS: These findings highlight white matter fibre alterations in both motor and non-motor circuits in ALS. Although direct associations with appetite and metabolism were not observed, the results provide evidence of structural degeneration within reward- and behaviour-related pathways. Taken together, these findings reinforce that ALS is not confined to motor pathways but represents a multisystem neurodegenerative disease with both motor and extra-motor network involvement, offering important insights for future research into disease mechanisms and therapeutic targets.}, }
@article {pmid41897327, year = {2026}, author = {Romano, R and Ruotolo, G and Perrone, F and Tomaselli, S and Mazzoni, M and Spataro, R and Conforti, FL and Rosati, J and Bucci, C}, title = {Selective Silencing of TDP-43 P. G376D Mutation Reverses Key Amyotrophic Lateral Sclerosis-Related Cellular Deficits.}, journal = {Biomolecules}, volume = {16}, number = {3}, pages = {}, doi = {10.3390/biom16030393}, pmid = {41897327}, issn = {2218-273X}, support = {PRIN2022 N. 2022XTM2S3//Ministero dell'universit&#xe0; e della ricerca/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; RNA, Small Interfering/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Mutation ; Oxidative Stress ; Cell Survival ; Lysosomes/metabolism ; Gene Silencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is currently no cure. Dominant mutations in the TARDBP gene are causative of ALS. In particular, the p. G376D substitution in TDP-43 causes familial ALS and it is associated with TDP-43 mislocalization in the cytosol, increased presence of cytoplasmic aggregates, and lysosomal and mitochondrial dysfunction. We previously designed a small interfering RNA (siRNA) that specifically targets and silences the mutant allele and we demonstrated that, in patient-derived fibroblasts, it can reduce TDP-43 aggregation, decrease oxidative stress, and improve cell viability. Here, we investigated the ability of this siRNA to revert some ALS-associated pathological phenotypes in motor neurons derived from induced pluripotent stem cells (iPSCs), as motor neurons are the primary cells affected in ALS. siRNA treatment reduced TDP-43 mislocalization, enhanced lysosomal function and cell viability, and decreased oxidative stress. These findings indicate that this allele-specific siRNA effectively reverses key ALS-related cellular deficits in motor neurons, representing a promising candidate for targeted therapy in patients carrying the TDP-43 G376D mutation.}, }
@article {pmid41898328, year = {2026}, author = {Nesci, S}, title = {Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/biomedicines14030682}, pmid = {41898328}, issn = {2227-9059}, abstract = {Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.}, }
@article {pmid41898412, year = {2026}, author = {Rakovskaya, A and Volkova, E and Pchitskaya, E}, title = {Neuronal Calcium Signaling and Cytoskeletal Dynamics in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {27}, number = {6}, pages = {}, doi = {10.3390/ijms27062550}, pmid = {41898412}, issn = {1422-0067}, support = {25-74-10019//Russian Science Foundation/ ; }, mesh = {Humans ; *Calcium Signaling ; *Cytoskeleton/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neurons/metabolism/pathology ; Calcium/metabolism ; }, abstract = {Neuronal function relies on the precise coordination between intracellular calcium (Ca[2+]) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium-cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca[2+]-dependent cytoskeletal remodeling governs long-term potentiation and depression, dendritic spine morphology, and presynaptic function, highlighting the functions of end-binding proteins, STIM (Stromal Interaction Molecule)/Orai-mediated store-operated calcium entry, and the spine apparatus. Disease-specific manifestations of cytoskeletal-calcium dysregulation are reviewed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies, and prion disorders. Finally, we evaluate emerging therapeutic strategies targeting calcium homeostasis, cytoskeletal dynamics, and their downstream effectors, including multi-target approaches.}, }
@article {pmid41898662, year = {2026}, author = {Katz, M and Robertson, T and Ngo, ST and Yarlagadda, S and Henderson, RD and McCombe, PA and Noakes, PG}, title = {Review of the Pathology of Muscle in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {6}, pages = {}, doi = {10.3390/ijms27062802}, pmid = {41898662}, issn = {1422-0067}, support = {DIS-202403-01216//Fight MND/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism ; Humans ; Animals ; *Muscle, Skeletal/pathology/metabolism ; Neuromuscular Junction/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Disease Models, Animal ; Biomarkers/metabolism ; }, abstract = {In amyotrophic lateral sclerosis (ALS), a central event is the withdrawal of the motor nerve terminal from its target muscle. Whether this defect is driven by faults in the motor neuron or faults that originate within the muscle remains an area of investigation. In this review, we focus on the pathological abnormalities that are found in skeletal muscle, focusing, when possible, on human ALS, with support from ALS animal models. We begin with an overview of skeletal muscle, including a review of muscle fiber type, motor units and the neuromuscular synapse. Next, we provide a description of the clinical and biomarker changes that occur in the muscles of patients with ALS. We provide an extensive account of the histopathological changes that are evident in ALS muscle, such as fiber type grouping, muscle inflammation, protein misfolding, mitochondrial dysfunction, and alterations in neuromuscular junctions and muscle satellite cells. Our review then concludes with an update of metabolic and molecular-genetic changes that are found in ALS muscle. The evidence shows that muscle can be an additional target for therapy in ALS, in combination with therapies targeting neurons and glia within the central nervous system (CNS).}, }
@article {pmid41899342, year = {2026}, author = {Hermann, M and Stoiber, A and Schmid, A and Hamp, T and Santos, AA and Grassmann, D and Krammel, M and Lintschinger, JM and Ulbing, S and Stria, A and Hafner, C}, title = {Relevance of Reversible Causes of Out-of-Hospital Cardiac Arrest: The "REBECCA" Interactive Checklist.}, journal = {Journal of clinical medicine}, volume = {15}, number = {6}, pages = {}, doi = {10.3390/jcm15062422}, pmid = {41899342}, issn = {2077-0383}, abstract = {Background/Objectives: Adequate cardiopulmonary resuscitation (CPR), defibrillation, and treatment of reversible causes are essential for improving the survival of patients suffering from out-of-hospital cardiac arrests (OHCAs). The Advanced Life Support (ALS) algorithm includes reversible causes for cardiac arrest. This study aimed to develop an interactive mobile checklist to identify reversible causes of OHCA (REBECCA) and evaluate their usability and usefulness among emergency physicians. Methods: This mixed-methods study was conducted at the Emergency Medical Service Vienna, Austria. All participants were emergency physicians from the Medical University of Vienna. An interactive mobile checklist was developed using a participatory design approach involving a focus group of 10 emergency physicians. Usability and applicability were assessed using structured questionnaires. Descriptive statistics were used to summarize participant characteristics and evaluation outcomes. Results: Among the included participants, 70% were specialists with a median prehospital experience of 2.0 (1.0-4.3) years. Although most participants were confident about their level of professional experience with OHCA, 85% still found the checklist to be helpful. The majority of the participants preferred the digital checklist over the paper-based checklist and appreciated its integration with the point-of-care ultrasound (POCUS) application. Although the participants did not communicate a significant need for further details on most causes, a small majority favored more information on intoxication and electrolyte disorders. Conclusions: The majority of the included emergency physicians found the REBECCA checklist helpful regardless of training level, whereas almost no physician needed further detailed information on the reversible causes. Our findings underscore the potential importance of future investigations aiming to reduce the cognitive load of emergency physicians during OHCA scenarios.}, }
@article {pmid41900026, year = {2026}, author = {Jamerlan, A and Hulme, J}, title = {Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {6}, pages = {}, doi = {10.3390/molecules31060924}, pmid = {41900026}, issn = {1420-3049}, support = {RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; RS-2021-NR060117//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Autophagy/drug effects ; *TDP-43 Proteinopathies/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; Oligonucleotides, Antisense/pharmacology ; Proteolysis ; }, abstract = {The cytoplasmic accumulation of TDP-43 aggregates remains a persistent pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The cell's natural clearance mechanisms, the Ubiquitin-Proteasome System (UPS) and the autophagy-lysosome pathway (ALP), are hypothesized to fail, at least in part, due to the sequestration of key components of these pathways by pathological TDP-43 species, thereby impairing autophagosome-lysosome fusion and lysosomal competence. Classical autophagic activators (e.g., rapamycin) can initiate upstream steps in the pathway but cannot address downstream flux bottlenecks, limiting their ability to restore effective TDP-43 clearance. This review revisits classical strategies and discusses newer approaches to modulate TDP-43 clearance, including transcription factor EB (TFEB) activators, proteolysis-targeting chimeras (PROTACs), and antisense oligonucleotides (ASOs). We propose that adopting multi-targeting strategies and developing better biomarkers are vital for clinical success.}, }
@article {pmid41900140, year = {2026}, author = {Krzymiński, K and Zadykowicz, B and Czechowska, J and Rudnicki-Velasquez, P and Serdiuk, I and Sieradzan, AK and Holec-Gąsior, L}, title = {Acridinium Chemiluminogenic Labels-Synthesis, Analytical Performance, and Mechanism of Light Generation-A Comparison in View of Biomedical Diagnostics.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {6}, pages = {}, doi = {10.3390/molecules31061041}, pmid = {41900140}, issn = {1420-3049}, support = {2011/03/D/ST4/02419//National Science Centre/ ; }, mesh = {*Acridines/chemistry/chemical synthesis ; Humans ; *Luminescent Measurements/methods ; Immunoassay/methods ; Luminescence ; Immunoglobulin G/chemistry ; }, abstract = {This paper presents the synthesis, physicochemical characterisation, and analytical applications of chemiluminescent (CL) labels based on acridinium salts (ALs) for biomedical diagnostics. These compounds emit light as a result of oxidative reactions and represent an established class of reagents widely employed in chemiluminescence immunochemical assays (CLIAs) today. A series of structurally differentiated acridinium labels (AL1-AL5) was synthesised applying mostly original synthetic routes and purified to chromatographic purity (>90%, RP-HPLC). The compounds, including a commercial product treated as a reference, were successfully conjugated to anti-human IgG, yielding stable immunochemical reagents suitable for immunoassays with CL detection. The chemiluminescence properties of the obtained labels and their protein conjugates were investigated in aqueous buffers and in the presence of surfactants. The emission profiles exhibited characteristic flash-type kinetics with emission maxima occurring within 0.15-0.25 s after reaction initiation. The presence of surfactants more or less significantly enhanced the emission intensity, with signal increases of up to approx. 2-fold compared to surfactant-free systems. Analytical calibration demonstrated a linear response of signal derived from native labels over at least one order of magnitude of concentration, with detection limits falling in the range of 10[-9]-10[-10] M, confirming the high sensitivity of the developed compounds. The experimental results were supported by theoretical studies using density functional theory (DFT), which confirmed the energetic feasibility of the CL reaction pathway and identified structural factors influencing activation barriers. Additional semiempirical calculations (PM7) indicated that the dielectric environment and proximity of ionic species can influence the reaction energetics, providing mechanistic support for the experimentally observed effects of surfactants. The results demonstrate that both molecular structure and microenvironment influence CL efficiency and kinetics of the investigated systems. The developed acridinium labels exhibit analytical performance better or comparable to commercial reagents and are fully compatible with standard immunodiagnostic conjugation protocols, confirming their suitability for use in modern chemiluminescent immunoassays.}, }
@article {pmid41900340, year = {2026}, author = {Iungin, O and Potters, G and Kalinichenko, O and Prekrasna-Kviatkovska, Y and Moshynets, O and Kazakov-Kravchenko, O and Sidorenko, M and Okhmat, O and Mickevičius, S}, title = {Temperature-Dependent Biofilm Development in Antarctic Endophytic Microbial Communities.}, journal = {Microorganisms}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/microorganisms14030580}, pmid = {41900340}, issn = {2076-2607}, support = {0124U003829//National Antarctic Scientific Center of Ukraine/ ; 0125U003135//National Antarctic Scientific Center of Ukraine/ ; 984834//NATO SPS/ ; }, abstract = {Climate change is reshaping Antarctic ecosystems, where the resilience of Deschampsia antarctica and Colobanthus quitensis is mediated by endophytic microbial communities assembled under strong abiotic drivers. This study explores the temperature-dependent biofilm development in two Antarctic endophytic microbial communities (ALS and LS). Multivariate analysis revealed a fundamental trade-off between planktonic expansion and biofilm matrix investment as a function of thermal cues. While moderate warming (15-25 °C) optimized cell viability and turbidity, extreme thermal stress at 37-42 °C in nutrient-rich conditions triggered a significant shift toward a matrix-rich signature, characterized by a synergistic increase in total DNA and cellulose. Crucially, at the thermal extreme of 42 °C, we observed a decoupling of optical density from culturable biomass, where high turbidity did not translate into viable cells, signaling a state of severe environmental stress. These results identify 25 °C as the quantitative threshold for optimal growth, while temperatures of 37-42 °C act as a specific trigger for protective matrix production. Such thermal plasticity suggests that Antarctic endophytes are evolutionarily primed for persistence not only in cold native niches but also during bird-mediated dispersal at endothermic host temperatures.}, }
@article {pmid41900568, year = {2026}, author = {Kostadinova-Slaveva, A and Savov, V and Antov, P and Malcheva, B and Todorova, E and Yusein, J and Dudeva, V and Ivanov, G}, title = {Aesthetic Profiling and Exploratory Composting Screening of Wood-Fiber Biocomposites Bonded with Spent Coffee Grounds and Ammonium Lignosulfonate.}, journal = {Materials (Basel, Switzerland)}, volume = {19}, number = {6}, pages = {}, doi = {10.3390/ma19061077}, pmid = {41900568}, issn = {1996-1944}, support = {BG16RFPR002-1.014-0015//European Regional Development Fund through Bulgarian Programme "Research, Innovation and Digitalisation for Smart Transformation"/ ; }, abstract = {Spent coffee grounds (SCGs) and lignin-derived binders, such as ammonium lignosulfonate (ALS), are increasingly being explored as renewable resources to reduce reliance on conventional formaldehyde-based resins in wood-fiber biocomposites. Although prior work has shown that SCG-ALS adhesive systems can achieve promising mechanical performance, two practical aspects essential for industrial applications and circular design remain insufficiently explored: a predictable and reproducible visual appearance and credible end-of-life options. In this study, sustainable wood-fiber biocomposites bonded with SCG and ALS were assessed from an aesthetic performance and end-of-life perspective. Color was quantified in the CIE L*a*b* (CIELAB) space and expressed as total color difference (ΔE*) relative to a reference panel. Increasing total SCG + ALS content from 40 to 75 wt.% based on oven-dry fibers produced pronounced darkening, with lightness decreasing from L* = 47.1 to 34.3 and ΔE* increasing from 18.38 to 32.51. Short-term composting behavior was explored by embedding fragments from formulations with 40-60 wt.% total SCG + ALS (based on oven-dry fibers; equal SCG/ALS shares) into a mixed organic substrate adjusted to an initial C/N ≈ 30 and monitored for 30 days in pots and trays. The process remained predominantly mesophilic (≈14-22 °C); nevertheless, visible microbial colonization and progressive surface degradation were observed, indicating susceptibility to biological activity under moist, nutrient-rich conditions. Overall, the results show that SCG-ALS content strongly governs the visual identity of the biocomposites and suggest composting-oriented routes as a potential end-of-life direction at an exploratory level, while highlighting the need for standardized compostability assessment and longer-term monitoring to substantiate circularity claims.}, }
@article {pmid41900684, year = {2026}, author = {Pigato, M and Agresti, F and Benato, A and Bucci, C and Calliari, I and Cortis, D and D'Eramo, S and Fu, S and Giancarli, C and Pezzato, L and Zambon, A and D'Addabbo, A}, title = {Microstructural and Mechanical Characterization of Ultra-Pure Aluminum for Low-Amplitude-Vibration Cryogenic Applications.}, journal = {Materials (Basel, Switzerland)}, volume = {19}, number = {6}, pages = {}, doi = {10.3390/ma19061195}, pmid = {41900684}, issn = {1996-1944}, support = {2022KRKM2X//Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale/ ; }, abstract = {In fundamental physics, sensors operating below liquid helium temperatures are highly vulnerable to vibrations, which can affect the sensitivity, for example, of high-performance particle detectors. Pulse-tube refrigerators, while generating vibrations lower than those of conventional systems, may still introduce several disturbances. Hence, flexible thermal connections are a commonly used mechanical solution to mitigate these undesirable effects. Among the materials that can be used, ultra-high-purity aluminum (UHP-Al) has attracted the attention for low-amplitude-vibration cryogenic applications, including gravitational wave interferometry, quantum information systems, precision space instrumentation, and cryogenic resonators. Thus, the aim of the paper is the characterization of the mechanical and microstructure properties of three UHP-Als (i.e., 5N-99.999 wt%, 5N5-99.9995 wt% and 6N-99.9999 wt%) intended for the production of thermal flexible connections with low stiffness, specifically designed to reduce vibration transmission in cryogenic environments. Mechanical properties were evaluated through standard tensile tests from room (+25 °C) to low temperature (i.e., -150 °C), providing insights into yield strength, ultimate tensile strength, elongation and elastic modulus. In addition, the dynamic elastic modulus of material loads, at cryogenic conditions (i.e., about -180 °C), was determined by measuring the natural resonance frequency, thereby assessing the material's response to vibrational. Moreover, an extensive microstructural analysis was conducted using electron backscatter diffraction and x-ray diffraction. The correlation between the observed microstructure and the elastic properties was systematically examined. The results underscore the pivotal role of microstructural characteristics in dictating the elastic behavior of UHP Als. Eventually, the analysis provides valuable guidelines for the materials employment inside cryogenic systems, where severe vibration control is critical to maintain high operational performance.}, }
@article {pmid41885638, year = {2026}, author = {Sadhukhan, A and Chauhan, A and Kumar, M and Singh, TG and Mujwar, S and Awasthi, A}, title = {Cryptoxanthin as a multitarget neuroprotective agent: mechanistic and in silico perspectives.}, journal = {The Journal of pharmacy and pharmacology}, volume = {78}, number = {3}, pages = {}, doi = {10.1093/jpp/rgag029}, pmid = {41885638}, issn = {2042-7158}, mesh = {*Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Xanthophylls/pharmacology/therapeutic use ; Animals ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Computer Simulation ; }, abstract = {OBJECTIVES: Neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS) are complex disorders driven by multiple pathological processes, including oxidative stress, mitochondrial dysfunction, protein misfolding, and neuroinflammation. Due to this multifactorial nature, there is a growing interest in identifying natural compounds with multi-targeted neuroprotective properties. This review aims to evaluate the therapeutic potential of β-cryptoxanthin, a naturally occurring xanthophyll carotenoid, as a candidate molecule for mitigating neurodegenerative diseases.<br><br>METHODS: A comprehensive literature review was conducted to examine the neuroprotective mechanisms of &#x3b2;-cryptoxanthin, focusing on its antioxidant, anti-inflammatory, and immunomodulatory properties. In addition, in silico molecular docking studies were performed using AutoDock Vina to investigate the binding interactions of &#x3b2;-cryptoxanthin with key molecular targets associated with inflammation and neurodegenerative pathways.<br><br>KEY FINDINGS: &#x3b2;-Cryptoxanthin demonstrated strong neuroprotective potential due to its ability to scavenge reactive oxygen species (ROS) and modulate key molecular pathways involved in neuroinflammation and oxidative damage. Structurally characterized by a hydroxylated &#x3b2;-carotene backbone with 11 conjugated double bonds, &#x3b2;-cryptoxanthin showed favorable binding affinities with several inflammation- and neurodegeneration-related targets, including COX-2 (-11.6 kcal/mol), PI3K (-9.6 kcal/mol), mTOR1 (-9.2 kcal/mol), and GSK-3&#x3b2; (-8.7 kcal/mol). Additionally, interactions with JAK2, MAPK1, NF-&#x3ba;B, NRF2, and TLR4 suggest its involvement in regulating neuroimmune signalling pathways and inflammatory mediators.<br><br>CONCLUSIONS: The findings of this review highlight &#x3b2;-cryptoxanthin as a promising candidate for future neurotherapeutic investigation due to its multi-targeted mechanisms of action against key pathways implicated in neurodegeneration. Molecular docking results support its potential mechanistic role in modulating inflammation- and oxidative stress-related targets. However, these findings represent mechanistic plausibility rather than confirmed clinical efficacy, and further validation through preclinical and clinical studies is required.}, }
@article {pmid41885937, year = {2026}, author = {Akiyama, T and Zeng, Y and Guo, C and Gautier, O and Koepke, L and Lyons, H and Molotsky, E and Bombosch, JS and Sianto, O and Ross, JP and Hoang, P and Zhao, L and Spencer, C and Sumner, CJ and Monje, M and Day, JW and Gitler, AD}, title = {KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.197941}, pmid = {41885937}, issn = {2379-3708}, abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.}, }
@article {pmid41888300, year = {2026}, author = {Sanchez-Mico, MV and Calvo-Rodriguez, M and Bacskai, BJ}, title = {Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.}, journal = {Nature reviews. Neuroscience}, volume = {}, number = {}, pages = {}, pmid = {41888300}, issn = {1471-0048}, abstract = {Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca[2+] dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca[2+] signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca[2+] alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca[2+] homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca[2+] signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.}, }
@article {pmid41888437, year = {2026}, author = {McLellan, C and Campos-Melo, D and Hammond, R and Strong, MJ}, title = {Preservation of miR-9-5p and miR-124-3p in ALS-resistant oculomotor neurons contrasts with their downregulation in vulnerable spinal motor neurons, irrespective of TDP-43 pathology.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41888437}, issn = {1432-0533}, support = {201806SOP-411481/CAPMC/CIHR/Canada ; }, mesh = {*MicroRNAs/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; Humans ; Male ; Middle Aged ; Female ; Down-Regulation ; *DNA-Binding Proteins/metabolism ; Aged ; *Spinal Cord/pathology/metabolism ; Adult ; }, abstract = {Selective vulnerability of motor neurons is a defining feature of amyotrophic lateral sclerosis (ALS) and provides a valuable framework for uncovering mechanisms that distinguish resilient from vulnerable neuronal populations. We investigated whether dysregulation of neuroprotective microRNAs (miRNAs), miR-9-5p and miR-124-3p, contributes to the differential susceptibility of motor neuron subtypes. We focused on cervical spinal motor neurons (SMNs), which undergo drastic degeneration in ALS, and oculomotor neurons (OMNs), which remain functionally intact and rarely degenerate, allowing preservation of eye movement in ALS patients. Using a modified multiplexed fluorescent in situ hybridization protocol combined with immunofluorescence, we quantified the expression of miR-9-5p and miR-124-3p in cervical SMNs and OMNs from ALS and control cases. We observed significant downregulation of both miRNAs in ALS SMNs, while their expression was maintained in ALS OMNs. Stratification of ALS SMNs by TDP-43 pathological status revealed similarly reduced miRNA expression in neurons with and without cytoplasmic inclusions, suggesting that miRNA downregulation occurs independently of visible TDP-43 pathology. We assessed the localization of the Dicer cofactor TRBP and found that it colocalized with TDP-43 inclusions in ALS SMNs, suggesting that TRBP sequestration could prevent proper miRNA processing. However, TRBP remained normally localized in neurons without cytoplasmic inclusions, indicating that sequestration cannot fully account for miRNA reduction across all ALS motor neurons. These findings support a model in which early or subtle disruptions, preceding visible pathology, may also contribute to miRNA downregulation in ALS. By identifying preserved miRNA networks as correlates of oculomotor neuron resilience in ALS, this work also exposes new therapeutic targets potentially capable of reinstating miRNA expression and reprogramming vulnerable SMNs.}, }
@article {pmid41888964, year = {2026}, author = {Haddouali, K and Simma, K and Bellakhdar, S and El Otmani, H and El Moutawakil, B and Rafai, MA}, title = {Multifocal motor neuropathy secondary to gluten intolerance: a case report.}, journal = {Journal of medical case reports}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13256-026-05968-2}, pmid = {41888964}, issn = {1752-1947}, abstract = {BACKGROUND: Peripheral nervous system manifestations of gluten sensitivity usually present as distal symmetric axonal polyneuropathy, small fiber neuropathy, or sensory neuropathy, often accompanied by ataxia or painful symptoms. By contrast, motor neuropathies are extremely rare, with only a few cases of multifocal motor neuropathy reported. Notably, the most recent guidelines of the European Society for the Study of Coeliac Disease do not recognize multifocal motor neuropathy as a classical neurological manifestation of gluten-related disorders. The main differential diagnoses include amyotrophic lateral sclerosis and chronic inflammatory demyelinating polyneuropathy. Currently, strict adherence to a gluten-free diet remains the only therapeutic option. Although clinical improvement is not universal, when observed, it strongly supports the causal role of gluten-related neurotoxicity.<br><br>CASE PRESENTATION: We report the case of a 50-year-old North African man with a history of dermatitis herpetiformis and persistent chronic diarrhea. Over the past 5&#xa0;years, he developed progressive asymmetric motor weakness. Clinical examination revealed an asymmetric, pure motor, peripheral neurogenic syndrome, confirmed by nerve conduction studies, without evidence of proximal conduction block. Cerebrospinal fluid analysis showed elevated protein levels (0.75&#xa0;g/L), and serum anti-GD3 IgM antibodies were positive. Brachial plexus magnetic resonance imaging revealed bilateral hypertrophy on T1-weighted sequences, with hyperintensity on short tau inversion recovery sequences but no contrast enhancement. The motor deficit gradually improved after the introduction of a gluten-free diet. The patient also received intravenous immunoglobulin without significant clinical benefit. On the basis of clinical, paraclinical, and follow-up findings, a diagnosis of multifocal motor neuropathy secondary to gluten intolerance was established.<br><br>CONCLUSION: This case highlights the importance of considering gluten intolerance as a potential etiology, particularly given the reversible nature of this neuropathy, which can otherwise be misdiagnosed as a more severe condition such as amyotrophic lateral sclerosis. Further studies are needed to better elucidate the pathophysiology of this rare gluten-related neurological phenotype.}, }
@article {pmid41889878, year = {2026}, author = {Hines, TJ and Funke, JR and Pratt, SL and Rice, AD and Twiss, JL and Burgess, RW}, title = {A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.06.710113}, pmid = {41889878}, issn = {2692-8205}, abstract = {Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36 [Y1003N]) and alpha-tubulin 4A (Tuba4a [Q176P]) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6J mice, which confirmed the Tuba4a [Q176P] variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.}, }
@article {pmid41890126, year = {2026}, author = {Spence, H and Read, FL and Waldron, FM and Gregory, JM}, title = {Metabolic signatures of ferritin and TDP-43 co-pathology provide a mechanistic basis for stratified therapeutic approaches in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.03.13.711539}, pmid = {41890126}, issn = {2692-8205}, abstract = {BACKGROUND: ALS is increasingly recognized as a biologically heterogeneous disease in which several molecular and pathological mechanisms converge on a similar clinical phenotype. One of these molecular markers is ferritin accumulation which is observed in a subset of ALS cases and has been shown to directly correlate with TDP-43 pathology in some brain regions. Additionally, TDP-43 proteinopathy is observed outside of ALS which may complicate the interpretation of case vs control approaches to target discovery. Here, we propose a pathology-stratified approach to empower targeted theranostics. We hypothesised that biologically distinct ALS subtypes may be defined by specific metabolic dysfunction linked to brain-accumulated ferritin and TDP-43 pathology.<br><br>METHODS: Post-mortem primary motor cortex tissue from 15 ALS cases and 20 age- and sex-matched controls was stratified, using immunohistochemistry, by single- or co-occurrence of ferritin accumulation, and pathological TDP-43. Untargeted metabolomics (>1,000 metabolites) was performed, and samples were stratified into dual positive (ferritin and TDP-43), single positive (either), or negative. Group-discriminating metabolites were identified using partial least squares discriminant analysis.<br><br>RESULTS: Dual ferritin and TDP-43 pathology reflected a distinct metabolomic profile, separable from single-pathology states. This dual positive metabolic signature was characterised by disruption of lysophospholipid, lysoplasmalogen, and fatty acid metabolism, consistent with impaired membrane and energy homeostasis. In contrast, pathological TDP-43 presence without ferritin, was characterised metabolically by significant depletion of secondary bile acids and increase in glycosylation markers, whilst ferritin accumulation alone reflected significant increase in oxidative stress and depletion of lipid peroxidation inhibition markers. The dual positive state suggests failure of compensatory metabolic responses present in single-pathology conditions.<br><br>CONCLUSIONS: Ferritin accumulation and TDP-43 pathology define biologically distinct subtypes associated with ALS with divergent metabolic vulnerabilities. The metabolic signature associated with dual pathology provides a mechanistic correlate to MRI-visible ferritin accumulated iron, supporting paired non-invasive biomarker and target discovery for pathology-dependent patient stratification. These findings argue for pathway-targeted, subtype-specific therapeutic strategies and highlight the necessity of precision medicine approaches in ALS.<br><br>SHORT ABSTRACT: Amyotrophic lateral sclerosis (ALS) exhibits profound molecular heterogeneity that is not captured by current clinical classifications. Additionally, TDP-43 proteinopathy is observed outside of ALS which may complicate the interpretation of case vs control approaches to target discovery. Here, we propose a pathology-stratified approach to therapeutic target discovery, identifying convergent iron dysregulation and TDP-43 pathology with specific metabolic consequences. Post-mortem primary motor cortex tissue from 15 ALS cases and 20 controls was investigated for ferritin, and pathological TDP-43 using RNA aptamer-based immunostaining. Untargeted metabolomics (>1,000 metabolites) was performed with stratification into dual positive, single positive, or negative groups, followed by partial least squares discriminant analysis. Dual ferritin and TDP-43 pathology produced a distinct metabolic state characterised by disruption of lysophospholipid, lysoplasmalogen, and fatty acid metabolism, indicating impaired membrane integrity and energy homeostasis. In contrast, single positive states engaged divergent compensatory pathways involving bile acid metabolism, glycosylation, or oxidative stress regulation. Ferritin-TDP-43 convergence defines a metabolically decompensated ALS subtype corresponding to MRI signatures, providing a mechanistic basis for imaging-guided, pathology-dependent patient stratification and targeted intervention.<br><br>KEY FINDINGS: Metabolically distinct subtypes were defined by the presence or absence of ferritin-associated iron accumulation and TDP-43 pathology in the primary motor cortex.Concurrent ferritin and TDP-43 pathology produce a unique, metabolically decompensated state characterised by disrupted lipid, membrane, and energy metabolism, distinct from either pathology alone.Single positive states engage divergent compensatory metabolic pathways, which are lost when ferritin and TDP-43 co-occur.The metabolic signature of dual positivity provides a mechanistic correlate to the MRI-visible motor band sign.These findings support the use of pathology-based stratification of ALS patients and a foundation for pathway-targeted, precision therapeutic approaches.}, }
@article {pmid41890230, year = {2026}, author = {Aguerd, A and Nouadi, B and Ezaouine, A and Fenjar, I and Bennis, F and Chegdani, F}, title = {An in silico protocol for predicting genetic biomarkers in rare diseases: a case study in sporadic amyotrophic lateral sclerosis.}, journal = {Frontiers in genetics}, volume = {17}, number = {}, pages = {1742595}, pmid = {41890230}, issn = {1664-8021}, abstract = {Studying the genetics of rare diseases is challenging because small sample sizes limit the statistical power of standard methods like Genome-wide association studies (GWAS). We created a new machine-learning approach to find candidate Single Nucleotide Polymorphisms (SNPs) when data is scarce. Our method trains a Random Forest model to spot similarities between SNPs. We used 189 known Sporadic Amyotrophic Lateral Sclerosis (sALS)-linked SNPs as positive examples and 938,544 unrelated SNPs as negatives. The model learns from genomic location, significance levels, nearby genes, and other features. When we tested it on sALS, it performed exceptionally well, with 93.8% accuracy and near-perfect AUC scores. The method uncovered 1,890 new SNP candidates for sALS. Among these, 209 reached genome-wide significance, and 50 appeared repeatedly in our analyses, making them strong candidates. Key genes like SARM1, OPHN1, and BPTF emerged from the results, all connected to neural health and survival pathways. Our examination revealed a notable excess of SNPs on chromosome 18 compared to expectations. This non-random distribution underscores the region's particular interest. Here, our approach demonstrates its ability to extract meaningful signals from a restricted sample. The results generated by this approach enable early diagnosis of the disease under study, explanation of its mechanism, and identification of therapeutic targets.}, }
@article {pmid41890274, year = {2026}, author = {Silva-Hucha, S and Hernández, RG and Baena-López, D and Fernández de Sevilla, ME and Paradas, C and Morcuende, S}, title = {Excitotoxicity in amyotrophic lateral sclerosis: a key pathogenic mechanism.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag098}, pmid = {41890274}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a complex neurodegenerative disease affecting motor neurons, characterized by the involvement of various factors, including oxidative stress, inflammatory processes, glutamate excitotoxicity, mitochondrial dysfunction, protein aggregation, axonal transport abnormalities, and apoptosis. The complexity of amyotrophic lateral sclerosis arises from its multifactorial aetiology involving diverse genetic, protein, metabolic, and cellular alterations. Mutations of different genes, such as SOD1, C9ORF72, TARDBP, and FUS, have been identified as critical contributors to disease pathophysiology through their facilitation of aberrant protein misfolding and aggregation. All these factors disrupt glutamate homeostasis, leading to calcium-mediated neurotoxicity. Under oxidative stress, motor neurons exhibit a diminished capacity to regulate calcium influx, along with impaired functioning of the mitochondria and endoplasmic reticulum, further compromising cellular integrity. Dysregulation of glutamate signalling also triggers astrocytic stress responses, leading to reduced glutamate clearance, thus worsening neuronal damage through excitotoxic mechanisms. These factors contribute to the excessive production of reactive oxygen species, which exacerbates glutamate imbalance and establishes a detrimental cycle of neuronal damage and glial dysfunction, ultimately intensifying excitotoxicity. This review aims to highlight the role of excitotoxicity in motor neuronal degeneration and to explore the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis. It also examines current therapeutic approaches, including approved treatments and ongoing clinical trials to reduce excitotoxicity, while emphasizing the urgent need for novel, targeted strategies. Given the lack of definitive diagnostic tools and curative therapies, advancing our understanding of the molecular mechanisms driving excitotoxicity and neurodegeneration is, therefore, crucial for the development of more effective, disease-modifying treatments to slow amyotrophic lateral sclerosis progression.}, }
@article {pmid41890591, year = {2026}, author = {Gabbay, U}, title = {Axonal transport impairment as an upstream mechanism in amyotrophic lateral sclerosis pathogenesis.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1802313}, pmid = {41890591}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons. Despite marked genetic and pathological heterogeneity, a unifying pathogenic framework remains lacking. We propose that axonal transport impairment represents an early and convergent but genotype-modulated upstream vulnerability in ALS, contributing to distal synaptic failure, bioenergetic stress, protein aggregation, neuroinflammation, and neuronal death. Across many ALS models, including SOD1, TARDBP (TDP-43), FUS, and C9orf72, transport deficits are frequently detectable in presymptomatic stages, often preceding overt motor neuron loss or clinical manifestation, although temporal ordering varies by molecular subtype. Human data from induced pluripotent stem cell-derived motor neurons and neuroimaging in mutation carriers further support early transport dysfunction in both familial and sporadic ALS. We synthesize genetic, cellular, and systems-level evidence demonstrating that diverse ALS-associated mutations converge on intracellular trafficking machinery through distinct but interacting mechanisms, disrupting long-range cargo delivery and clearance in motor neurons. This framework provides a mechanistic basis for selective motor neuron vulnerability, the dying-back pattern of neuromuscular junction degeneration, and the emergence of downstream pathological hallmarks including mitochondrial dysfunction, excitotoxicity, aggregation, and inflammation. This model generates testable predictions regarding presymptomatic transport biomarkers and the timing of therapeutic intervention. We discuss implications for biomarker development and therapeutic strategy, proposing restoration of axonal transport as a central component of rational multimodal disease modification in ALS.}, }
@article {pmid41892827, year = {2026}, author = {Pérez-Bonilla, M and Mora-Ortiz, M and Díaz-Borrego, P and Muñoz-Alcaraz, MN and Mayordomo-Riera, FJ and Girela-López, E}, title = {Biomechanical Voice Parameters as Potential Biomarkers for Phenotype Differentiation in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, doi = {10.3390/medsci14010112}, pmid = {41892827}, issn = {2076-3271}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; Aged ; Biomechanical Phenomena ; Phenotype ; Biomarkers ; *Voice/physiology ; *Voice Disorders/physiopathology/diagnosis/etiology ; Adult ; Phonation/physiology ; }, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease in which bulbar involvement frequently affects speech and voice production. Although acoustic voice analysis can detect phonatory alterations in ALS, its ability to differentiate clinical phenotypes remains limited. This study investigated whether biomechanical voice parameters provide complementary information for characterizing bulbar involvement across bulbar-onset ALS (ALS-B) and spinal-onset ALS (ALS-S) and explored their association with clinical and functional measures. Methods: This cross-sectional observational study included 50 patients with ALS (20 ALS-B, 30 ALS-S) and 50 controls with non-neurological voice disorders. Sustained vowel phonation was analyzed using acoustic measures and biomechanical voice parameters derived from a standardized model of vocal fold vibration. Perceptual voice severity was assessed using the GRBAS scale, while functional status was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Barthel Index. Associations with clinical measures were explored in secondary analyses. Results: Compared with controls, ALS patients showed significant differences in acoustic measures and several biomechanical parameters related to glottal closure and vibratory stability. Biomechanical analysis revealed significant differences between ALS-B and ALS-S, particularly in parameters reflecting vibratory asymmetry, glottal tension and cycle-to-cycle instability. Unexpectedly, ALS-B showed greater perceptual voice severity and higher Barthel Index scores than ALS-S, while no differences were observed in global ALSFRS-R total scores. Conclusions: Biomechanical voice analysis appears to capture physiologically meaningful alterations in vocal fold function in ALS and provides complementary information for characterizing bulbar motor involvement across clinical phenotypes, particularly ALS-B disease. When combined with acoustic and clinical assessments, this approach may enhance the evaluation of bulbar involvement and functional status in ALS.}, }
@article {pmid41893050, year = {2026}, author = {Duranti, E and Villa, C}, title = {Misfolded Proteins and Cognitive Decline: Mechanistic Insights into Neurodegenerative Disorders.}, journal = {Neurology international}, volume = {18}, number = {3}, pages = {}, doi = {10.3390/neurolint18030048}, pmid = {41893050}, issn = {2035-8385}, abstract = {Cognitive decline represents one of the most common clinical manifestations of neurodegenerative diseases (NDs), substantially affecting the quality of life of both patients and their families. Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are major NDs characterized by a progressive degeneration of the central nervous system, with functional impairments extending beyond motor symptoms to multiple cognitive domains, including memory, attention, language, and executive functions. Increasing evidence highlights misfolded protein accumulation as a key driver of neuronal dysfunction and cognitive deterioration. This narrative review examines the major cognitive deficits associated with these disorders, focusing on the underlying molecular mechanisms, particularly protein aggregation, as well as clinical manifestations and their effects on daily life. Furthermore, current diagnostic tools and emerging therapeutic options for mitigating cognitive decline will be further discussed.}, }
@article {pmid41894152, year = {2026}, author = {Kutahyalioglu, NS and Onan, N}, title = {The Relationship Between Academic Literacy and Critical Thinking Disposition on Nursing Students.}, journal = {The Journal of nursing education}, volume = {}, number = {}, pages = {1-9}, doi = {10.3928/01484834-20260317-02}, pmid = {41894152}, issn = {1938-2421}, abstract = {BACKGROUND: Evidence-based nursing practice requires strong academic literacy (AL) and critical thinking (CT) skills, yet the link between these two competencies has not been adequately explored. This study aimed to assess nursing students' AL and CT levels and to examine the relationship between them.<br><br>METHOD: A descriptive and correlational design was used with 120 nursing students. Data was collected using a Socio-demographic Information Form, the Academic Literacy Scale (ALS), and the Critical Thinking Disposition Scale (CTDS), and analyzed through descriptive statistics and correlation analyses.<br><br>RESULTS: Students' mean ALS score was 86.54 (SD = 9.54), and the mean CTDS score was 3.85 (SD = 0.56). AL was strongly correlated with CT disposition (r = .641, p < .01). Regression analysis indicated that CT disposition explained 41% of the variance in AL (R[2] = .410).<br><br>CONCLUSION: Critical thinking significantly predicts academic literacy, underscoring the need for educational strategies that foster both skills.}, }
@article {pmid41894255, year = {2026}, author = {Hirata, Y and Kobatake, Y and Koyama, H and Furuta, K and Takemori, H and Kamatari, YO}, title = {Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00668}, pmid = {41894255}, issn = {1948-7193}, abstract = {Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to familial amyotrophic lateral sclerosis (ALS), yet the identity of the toxic molecular species remains unclear. We investigated the relationship between protein misfolding and pathogenicity by expressing GFP-tagged wild-type and mutant SOD1 (A4V, H46R, G93A) in mouse hippocampal HT22 cells. Western blotting under nonreducing conditions suggested that A4V, associated with rapid disease progression, was largely depleted of properly folded soluble SOD1 and instead produced highly destabilized soluble species. In contrast, H46R, associated with a milder phenotype, showed a moderate reduction in properly folded soluble SOD1 and generated partially folded/native-like conformers. G93A exhibited biochemical characteristics intermediate between those of A4V and H46R. A4V also showed a pronounced loss of GFP fluorescence, indicating severe structural destabilization; the extent of fluorescence loss in A4V, G93A, and H46R broadly correlated with clinical severity. Neither CuATSM nor ebselen─targeting metal binding and disulfide formation, respectively─rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates.}, }
@article {pmid41895196, year = {2026}, author = {Schmidlin, D and Thaysen, EM and Platikanov, S and Xu, J and Chesa, MJ and Tauler, R and Vázquez-Suñé, E and Teixidó, M}, title = {Impact of the superblock model on key components of the urban water cycle: Trace metals and dissolved organic matter dynamics across the built environment.}, journal = {Journal of hazardous materials}, volume = {508}, number = {}, pages = {141867}, doi = {10.1016/j.jhazmat.2026.141867}, pmid = {41895196}, issn = {1873-3336}, abstract = {Climate change, growing urban pollution, and increasing water scarcity are forcing cities to adopt strategies that enhance resilience to both climatic and anthropogenic pressures. The Barcelona Superblock model is a novel urban planning strategy that highly restricts vehicle traffic, converts streets into pedestrian-priority corridors, and promotes green spaces. Within this framework, green infrastructures, also called sustainable urban drainage systems (SUDS), are implemented as local, site-specific measures to capture (i.e., flood control), treat, and infiltrate treated stormwater (i.e., aquifer recharge). To evaluate the Superblock model impact on urban water quality, we conducted seven sampling campaigns across three Barcelona districts, targeting rainfall, stormwater "first-flush" from roads and pedestrianized streets, as well as SUDS influent and effluent within and in the vicinity to Superblocks, with a focus on dissolved trace metals and dissolved organic matter (DOM). Results showed that Superblocks reduced pollutant loads and mitigated ecotoxicological risks. Trace metal and DOM concentrations followed the trend: Rain < SUDS effluent < Pedestrian Street runoff < Road runoff, highlighting traffic-related impacts and SUDS treatment capacity (23-70% in best case scenario). Risk assessment indicated episodic ecotoxicological risk in stormwater, especially in road runoff due to elevated concentrations of Cu and Zn, while SUDS consistently remained below risk thresholds. SUDS also transform DOM into more stable, humic-like forms. Trace metals and DOM emerged as biogeochemical proxies for stormwater quality, enabling more effective and sustainable urban water management. These findings support the integration of Superblock-like strategies into urban planning to control and reduce contaminant urban discharges.}, }
@article {pmid41881396, year = {2026}, author = {Zhou, R and Lin, X and Lin, J and Liao, Z and Ni, H and Lin, X and He, Q and Ning, W}, title = {Cellular senescence in neurodegenerative diseases: a bibliometric analysis and mechanistic synthesis linking translational pathways to therapeutic implications.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103110}, doi = {10.1016/j.arr.2026.103110}, pmid = {41881396}, issn = {1872-9649}, abstract = {BACKGROUND: Cellular senescence is now recognized as a pivotal driver of neurodegenerative diseases (NDs). Despite advances in understanding senescence mechanisms, such as the p16[INK4A]/p53-p21[CIP1] pathways and the senescence-associated secretory phenotype (SASP), along with the development of therapeutic strategies like senotherapeutics, the research landscape remains fragmented.<br><br>OBJECTIVE: Systematically addresses the fragmentation characterizing current research on cellular senescence in NDs, integrating bibliometric analysis with a mechanistic synthesis of translational relevance and therapeutic implications.<br><br>METHODS: A comprehensive bibliometric analysis was performed. Literature retrieval on cellular senescence and four NDs (AD, PD, ALS, HD) was executed in Web of Science Core Collection (WoSCC) on April 30, 2025. CiteSpace V.6.4 R1 and VOSviewer 1.6.20 reconstructed networks for temporal trends, burst detection, and co-occurrence visualization. In addition to bibliometric mapping, we provide a mechanistic synthesis of emerging translational pathways.<br><br>RESULTS: Analysis included 269 relevant articles (2002-April 2025). Annual publications and cumulative citations increased markedly since 2018. The US led in output/influence, followed by China and Italy. Key collaborative institutions included Chinese Academy of Sciences, University of Texas System, and University of California System. Leading authors were Lorenz Studer, Judith Campisi, and Julie K. Andersen. Tyler J. Bussian and Peisu Zhang were highly co-cited. Top-cited journals were Nature, PNAS, and PLOS One. Research hotspots focus on abnormal tau protein in senescence and senescent microglia mediating chronic neuroinflammation, development of multi-target senomorphics targeting SASP is emerging as a promising therapeutic direction.<br><br>CONCLUSION: Cellular senescence research in NDs (notably AD, PD) shows broad promise from mechanisms to therapy. Future priorities include elucidating tau dysregulation's core role in senescence, developing specific biomarkers and targeted interventions. Senescent microglia are new therapeutic targets. Multi-target senomorphics modulating SASP offer new mechanisms for delaying ND progression. Understanding senescence mechanisms and precise interventions may provide novel ND therapies.}, }
@article {pmid41882018, year = {2026}, author = {Lin, J and Agote-Aran, A and Liao, Y and Cloarec, M and Andronov, L and Schoch, RL and Ronchi, P and Cochard, V and Zhu, R and Grandgirard, E and Liu, X and Lemée, MV and Kleiss, C and Golzio, C and Ruff, M and Chevreux, G and Schwab, Y and Klaholz, BP and Sumara, I}, title = {RanBP2-dependent annulate lamellae drive nuclear pore assembly and nuclear expansion.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71101-y}, pmid = {41882018}, issn = {2041-1723}, support = {ANR-22-CE13-0025//Agence Nationale de la Recherche (French National Research Agency)/ ; }, abstract = {Nuclear pore complexes (NPCs) enable nucleocytoplasmic transport. While NPCs primarily localize to the nuclear envelope (NE), they also appear in cytoplasmic endoplasmic reticulum (ER) membranes called annulate lamellae (AL). Though discovered in the mid-20th century, AL's function and biogenesis remain unclear. Previously considered exclusive to embryonic and malignant cells, we find AL in somatic mammalian cells. Under normal conditions, AL store pre-assembled AL-NPCs that integrate into the NE, producing approximately one-third of newly formed nuclear pores and supporting nuclear expansion during G1. Upon pathological stimuli, AL transfer to the NE is impaired, leading to their cytoplasmic accumulation. RanBP2 (Nup358) is essential for AL biogenesis, with its phenylalanine-glycine repeats promoting AL-NPC scaffold oligomerization. ER-associated Climp63 (CKAP4) directs AL-NPCs to ER sheets and the NE. This AL-driven nuclear pore formation is complementary to the canonical routes, constituting a distinct NPC assembly pathway. Our work uncovers the biogenesis mechanism of AL and the nuclear function of this key cellular organelle.}, }
@article {pmid41883703, year = {2026}, author = {Nassan, M and Ayala, I and Sloan, J and Bonfitto, A and Stark, B and Song, S and Naymik, M and Geula, C and Gefen, T and Barbieri, E and Piras, I and Mesulam, MM and Huentelman, M}, title = {The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.}, journal = {Neurology. Genetics}, volume = {12}, number = {2}, pages = {e200369}, pmid = {41883703}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Frontotemporal lobar degeneration TDP43 type C (TDP-C) is a rare and unique neurodegenerative disease that attacks the anterior temporal lobe. Recently, it was shown that Annexin-A11 and TDP-43 coaggregate specifically in TDP-C. Current literature on the genetic associations with TDP-C, reviewed here, lacks a discernible corpus of robust or replicated findings. In this study, using blood tissue, we completed whole genome sequencing to investigate ANXA11 and TARDBP genetic variants for their association with TDP-C. Then, we completed genome-wide hypothesis-free analyses using artificial intelligence to identify rare pathogenic variants associated with TDP-C.<br><br>METHODS: (1) We tested common variants in ANXA11 and TARDBP for their association with 37 TDP-C cases vs 290 controls. We attempted to replicate our findings in a different cohort of 467 TDP-C cases vs 3,153 controls and contrasted them with cohorts of TDP-A and TDP-B. (2) AI-guided analyses were completed to prioritize pathogenic rare variants associated with TDP-C in our cohort.<br><br>RESULTS: (1) Four common variants in ANXA11 (rs113772135, rs2789686, rs1079242, rs61860017) were significantly associated with TDP-C in the discovery cohort and replicated in the other cohort of TDP-C but not in TDP-A or TDP-B, providing evidence for ANXA11 specific association with TDP-C. Rs1079242-A showed the most robust replication (p = 7.35 &#xd7; 10[-05]) and correlates with higher ANXA11 level in CSF (p = 4 &#xd7; 10[-11]). No associations were found between TARDBP and TDP-C (p > 0.05). Using AI-guided rare variant analyses, we identified a pathogenic variant in FIG4, a gene that has been implicated in amyotrophic lateral sclerosis (ALS). Because of the observed potential genetic overlap between some ALS genes and TDP-C, we leveraged mendelian randomization and found that ALS genetic load is associated with TDP-C risk (p = 0.0046).<br><br>DISCUSSION: This study provides replicated evidence for the association between common variants in ANXA11 with TDP-C. Knowing rs1079242-A affects ANXA11 level in CSF, future studies may aim to investigate ANXA11 level as potential CSF biomarker for TDP-C. Moreover, FIG4 and ANXA11 have been implicated in the inositol pathway. Our results provide novel insights into the genetic risk of TDP-C and offer new clues about its underpinning mechanisms.}, }
@article {pmid41884057, year = {2026}, author = {Tannoury, C and Denwood, H and Khan, RR and Kyada, RJ and Zhou, OT and Atassi, S and Saade, A and Chahine, MN and Tannoury, T}, title = {Is the antepsoas oblique lumbosacral interbody fusion safe in patients with aortoiliac calcification?.}, journal = {North American Spine Society journal}, volume = {25}, number = {}, pages = {100867}, pmid = {41884057}, issn = {2666-5484}, abstract = {BACKGROUND: The anterior approaches to lumbar arthrodesis, including direct anterior (ALIF) and antepsoas (ATP)/oblique (OLIF) fusions, require careful manipulation of the abdominal prevertebral vessels for safe and adequate spinal access. Therefore, surgeons who perform anterior lumbar fusions in patients with aortoiliac calcifications are often cautious due to concerns for perioperative vascular complications, as well as the associated risks of concomitant medical comorbidities. This study sought to compare the incidence of perioperative vascular and medical complications in patients with and without abdominal aortoiliac calcification (AAC) undergoing the minimally invasive antepsoas (MIS-ATP) lumbosacral fusion.<br><br>METHODS: This was a retrospective matched cohort study including 482 adult patients undergoing MIS-ATP lumbosacral fusions at a single institution between 2014 and 2020 (227 with AAC and 255 without AAC), matched by sex and American Society of Anesthesiologists (ASA) scores. Through preoperative standing lateral lumbar radiographs, using Kaupilla et al.'s AAC grading system, we graded anterior and posterior aortic wall calcification from L1 to L4. Electronic medical records were reviewed to identify and collect the perioperative complications.<br><br>RESULTS: While there was no occurrence of intraoperative vascular injuries in either group, patients with AAC were more likely to develop medical complication (34.8% vs. 13.3%, p < .001), with anemia (18.9% vs. 9.2%), ileus (16.3% vs. 2.7%) and acute kidney injury (6.6% vs. 5.5%) being the most common. Overall, individuals with AAC had 2.62 times increased odds of developing a postoperative medical complication. Moreover, moderate AAC was found to be a significant risk factor (OR = 3.48).<br><br>CONCLUSIONS: Presence of AAC in patients undergoing MIS-ATP fusion was not associated with increased risk of direct surgical or exposure related vascular complications. However, patients with AAC were significantly more likely to experience medical complications following MIS-ATP fusion.}, }
@article {pmid41884172, year = {2026}, author = {Seki, S and Enomoto, A and Tanaka, S}, title = {The mesencephalic trigeminal neuron: electrophysiological insights into function and dysfunction.}, journal = {Frontiers in cellular neuroscience}, volume = {20}, number = {}, pages = {1752701}, pmid = {41884172}, issn = {1662-5102}, abstract = {Mesencephalic trigeminal neurons (MTNs) are the sole primary afferent neurons with cell bodies located within the central nervous system. MTNs convey proprioceptive inputs from masticatory muscles and periodontal ligaments, thereby contributing to the precise regulation of jaw-oral motor functions. Through ionic mechanisms such as currents generated by the voltage-dependent sodium (Nav) channel isoform Nav1.6, hyperpolarization-activated currents, and persistent inward currents, MTNs generate sustained and burst firing that regulate masticatory rhythm and jaw-jerk reflex timing. Their activity is further modulated by neurotransmitters, including serotonin and norepinephrine, which provide flexibility in sensorimotor integration. Pathological conditions such as chronic stress and sodium channel dysfunction induce MTN hyperexcitability or irregular firing, contributing to bruxism, temporomandibular disorders, and feeding impairment in amyotrophic lateral sclerosis models. In addition, aging and tooth loss lead to Piezo2 downregulation and neuronal death, potentially resulting in masticatory dysfunction and cognitive decline. Recent findings suggest that interventions targeting vesicular glutamate transporter 1 projections, melanocortin 4 receptor signaling, and nitric oxide pathways represent novel therapeutic approaches. Taken together, MTNs have emerged as promising targets for treating conditions ranging from masticatory motor disorders to neurodegenerative diseases.}, }
@article {pmid41884597, year = {2026}, author = {Milioto, C and Carcolé, M and Zanovello, M and Ahmed, M and Nirujogi, RS and Biggs, D and Roberts, MJ and Schweers, K and Cammack, AJ and Marchi, PM and Katona, E and Glaria, I and Santos, A and Devoy, A and Fratta, P and Alessi, DR and Davies, B and Greensmith, L and Fisher, EMC and Isaacs, AM}, title = {C9orf72 poly(glycine-alanine) knock-in mice exhibit mild rotarod and proteomic changes consistent with amyotrophic lateral sclerosis/frontotemporal dementia.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag087}, pmid = {41884597}, issn = {2632-1297}, abstract = {A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion is translated into five different dipeptide repeat proteins: poly(glycine-alanine) (polyGA), poly(glycine-proline) (polyGP), poly(glycine-arginine) (polyGR), poly(alanine-proline) (polyAP) and poly(proline-arginine) (polyPR). To investigate the effect of polyGA, which is the most abundant dipeptide repeat protein in patient brains, we used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated nuclease 9 (Cas9) to insert 400 codon-optimized polyGA repeats immediately downstream of the mouse C9orf72 start codon. This generated (GA)400 knock-in mice driven by the endogenous mouse C9orf72 promoter, coupled with heterozygous C9orf72 reduction. PolyGA remains soluble up to 18 months of age and (GA)400 mice develop subtle dysfunction characterized by impaired rotarod performance, without overt neuropathological alterations. Quantitative proteomics revealed polyGA expression caused protein alterations in the spinal cord, including changes in previously identified polyGA interactors. Our findings show that (GA)400 mice are a complementary in vivo model to better understand C9orf72 ALS/FTD pathology and determine the specific role of individual DPRs in disease.}, }
@article {pmid41884646, year = {2026}, author = {Sudwarts, A and Thinakaran, G}, title = {Female-specific Cx3cr1-driven regulation of ALS and Alzheimer's risk genes in tauopathy.}, journal = {Molecular neurodegeneration advances}, volume = {2}, number = {1}, pages = {16}, pmid = {41884646}, issn = {3059-4944}, abstract = {UNLABELLED: By introducing haploinsufficiency of Cx3cr1 in the P301S (PS19) transgenic model of tau pathology, we report remarkable transcriptional changes, including crucial amyotrophic lateral sclerosis and Alzheimer's disease risk genes, several of which showed co-expression, suggesting gene-gene interactions among these genetic risk factors.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00022-3.}, }
@article {pmid41884800, year = {2026}, author = {Nette, S and Purvis, JK and Helpard, H}, title = {Identifying Student Learning Challenges and Potential Solutions in Nursing Education Delivery in Rural Nova Scotia Using Photovoice.}, journal = {SAGE open nursing}, volume = {12}, number = {}, pages = {23779608251413674}, pmid = {41884800}, issn = {2377-9608}, abstract = {INTRODUCTION: Rural nursing programs encounter obstacles in providing nursing education opportunities relevant to the escalating needs of rural healthcare. Rural nursing programs often experience limited clinical placements, a stressed and burned-out rural nursing workforce, and difficulty finding nursing preceptors. Moreover, students studying in rural nursing programs experience increased travel, financial and social burden, and have less access to resources and support from their university. There is limited research giving voice to rural nursing students' experience and their suggestions for solutions.<br><br>OBJECTIVE: The purpose of this study was to understand the learning challenges of and potential solutions for baccalaureate nursing students attending a rural university.<br><br>METHODS: This is a descriptive qualitative study using photovoice methodology. Participants captured two pictures of things in their school surroundings or personal life that created learning challenges in rural nursing education, and two pictures of potential solutions to these challenges. Participants titled each picture and, using guided questions provided by the researcher, wrote a short reflection of what the photos represented.<br><br>RESULTS: Guided by empowerment education for critical consciousness and using Braun and Clarke's thematic analysis and Oliffe et al.'s layered photograph analysis, two overarching themes emerged: access to resources and clinical learning. Findings highlight financial, academic, and accessibility barriers in rural nursing programs as well as participant-determined solutions that could enhance learning experiences, student well-being, and retention in the rural healthcare workforce.<br><br>CONCLUSIONS: This study identified targeted resources for nursing students attending a rural nursing baccalaureate program to support their learning, wellbeing, and growth into graduate nurses. This study also identified areas for future research to explore nursing student experiences across rural and urban institutions and develop effective learning support strategies for rural nursing education.}, }
@article {pmid41885096, year = {2026}, author = {Wolfensberger, A and Faes Hesse, M and Sax, H and Clack, L}, title = {From plan to practice: a structured report on implementation strategies for preventing non-ventilator hospital-acquired pneumonia (nvHAP).}, journal = {Infection control and hospital epidemiology}, volume = {}, number = {}, pages = {1-9}, doi = {10.1017/ice.2026.10422}, pmid = {41885096}, issn = {1559-6834}, abstract = {BACKGROUND: There is increasing evidence on the effectiveness of prevention bundles against non-ventilator hospital-acquired pneumonia (nvHAP), but detailed reports on their implementation are lacking. This study aims to describe and structure the implementation activities undertaken in a single-center multimodal intervention that achieved a 31% reduction in nvHAP incidence.<br><br>DESIGN: Longitudinal descriptive qualitative study.<br><br>SETTING: Nine medical and surgical departments of a Swiss university hospital.<br><br>PARTICIPANTS: Healthcare professionals and implementation teams in study departments.<br><br>METHODS: We collected longitudinal data on implementation activities using (1) implementation activity logs, (2) drop-in interviews and observations, (3) "action plan meetings," (4) focus groups, and (5) unstructured recall sessions among the project team. Data were deductively coded using the "Expert Recommendations for Implementing Change" taxonomy, specified using Proctor et al.'s "Recommendations for specifying and reporting implementation strategies" and mapped to the "Exploration, Preparation, Implementation, Sustainment" framework phases.<br><br>RESULTS: A total of 174 activities were undertaken. Activities varied by implementation phase, most frequently involving "evaluative and iterative strategies," "develop stakeholder interrelationship strategies" and "training and education of stakeholders" during Exploration, Preparation, and Implementation, respectively. During Implementation, 54% of activities were initiated by department nurses, and 27% were initiated by the institutional implementation team. Activities included interdisciplinary kick-off events, education in various formats, posters, informational stickers for patients, provision of new equipment (e.g., toothbrushes), and electronic medical records order sets.<br><br>CONCLUSIONS: This report offers valuable insights for future implementation efforts by providing a structured overview of the concrete implementation activities performed in a successful one-hospital multimodal nvHAP prevention project.}, }
@article {pmid41885541, year = {2026}, author = {Chen, RF and Liu, KF and Lee, CC and Li, YT and Chen, WY and Kuo, YR}, title = {Transcriptomic Analysis of Adipose-Derived Stem Cell Therapy Modulating B Cell Immune Tolerance in Vascularized Composite Allotransplantation.}, journal = {Plastic and reconstructive surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/PRS.0000000000013074}, pmid = {41885541}, issn = {1529-4242}, abstract = {BACKGROUND: Adipose-derived stem cells (ADSCs) have been shown to prolong vascularized composite allotransplantation (VCA) survival in rodent hindlimb transplantation. However, the mechanisms by which ADSCs modulate B cell responses and induce immune tolerance remain unclear. This study used next-generation sequencing (NGS) to investigate B cell gene expression after ADSC treatment.<br><br>METHODS: A rodent orthotopic hind-limb transplantation model was established using Brown-Norway to Lewis rats. The tolerance treatment group received a combination of ADSCs, short-term cyclosporine A (CsA) and anti-lymphocyte serum (ALS), while the control rejection group received no treatment. B cells were isolated from the spleens of rejection control group at 10-14 days post-transplantation when rejection was diagnosed, or tolerance group at least &#x2265;100 days post-transplantation without rejection. RNA sequencing (RNA-Seq) was conducted to assess transcriptomic differences. Differentially expressed genes (DEGs) were analyzed using the EBSeq bioinformatics tool and pathway enrichment analyses, with validation by qPCR.<br><br>RESULTS: RNA-Seq identified 94 DEGs (out of 13,284 mRNAs) between the tolerance and rejection groups. Gene ontology and KEGG pathway analyses revealed significant enrichment in pathways associated with cytokine secretion, B cell receptor signaling, and humoral immunity. The tolerance group exhibited upregulation of key chemokines (e.g., Cxcl1, Cxcl2, Ccl4) and downregulation of pro-inflammatory genes (e.g., Tlr3, Siglec5, C3). qPCR validation confirmed the RNA-Seq findings. These results suggest that ADSCs modulate B cell-mediated immune responses and promote a shift toward an anti-inflammatory, tolerogenic profile.<br><br>CONCLUSIONS: ADSC-based therapy combined with short-term immunosuppression promotes immune tolerance in VCA by modulating B cell-related gene expression. These findings suggest that targeting B cell-mediated pathways may provide a novel approach may offer a novel therapeutic strategy for clinical application in VCA.}, }
@article {pmid41876403, year = {2026}, author = {Yan, K and Jiang, Y and Yong, Y and Zhang, T and Zhang, N and Zeng, Q and Gong, X and Meng, L and Bi, F and Liu, Y}, title = {ALDOA Promotes Glycolysis and NLRP3/GSDMD Pyroptosis to Accelerate ALS Progression.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70372}, pmid = {41876403}, issn = {2328-9503}, support = {81760238//National Natural Science Foundation of China/ ; 82171433//National Natural Science Foundation of China/ ; 2022JJ30918//Natural Science Foundation of Hunan Province/ ; 2023JJ30927//Natural Science Foundation of Hunan Province/ ; TSYC202401B119//Xinjiang Uygur Autonomous Region Health Commission "Tianshan Talent" High-Level Medical and Health Personnel Project/ ; 2025D01E38//Natural Science Foundation of Xinjiang Uygur Autonomous Region/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration. Glycolytic dysregulation is implicated in disease progression, yet the underlying mechanisms remain unclear. This study investigates how Aldolase A (ALDOA) drives ALS progression through glycolysis-mediated motor neuron pyroptosis.<br><br>METHODS: In vivo, tamoxifen-induced TDP-43 cKO mice were assessed for motor function (rotarod/suspension tests), motor cortex L-lactic acid, and ALDOA/NLRP3/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In&#xa0;vitro, TDP-43 KO NSC34 cells were used to measure viability, glucose uptake, and L-lactic acid.<br><br>RESULTS: ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L-lactic acid accumulation, and NLRP3/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3/GSDMD-mediated pyroptosis. In&#xa0;vitro, TDP-43-deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3/GSDMD pathway activation, and impaired proliferation.<br><br>CONCLUSION: We show that ALDOA-mediated glycolytic dysregulation activates the NLRP3/GSDMD inflammasome, leading to pyroptosis in motor neurons. Pharmacological inhibition of ALDOA alleviates glycolytic dysregulation and extends survival, identifying ALDOA as a potential therapeutic target.}, }
@article {pmid41877227, year = {2026}, author = {Estiar, MA and Yu, E and Varghaei, P and Ross, JP and Ashtiani, S and Bayne, AN and Coarelli, G and Timmann, D and Klockgether, T and Beijer, D and Mengel, D and Coutelier, M and ,  and Dion, PA and Suchowersky, O and Ewenczyk, C and Goizet, C and Stevanin, G and Van Damme, P and Al-Chalabi, A and Zuchner, S and Synofzik, M and Veldink, JH and Trempe, JF and Durr, A and Rouleau, GA and Gan-Or, Z}, title = {Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders.}, journal = {BMC medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12916-026-04805-z}, pmid = {41877227}, issn = {1741-7015}, abstract = {BACKGROUND: Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders.<br><br>METHODS: We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2.<br><br>RESULTS: Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement.<br><br>CONCLUSIONS: Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.}, }
@article {pmid41877246, year = {2026}, author = {Shen, R and Sung, K and Ding, J and Wu, C}, title = {Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {15}, number = {1}, pages = {}, pmid = {41877246}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/therapy ; *Axons/pathology ; Animals ; }, abstract = {Axons are unique structural and functional features of nerve cells, which play a critical role in regulating neuronal homeostasis. Dysfunction and degeneration of axons (axonopathy) has been established as an early and prominent contributing mechanism to the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we briefly summarize the structure and function of axons, and highlight recent advances in the understanding of the role of axons in health and disease. We argue that axons are a potential target for developing novel therapies for neurodegenerative diseases.}, }
@article {pmid41879495, year = {2026}, author = {Singh, K and Sethi, P and Jain, D and Gupta, JK and Alsaidan, OA and Alzarea, SI and Kumar, A and Tabish, M and Sharma, MC}, title = {Emerging Roles of Small-molecule Derivatives in Modulating Neurodegenerative Pathways: From Molecular Targets to Therapeutic Applications.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575429412260112060311}, pmid = {41879495}, issn = {1875-5607}, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease involve progressive neuronal dysfunction driven by mechanisms including protein aggregation, oxidative stress, mitochondrial impairment, and neuroinflammation. Current treatments are largely symptomatic, with limited disease-modifying options. Advances in medicinal chemistry have led to the development of small-molecule derivatives targeting specific pathological pathways, offering new therapeutic opportunities. This review summarizes recent progress in designing and optimizing such molecules to modulate amyloid-β metabolism, tau acetylation, α-synuclein aggregation, RNA-binding protein interactions, and NLRP3 inflammasome activation. Compounds acting on key signaling cascades, including PI3K/Akt, MAPK/ERK, Nrf2/ARE, and Wnt/β-catenin, are discussed, alongside drug repurposing strategies and preclinical-to-clinical translation. Special focus is given to microglial modulation, challenges in crossing the blood-brain barrier, and integration of precision medicine, metabolomics, and artificial intelligence into drug discovery. The review also highlights novel therapeutic concepts such as multi- target ligands, metal-chelation approaches, and modulation of neuroinflammatory pathways. Despite promising leads, significant challenges remain in optimizing pharmacokinetics, target selectivity, and delivery. Future directions include the identification of robust biomarkers, advanced imaging techniques, and computational tools to accelerate candidate validation. Collectively, smallmolecule therapeutics hold considerable promise in addressing unmet needs in neurodegenerative disease management, but their successful translation will require multidisciplinary approaches bridging molecular insights and clinical application.}, }
@article {pmid41880105, year = {2026}, author = {Ng, CA and Sousa, M and Patterson, T and Mulhern, B and Luckett, T}, title = {A qualitative study of cancer clinical trial network consumers' acceptability of the modular approach to patient-reported outcome measurement: how much of it is "common sense"?.}, journal = {Journal of patient-reported outcomes}, volume = {}, number = {}, pages = {}, doi = {10.1186/s41687-026-01045-w}, pmid = {41880105}, issn = {2509-8020}, abstract = {BACKGROUND: There is growing interest in customising patient-reported outcome measures (PROMs). This involves selecting specific domains (i.e., subscales) that focus on key health-related quality of life (HRQoL) issues most relevant to a particular study's context, referred to as the modular approach. Despite available recommendations from international stakeholders and PROM developers, the modular approach has not been widely adopted in cancer clinical trials. This qualitative study explored the acceptability of the modular approach to administering PROMs from the perspectives of cancer consumers.<br><br>METHODS: Consumers (patients, family members and/or caregivers) who have experience with cancer were recruited through cancer clinical trial networks in Australian and New Zealand. Data were collected through online focus groups. Interview probes and analysis were guided by Sekhon et al.'s Theoretical Framework of Acceptability.<br><br>RESULTS: Ten consumers, all with prior experience in clinical trial design, participated across four focus groups. The acceptability of the modular approach was discussed in reference to four themes: (1) minimising respondent burden is not simply about shortening PROMs; (2) competing priorities of reducing burden, preserving PROM measurement properties and assessing breadth versus depth of issues; (3) new strategies are needed to improve PROM relevance; and (4) who should select the domains, and how? Acceptable features of the modular approach included its potential to increase the relevance of questions, minimise duplication, and allow for more in-depth assessment of priority HRQoL issues. Participants also believed that involving consumer representatives in domain selection could alleviate the burden on researchers during trial design and were supportive of giving individual clinical trial patients the option to self-select domains that are personally meaningful.<br><br>CONCLUSIONS: Consumers were generally supportive of using the modular approach in administering PROMs in clinical trials, while also identifying ways to strengthen its acceptability. These included the need for clearer consensus and guidance on what constitutes a well-justified selection of domains and further personalisation of PROM domains (e.g., through branching questions). These insights can help inform regulatory agencies and other stakeholders about consumer needs and highlight the support needed if there is to be a paradigm shift in trial design towards tailored PROM administration.}, }
@article {pmid41871620, year = {2026}, author = {Silva, DJD and Silveira, SCD and Souza, LC and Cruzeiro, MM and Vale, TC}, title = {Clinical and Sociodemographic Profile of Familial Amyotrophic Lateral Sclerosis Type 8 Compared to the Sporadic Form.}, journal = {Arquivos de neuro-psiquiatria}, volume = {84}, number = {3}, pages = {1-8}, doi = {10.1055/s-0046-1817037}, pmid = {41871620}, issn = {1678-4227}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/genetics/physiopathology/classification ; Female ; Male ; Middle Aged ; Adult ; Brazil/epidemiology ; Aged ; Age of Onset ; Socioeconomic Factors ; Retrospective Studies ; Sociodemographic Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare degenerative disease of motor neurons, predominantly sporadic, with approximately 10% of the cases showing familial inheritance.To characterize the clinical and sociodemographic profile of patients with familial ALS type 8 (fALS8) and compare it with sporadic ALS (sALS).We reviewed the medical records (1997-2022) from a specialized Brazilian center. Patients with a confirmed diagnosis of ALSs were included, and sociodemographic and clinical data were collected.The sample was composed of 89 ALS patients, with a slight female predominance (53%) and a high frequency of fALS8 cases (45%). The fALS8 patients were diagnosed at a younger age, at approximately 50 years, compared to 53 years among the sALS patients (p = 0.043). Lower limb onset predominated in the fALS8 group (87%), while the sALS group showed more heterogeneous presentations, including bulbar onset (14%). The time until the diagnosis was significantly longer in the fALS8 group compared to the sALS group, both from symptom onset (approximately 51 versus 30 months respectively; p < 0.001) and after admission to a specialized center (7 versus 4 months respectively; p = 0.002). Dysphagia and gastrostomy were more frequent in the sALS group compared to the fALS8 group (p = 0.02 and p < 0.01 respectively), and older age at diagnosis was associated with worse functional scores.The fALS8 group presented with distinct clinical and demographic features compared to the sALS group, including younger age at diagnosis, more homogeneous symptom onset, and lower frequency of dysphagia and need for gastrostomy. The diagnosis was more delayed in the fALS8 group, and older age at diagnosis was associated with worse functional status. The current study contributes to the scarce data on fALS8 in South America.}, }
@article {pmid41872337, year = {2026}, author = {Croteau, E and Rousseau, E and Tremblay, S and Rousseau, JF and Espinosa-Betancourt, E and Lavallée, E and Dubreuil, S and Ait-Mohand, S and Lareau-Trudel, &#xc9; and Gosselin, S and Carrier, V and Côté-Bigras, S and Allard, C and Maier, M and Salzmann, M and Tétu, A and Houde, MP and Turcotte, &#xc9; and Guérin, B}, title = {A phase I study to evaluate the dosimetry and safety of [[89]Zr]Zr-DFO-AP-101, a new antibody-based radiopharmaceutical to detect misfolded SOD1 in amyotrophic lateral sclerosis.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {41872337}, issn = {1619-7089}, support = {Fonds d'acc&#xe9;l&#xe9;ration des collaborations en sant&#xe9; (FACS)//Minist&#xe8;re de la Sant&#xe9; et des Services sociaux/ ; }, }
@article {pmid41872984, year = {2026}, author = {Toomey, A and Kleinerova, J and Tan, EL and Siah, WF and Bede, P}, title = {Muscle MRI and Muscle Ultrasound Applications in MND/ALS: Academic Insights and Clinical Opportunities.}, journal = {European journal of neurology}, volume = {33}, number = {3}, pages = {e70582}, doi = {10.1111/ene.70582}, pmid = {41872984}, issn = {1468-1331}, support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND-2025"Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI-SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Ultrasonography/methods ; *Muscle, Skeletal/diagnostic imaging ; }, abstract = {BACKGROUND: There is an unmet need for the clinically relevant ALS biomarkers to facilitate an accurate diagnosis in suspected cases, monitor disease progression and evaluate response to therapy in clinical trials. While the MND/ALS literature is dominated by innovative brain studies, motor disability in ALS is primarily driven by neurogenic muscle change impacting mobility, dexterity, respiratory and bulbar function.<br><br>METHODS: With the intention of raising awareness of muscle-derived imaging markers in ALS, a systematic review has been conducted. Study designs, imaging methods, data interpretation frameworks, and cohort characteristics were systematically evaluated to identify innovative approaches and barriers to clinical implementation.<br><br>RESULTS: A total of 219 studies were screened and 73 original studies selected for systematic review; 37 muscle MRI studies and 36 studies using ultrasound, PET or CT. All of the selected studies successfully captured ALS-associated muscle degeneration and their methods included the evaluation of muscle dimensions (thickness/volumes n&#x2009;=&#x2009;34), 'acute' denervation (water content, n&#x2009;=&#x2009;15), fasciculation counts (n&#x2009;=&#x2009;14), 'chronic' neurogenic change (fat content, n&#x2009;=&#x2009;21), metabolic changes (n&#x2009;=&#x2009;4), diffusion alterations (n&#x2009;=&#x2009;8) and echo intensity changes (n&#x2009;=&#x2009;13).<br><br>CONCLUSIONS: Despite the huge impact of lower motor neuron dysfunction on the patients' independence, survival and quality of life, muscle imaging is a glaringly overlooked frontier of MND/ALS research. This is a missed opportunity, as a variety of non-invasive quantitative muscle imaging techniques have been successfully used in other neurological conditions; these protocols are easy to implement on commercial MRI and ultrasound platforms and recent studies have demonstrated their ease of use and potential clinical utility.}, }
@article {pmid41873182, year = {2026}, author = {Hinten, AE and Imuta, K}, title = {Executive Function Costs of Fantastical Interference in Narrative Comprehension: A Response to Lillard's (2026) Commentary.}, journal = {Developmental science}, volume = {29}, number = {3}, pages = {e70177}, doi = {10.1111/desc.70177}, pmid = {41873182}, issn = {1467-7687}, mesh = {Humans ; *Comprehension/physiology ; *Executive Function/physiology ; Child ; *Fantasy ; *Narration ; Child, Preschool ; Cognition ; }, abstract = {Through bringing together previous findings from 16 studies involving 121 effect sizes (based on 1,297 1.5- to 6-year-olds), Hinten et al.'s (2025) meta-analysis revealed that children who viewed fantastical media in an experimental setting performed worse on inhibitory control and cognitive flexibility tasks immediately post-viewing compared to those exposed to realistic media. Lillard's (2026) commentary provided one potential explanation for our findings, revolving around the idea that processing fantastical content is cognitively taxing because it conflicts with existing schemas. In this response, we extend Lillard's (2026) perspective by drawing on Loschky et al.'s (2020) Scene Perception and Event Comprehension Theory (SPECT) to provide an additional explanation: Fantasy overloads children's executive functions because it interferes with their narrative comprehension. SUMMARY: We present a novel perspective on why fantastical media may have adverse, short-term effects on children's executive functioning. Children's executive functions may become overloaded while watching fantastical media because fantastical elements can detract from and hamper narrative comprehension processes.}, }
@article {pmid41874673, year = {2026}, author = {Li, J and Gao, C and Wang, Q and Liu, J and Xie, Z and Zhao, Y and Yu, M and Zheng, Y and Lv, H and Zhang, W and Yuan, Y and Meng, L and Deng, J and Wang, Z}, title = {Aberrant SOD1 aggregates in skeletal muscle target fibers in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {151}, number = {1}, pages = {}, pmid = {41874673}, issn = {1432-0533}, }
@article {pmid41875078, year = {2026}, author = {Mamede, LD and Hu, M and Vaquer-Alicea, J and Titus, AR and Passos, PM and Lantelme, E and French, RL and Kirschner, PA and Diamond, MI and Miller, TM and Ayala, YM}, title = {A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.}, journal = {PLoS biology}, volume = {24}, number = {3}, pages = {e3003662}, doi = {10.1371/journal.pbio.3003662}, pmid = {41875078}, issn = {1545-7885}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Protein Aggregation, Pathological/metabolism/genetics ; Neurons/metabolism/pathology ; Exons ; Protein Aggregates ; RNA Splicing ; Amyotrophic Lateral Sclerosis/metabolism ; TDP-43 Proteinopathies/metabolism/genetics ; Genes, Reporter ; }, abstract = {TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures both aggregation and the resulting loss of function. Using this human biosensor cell line, we show that aggregation initiated by prion-like seeding drives progressive depletion of nuclear TDP-43 and induces signature features of diminished TDP-43 activity, such as increased DNA damage and activation of cryptic exon splicing. We find that aggregate seeding also induces cryptic exon splicing in human neurons implying that this pathological link extends to disease-relevant models. The seeding model provides a platform for dissecting mechanisms that underlie TDP-43 pathology and for identifying factors that modulate the aggregation-to-dysfunction transition. Our data shows that aggregate seeding impacts TDP-43 autoregulation, initiating a toxic feed-forward mechanism that disrupts TDP-43 homeostasis. Furthermore, reducing ataxin-2 levels decreases aggregation and restores TDP-43 activity. Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.}, }
@article {pmid41875115, year = {2026}, author = {Uversky, VN}, title = {Why is it so difficult to discover drugs for amyotrophic lateral sclerosis? A protein intrinsic disorder perspective.}, journal = {Expert opinion on drug discovery}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/17460441.2026.2648612}, pmid = {41875115}, issn = {1746-045X}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, now viewed as a spectrum disorder rather than a single entity. Because of the significant person-to-person variability in the disease's biology, driven by both genetic and environmental interactions, finding a single "magic bullet" drug is unlikely. Despite decades of research, only a few ALS drugs have being developed. Drug discovery has a 95% failure rate due to genetic complexity, lack of sensitive biomarkers, diagnostic delays, inadequate animal models, and poor clinical trial design.<br><br>AREAS COVERED: This article considers several aspects related to the prevalence of intrinsic disorder in ALS-related proteins and highlights how these features might hinder rational structure-based drug discovery.<br><br>EXPERT OPINION: There is a common oversight in current drug discovery methodologies, which is the neglect of intrinsically disordered proteins (IDPs) playing several crucial roles in the pathology of neurodegeneration in general and ALS in particular. Therefore, it seems that the 'one-size-fits-all' approach to ALS is hitting a wall because these 'shapeshifters' of the cellular world are ignored. Consequently, to be more successful in finding drugs treating ALS, gears should be shifted from rational structure-based models to intrinsic disorder-centric approaches.}, }
@article {pmid41866066, year = {2026}, author = {Qian, J and Li, C and Wang, Y and Tong, J}, title = {Extracorporeal sliding knot technique for simplified hysteroscopic suture fixation of levonorgestrel-releasing intrauterine device.}, journal = {Journal of minimally invasive gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmig.2026.03.020}, pmid = {41866066}, issn = {1553-4669}, abstract = {OBJECTIVE: Approximately 20% of adenomyosis cases occur in women under 40 years of age [1]. While LNG-IUD is the first-line medical therapy, its treatment failure is closely associated with uterine volume [2], with expulsion rates reported as high as 37.5% in uteri exceeding 12 gestational weeks [3]. Tong et al's hysteroscopic suture fixation technique (HCSS) reduced expulsion to 2.6% [4][5]. Although clinical studies have confirmed the safety and efficacy of this technique [5], its technical complexity and the requirement for repeated instrument exchanges have limited widespread adoption. We therefore developed an optimized extracorporeal sliding knot method to overcome these barriers.<br><br>SETTING: University hospital.<br><br>PARTICIPANTS: A 45-year-old woman diagnosed with adenomyosis and prior LNG-IUD expulsion.<br><br>INTERVENTIONS: The key modification involves three critical steps: Step 1) Construction of a secure multi-loop sliding knot using 2-0 Ethibond suture attached to the "T junction" of the LNG-IUD; Step 2) Introduction of the pre-formed knot into the uterine cavity in a single maneuver using a knot-pusher; Step 3) Adjustment of the knot position under the hysteroscopic cold-knife surgery system (HCSS), achieving secure device fixation. The complete procedure obviates repeated instrument exchanges and intracavitary knot manipulation required by the original technique.<br><br>CONCLUSION: The extracorporeal sliding knot optimization preserves therapeutic efficacy while simplifying intrauterine manipulation, significantly enhancing surgical reproducibility and accessibility for widespread clinical adoption.}, }
@article {pmid41866414, year = {2026}, author = {Li, X and Ding, W and Xu, E}, title = {Uncoupling of apnea-hypopnea index and oxygen desaturation in als: characterization and diagnostic implications of an "AHI-SpO2 dissociation" phenotype.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {4}, pages = {}, pmid = {41866414}, issn = {1590-3478}, support = {202610452//Health Commission of Jiangxi Province/ ; }, }
@article {pmid41866449, year = {2026}, author = {Wang, Z and He, F and Li, L and Wang, W and Zhang, L and Tang, J and Le, W}, title = {Sleep Disorders in Neurodegenerative Diseases: Pathological Correlations and Underlying Mechanisms.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {41866449}, issn = {1995-8218}, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and others, represent an escalating public health burden in aging populations. NDDs are characterized by progressive neuronal loss and misfolded protein aggregation. Despite distinct clinical heterogeneity, these diseases universally present with debilitating non-motor symptoms, among which sleep-wake disorders are highly prevalent. Once considered secondary to neuronal damage, growing evidence now highlights a bidirectional interplay: sleep disruption is not only a consequence of neurodegeneration but also exacerbates its progression. This review synthesizes this complex interplay, outlining sleep phenotypes across major NDDs, dissecting key underlying mechanisms (impaired protein homeostasis, glymphatic dysfunction, chronic neuroinflammation, sleep-regulatory nucleus vulnerability, and circadian dysregulation), and summarizing current pharmacotherapeutic and non-pharmacological interventions. Attenuating sleep disorders may therefore provide symptomatic relief and disease‑modifying effects for NDDs.}, }
@article {pmid41866924, year = {2026}, author = {Seyam, M and Morelli, KH and Waheed, W and van den Berg, LH and Tandan, R}, title = {Predicting Disease Progression and Survival in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70198}, pmid = {41866924}, issn = {1097-4598}, abstract = {Amyotrophic lateral sclerosis (ALS) progresses relentlessly and is characterized by a median survival of 2-5 years from symptom onset with death from respiratory failure. ALS is a complex, multi-system neurodegenerative disorder with significant phenotypic heterogeneity and markedly variable disease progression. This variability presents challenges in determining the optimal timing for therapeutic interventions, complicates clinical trial design due to lack of effective stratification methods, and makes it difficult to reliably measure the longitudinal impact of specific interventions. Accurately capturing disease progression in ALS can be challenging. We propose that early respiratory phenotyping offers a promising approach to facilitate patient stratification, improve assessments of disease progression, and predict survival.}, }
@article {pmid41867322, year = {2026}, author = {Alabdali, A and Alharkan, M}, title = {Comparative Cost Analysis of Ambulance Utilization: Advanced Life Support (ALS) vs Basic Life Support (BLS) at King Abdulaziz Medical City, Riyadh.}, journal = {ClinicoEconomics and outcomes research : CEOR}, volume = {18}, number = {}, pages = {570790}, pmid = {41867322}, issn = {1178-6981}, abstract = {PURPOSE: Unit-hour utilization (UHU) is the most common metric for evaluating the productivity of ambulances and crews for ambulance services. Calculating UHU is essential for maximizing profitability and evaluating the number of hours of ambulance utilization during a shift. This has not been examined previously at King Abdulaziz Medical City (KAMC). KAMC is a major tertiary-care medical center in Riyadh, Saudi Arabia, with dedicated ALS (Advanced Life Support) and BLS (Basic Life Support) ambulance units. This study aimed to determine the cost of operating the emergency calls (advanced life support [ALS]) unit and non-emergency calls (basic life support [BLS]) unit and compare the costs of emergency calls (ALS) and non-emergency calls (BLS). The study used a standardized institutional checklist that itemizes expenditures across logistics, equipment, maintenance, salary, pharmacy, and fuel cost components.<br><br>METHODS: This was a retrospective cross-sectional study. Institutional Review Board approval was obtained from King Abdullah International Medical Research Center. The study examined emergency and non-emergency calls for a period of 12 months. This study was based on a checklist assessing various expenditures to calculate the cost of ambulance utilization at KAMC in 2022.<br><br>RESULTS: The total average ambulance utilization cost per year for ALS was 4,806,245.7 SR, and the average ambulance utilization cost per hour was 548.65 SR; these costs were to operate the ALS crew for 24&#xa0;hours, seven days a week. Conversely, the total average ambulance utilization cost per year for BLS was 3,934,156.92 SR, and the average ambulance utilization cost per hour was 449.10 SR. The main expenses concerned salaries and overhead costs for ALS and BLS.<br><br>CONCLUSION: This study provides insights into the cost of ambulance utilization between ALS and BLS. The higher cost of ALS calls may be attributed to the higher level of training, equipment, and staffing required.}, }
@article {pmid41868461, year = {2026}, author = {Yu, J}, title = {Postoperative acute ultra-early fish mouthing of a Surpass Evolve flow diverter leading to ischemic complication.}, journal = {Radiology case reports}, volume = {21}, number = {6}, pages = {2346-2354}, pmid = {41868461}, issn = {1930-0433}, abstract = {Currently, the Surpass Evolve flow diverter (SE FD) is widely adopted for endovascular treatment of intracranial aneurysms. Although generally safe, acute ultra-early fish mouthing remains an exceptionally rare complication. Following Torche et al.'s 2023 report of the first case, the present case represents the second documented instance. A 66-year-old woman was diagnosed with a left posterior communicating artery aneurysm and a left ophthalmic artery aneurysm. Physical examination revealed no abnormalities. The endovascular treatment (EVT) procedure was performed. After advancing a microcatheter into the left middle cerebral artery, an SE FD with appropriate size was deployed to cover both aneurysms, achieving confirmed complete expansion and optimal wall apposition. Two hours postoperatively, the patient developed aphasia and hemiparesis. Subsequent angiography at 4 hours revealed thrombosis within the SE FD and fish mouthing at the proximal segment. Successful microguidewire traversal through the affected site restored complete FD expansion and wall apposition. Postoperatively, the patient's hemiparesis improved, and her motor aphasia resolved. Magnetic resonance imaging confirmed multiple acute infarctions, while computed tomography demonstrated proper FD expansion. At 3-month follow-up, near-normal functional recovery was observed. This case indicates that SE FD deployment may be complicated by acute ultra-early fish mouthing attributable to post-deployment tension release. Preventive strategies should emphasize appropriate device sizing, adequate landing zone selection, and post-implant tension assessment.}, }
@article {pmid41868729, year = {2026}, author = {Sethi, N and Levy, OA and Richardson, A and Harari, OA and Sellati, R}, title = {A Qualitive Investigation of Geographic Disparities in Genetic Testing and Care Access for Amyotrophic Lateral Sclerosis: Insights From Patient Journey Mapping.}, journal = {Patient preference and adherence}, volume = {20}, number = {}, pages = {566747}, pmid = {41868729}, issn = {1177-889X}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that is associated with a high patient burden, reduced lifespan, and reduced quality of life. People living with ALS (PLwALS) often experience delays in diagnosis of ~1 year, and while current treatment options can slow disease progression, improve quality of life, and offer modest benefits in functional decline, they do not reverse neuronal damage. Defining and understanding the experiences of PLwALS can help identify gaps and barriers to optimal care.<br><br>PATIENTS AND METHODS: This non-interventional study was intended to obtain insights on the patient experience from the perspective of PLwALS. We sought to develop an ALS patient journey map from initial presentation through to end-of-life care for 4 regions (North America, Asia-Pacific, Latin America, and Europe/Middle East/Africa). The map was based on results from a global audit of data sources (including publications, patient narratives, society guidelines, academic reports, industry white papers [n=104]), and one-to-one, 60-minute, semi-structured interviews with PLwALS (n=12) or those caring for PLwALS (n=2). The initial patient journey map was subsequently reviewed during 2 advisory sessions with patient advocates (7 PLwALS and 2 caregivers) in September and November 2023.<br><br>RESULTS: We identified several barriers and challenges that most impact PLwALS, caregivers, and clinicians, with many similarities but also some differences across the regions.<br><br>CONCLUSION: These insights will enable targeted improvements in education, personalized care, resource allocation, care coordination, policy development, and funding, ultimately improving patient outcomes.}, }
@article {pmid41869005, year = {2025}, author = {Lorenz, J and Hawkins, S and McCarthy, B}, title = {Griffiths et al.'s Study of Psilocybin with Religious Professionals: A Theological Response from a Christian Perspective.}, journal = {Psychedelic medicine (New Rochelle, N.Y.)}, volume = {3}, number = {4}, pages = {202-206}, pmid = {41869005}, issn = {2831-4433}, abstract = {Griffiths et al.'s recent "Effects of Psilocybin on Religious and Spiritual Attitudes and Behaviors in Clergy from Various Major World Religions" is an important study in the literature on psychedelic medicine and religious experience. In this commentary on the study, we argue: (1) The study design's implicit presupposition of perennialism in its conception of mysticism burdens it with metaphysical and theological freight it doesn't need to support its hypothesis; and (2) Psychedelic usage in pursuit of mysticism, however construed, risks two pathologies-hyper-individualism and idolatry-that religious traditions and communities are well-positioned to counter.}, }
@article {pmid41870290, year = {2026}, author = {Narayan, A and Neupane, K and Woodside, MT}, title = {Scalable assay to identify inhibitors of prion-like propagation of protein misfolding as potential therapeutics for neurodegeneration.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {4}, pages = {e70535}, doi = {10.1002/pro.70535}, pmid = {41870290}, issn = {1469-896X}, support = {PJT-185931/CAPMC/CIHR/Canada ; //NSERC Banting Postdoctoral Fellowship/ ; //Alberta Innovates Postdoctoral Fellowship/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/antagonists &amp; inhibitors ; *Protein Folding/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Prions/metabolism/chemistry/antagonists &amp; inhibitors ; }, abstract = {Protein misfolding is linked to many neurodegenerative diseases. In some cases, misfolding can propagate through a prion-like mechanism whereby natively folded molecules are converted into more copies of the misfolded isoform. Prion-like propagation of misfolding is an attractive therapeutic target, but difficulties with assaying conversion directly and simply have severely limited efforts to find drugs targeting conversion of disease-related proteins. Here, we demonstrate a scalable enzymatic assay for testing potential inhibitors of prion-like conversion in superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis (ALS). We tested several small-molecule inhibitors of SOD1 aggregation to determine if they also inhibited prion-like conversion. We found that some compounds, like telbivudine and cisplatin, did indeed significantly delay conversion, but others, like baicalein and quercetin, had little effect. Surprisingly, some compounds, like two statins tested, actually accelerated conversion, suggesting that they might act to promote ALS progression. These results underline the fact that conversion and aggregation are distinct biophysical processes. The ability of the assay to identify compounds effective at delaying prion-like conversion holds out promise for applications in future drug discovery efforts that target propagated misfolding specifically.}, }
@article {pmid41870380, year = {2026}, author = {Elhami Athar, M and Miller, JD and Lynam, DR}, title = {From controversy to confusion: A commentary on how Marcus et al.'s (2025) Psychopathic Boldness Scale further muddies the boldness construct.}, journal = {Psychological assessment}, volume = {38}, number = {4}, pages = {332-338}, doi = {10.1037/pas0001442}, pmid = {41870380}, issn = {1939-134X}, mesh = {Humans ; *Antisocial Personality Disorder/diagnosis/psychology ; *Psychometrics/standards ; *Psychiatric Status Rating Scales/standards ; Reproducibility of Results ; }, abstract = {The Psychopathic Boldness Scale (see record 2025-96918-001) is a newly developed 21-item self-report measure intended to assess boldness as it manifests within psychopathy. In this commentary, we raise concerns about the PBS's construct validity, particularly its conceptual and empirical overlap with antagonism-related traits. Drawing on theoretical analysis and results from Marcus et al., we evaluated how PBS items function relative to the Triarchic Psychopathy Measure. Intraclass correlations of overall correlational profiles revealed that the nomological network of the PBS more closely aligns with Triarchic Psychopathy Measure meanness than with boldness. Rather than clarifying the role of boldness within psychopathy, the PBS repackages maladaptive content typically captured by meanness/antagonism under the boldness label and results in a case of the jingle fallacy. We argue that this conflation undermines theoretical precision and sets the stage for a more difficult-to-integrate literature. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid41870498, year = {2026}, author = {Strojny, A and Kiszka, P and Strojny, P}, title = {Rethinking escapism and escape: A cognitive perspective on the C-DOG model.}, journal = {Journal of behavioral addictions}, volume = {}, number = {}, pages = {}, doi = {10.1556/2006.2025.00357}, pmid = {41870498}, issn = {2063-5303}, abstract = {This commentary builds on Giardina et al.'s (2021, 2024) conceptualization of escapism and escape in the C-DOG model, highlighting unresolved definitional ambiguities. We argue that the distinction between these constructs cannot rely solely on pre-game intentions (expectation to return vs. remain) due to potential cognitive biases and self-deception, particularly among players with Gaming Disorder (GD). Drawing on goal systems theory and research on maladaptive gaming-related beliefs, we propose that the post-game outcome, successful return vs. persistent difficulty disengaging, offers a more reliable criterion. This perspective reframes escapism and escape as goal-driven processes shaped by experiential avoidance and motivational rigidity.}, }
@article {pmid41870813, year = {2026}, author = {Upadhayay, S}, title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41870813}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Pentacyclic Triterpenes/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.}, }
@article {pmid41870864, year = {2026}, author = {Gomez, R and Brown, T and Zarate, D and Houghton, S and Stavropoulos, V}, title = {A Network Approach to the Association Between Emotional Regulation and ADHD Symptoms in Adults: Pathways between Difficulties in Emotional Regulation and ADHD Dimensions.}, journal = {The Psychiatric quarterly}, volume = {}, number = {}, pages = {}, pmid = {41870864}, issn = {1573-6709}, }
@article {pmid41862640, year = {2026}, author = {Onwunma, J and Binsabaan, S and Allen, SP and Thanthirige, SR and Gaur, D and Sankaran, B and Wohlever, ML}, title = {ALS mutations disrupt self-association between the ubiquilin STI1 hydrophobic groove and internal placeholder sequences.}, journal = {The EMBO journal}, volume = {}, number = {}, pages = {}, pmid = {41862640}, issn = {1460-2075}, support = {R35 GM137904-01S2//HHS | National Institutes of Health (NIH)/ ; P30 GM124169-01//HHS | National Institutes of Health (NIH)/ ; CAREER Award 2343131//National Science Foundation (NSF)/ ; }, abstract = {Ubiquilins are molecular chaperones that play multifaceted roles in proteostasis, with point mutations in UBQLN2 leading to altered phase-separation properties and amyotrophic lateral sclerosis (ALS). Our mechanistic understanding of this essential process has been hindered by a lack of structural information on the STI1 domain, which is essential for ubiquilin chaperone activity and phase separation. Here, we present the first crystal structure of a ubiquilin-family STI1 domain bound to a transmembrane domain (TMD), and show that ALS mutations disrupt the STI1-TMD interaction. We further demonstrate that ubiquilins contain multiple conserved internal sequences that bind to the STI1 domain, including the PXX-repeat region that is a hotspot for ALS mutations. We propose that these placeholder sequences prevent solvent exposure of the STI1 hydrophobic groove and contribute to the multivalency that drives ubiquilin phase-separation. Together, this work provides a new paradigm for understanding how STI1 domains modulate ubiquilin chaperone activity and phase separation, and offers insights into the molecular basis of ALS pathogenesis.}, }
@article {pmid41863273, year = {2026}, author = {Singh, DD}, title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X438970260115164001}, pmid = {41863273}, issn = {1875-6190}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.}, }
@article {pmid41863275, year = {2026}, author = {Singh, AK and Kush, A and Bhushan, B and Dhanawat, M and Sharma, PK}, title = {Targeting Autophagy with Bioactive Compounds: Therapeutic Potential in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X408653251130061347}, pmid = {41863275}, issn = {1875-6190}, abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the accumulation of misfolded proteins and impaired cellular clearance mechanisms. Autophagy, a critical lysosomedependent degradative pathway, plays a vital role in maintaining proteostasis and neuronal health. Dysregulation of autophagy has been implicated in the pathogenesis of multiple NDs, making it a promising therapeutic target. This review comprehensively examines the molecular mechanisms of autophagy and its dysfunction across major NDs. Furthermore, it highlights the potential of bioactive compounds such as flavonoids, alkaloids, polyphenols, and terpenoids to modulate autophagic flux, thereby promoting the clearance of toxic protein aggregates like amyloid-β, tau, and α- synuclein. Emerging strategies, including nanotechnology-based delivery systems, are also discussed for enhancing the bioavailability and efficacy of these compounds. The evidence suggests that pharmacological or natural induction of autophagy may alleviate neurodegenerative pathology, though context- and stage-specific modulation is essential. This work underscores the therapeutic promise of autophagy-enhancing bioactives and calls for further research into their clinical applications.}, }
@article {pmid41863659, year = {2026}, author = {Mullick, S and Chakraborty, A and Porel, P and Nath, R and Chaudhary, P and Islam, A and Das, J and Pramanik, S and Panigrahy, UP and Sridhar, SB and Mondal, M and Debnath, B and Ashique, S}, title = {Decoding Neuroinflammatory Pathways: The Role of the CXCL12-CXCR4/CXCR7 Axis in ALS-Related Cognitive Impairment.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41863659}, issn = {1559-1182}, mesh = {Humans ; *Chemokine CXCL12/metabolism ; *Receptors, CXCR/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/complications/pathology ; Animals ; *Receptors, CXCR4/metabolism ; *Cognitive Dysfunction/metabolism ; *Signal Transduction/physiology ; *Neuroinflammatory Diseases/metabolism/pathology ; Inflammation/metabolism/pathology ; }, abstract = {Cognitive impairment (CI) and accelerating neuronal deterioration are hallmarks of amyotrophic lateral sclerosis (ALS). Under these circumstances a crucial molecular mechanism in the pathophysiology of CI has been identified: the CXC chemokine receptor type 7 (CXCR7)/CXC chemokine receptor type 4 (CXCR4)/Cysteine-X-cysteine chemokine ligand 12 (CXCL12) region. Research on ALS shows that the CXCR7/CXCR4/CXCL12 complex plays a role in the degeneration of motor neurons and the resulting cognitive decline. JAK/STAT, PI3K/AKT, MAPK, and other signaling pathways are among the ways the axis controls neuronal inflammation, synaptic remodeling, and neuronal maintenance in each of these scenarios. The CXC motif chemokine ligand 12 (CXCL12) and CXC chemokine receptor type 4 (CXCR4) axis is crucial for the start of the inflammatory mechanism because of their function in mediating the chemotaxis of inflammatory cells. By preventing the migration of inflammatory cells via CXCL12 in the inflammatory area, the response to inflammation can be prevented or reduced. Consequently, the development of CXCR4 antagonists has emerged as a cutting-edge strategy for inflammation treatment. Recent research suggests that managing this relationship could reduce cognitive deficits and offer neuroprotective benefits. According to the current review, the CXCL12/CXCR4/CXCR7 pathway may be a promising target for treating cognitive dysfunction in neurodegenerative disorder. It also emphasizes the need for additional research to completely comprehend its function and identify efficient treatments which may result in improved clinical treatment modalities for these debilitating illnesses.}, }
@article {pmid41864292, year = {2026}, author = {Liu, H and Zhu, J and Chen, Y and Lin, X and Hua, C and Chen, H}, title = {Response to Jia et al.'s "Comment on the "genetic classification helps with precise sirolimus treatment in slow-flow vascular malformations"".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.03.041}, pmid = {41864292}, issn = {1097-6787}, }
@article {pmid41864411, year = {2026}, author = {Davias, A and Tang, IW and Hansen, J and Knekt, P and Rantakokko, P and Weisskopf, MG}, title = {Associations between pre-disease biomarkers of persistent organic pollutants and amyotrophic lateral sclerosis risk in four European cohorts.}, journal = {Environmental research}, volume = {}, number = {}, pages = {124337}, doi = {10.1016/j.envres.2026.124337}, pmid = {41864411}, issn = {1096-0953}, abstract = {OBJECTIVES: Previous retrospective studies suggested that occupational exposures to persistent organic pollutants (POPs) may be associated with amyotrophic lateral sclerosis (ALS), but prospective studies with biomarker exposure assessment are scarce. This study aimed to prospectively investigate the relationship between POP exposures and ALS risk in the Danish Diet, Cancer and Health study (EPIC) cohort and to conduct a meta-analysis including results from the prior study of 3 small prospective Finnish cohorts in addition to the Danish EPIC cohort.<br><br>METHODS: We identified 166 incident ALS cases between 1993 and 1997 using the Danish National Patient Register and randomly selected 334 controls by individual matching on birth-year and sex. Levels of 13 polychlorinated biphenyls, 9 organochlorine pesticides and 3 polybrominated diphenyl ethers were assessed from baseline plasma samples. We employed conditional logistic regression models using exposure quartiles, and generalized additive models (GAMs), adjusting for confounders. We conducted a meta-analysis combining 3 Finnish prospective cohorts with the Danish data using a random-effects model.<br><br>RESULTS: The Danish results suggested generally inverse trends between several POPs and the predicted ALS risk; especially for chlordane-related compounds (co-pollutant quartile model, p-value<0.01). GAMs supported these trends, although most were not statistically significant. However, hexachlorobenzene was positively associated with ALS risk in co-pollutant GAM (p-value=0.02). Additionally, the GAMs suggested higher ALS odds at the highest levels of exposure of some POPs, but the data at these levels was sparse. Meta-analysis results were mostly consistent with the Danish findings.<br><br>CONCLUSION: Our study suggested elevated ALS risk among those exposed to hexachlorobenzene when adjusting for co-pollutants. Higher level of some POPs suggested a positive association with ALS occurrence, but the data was scarce at these levels.}, }
@article {pmid41864543, year = {2026}, author = {Wu, J and Ma, H and Niu, X and Zhang, Z and Guo, R and Shen, N and Tian, Y and Zhao, H and Yang, Y and Chen, Y}, title = {The p75NTR Signaling Axis: Bridging Neurodevelopmental Homeostasis, Pathological Mechanisms, and Therapeutic Strategies in Neurodegenerative Diseases.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103105}, doi = {10.1016/j.arr.2026.103105}, pmid = {41864543}, issn = {1872-9649}, abstract = {The neurotrophin receptor p75 (p75NTR) plays dual, context-dependent roles in the nervous system that are regulated by ligand binding, co-receptor interactions, and microenvironmental cues. During neurodevelopment, synaptic plasticity, and in neurodegenerative disorders, p75NTR orchestrates opposing cellular responses: it can support neuronal homeostasis through pro-survival pathways, while also initiating apoptotic and inflammatory cascades that exacerbate disease progression. In Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), activation of p75NTR drives pathological processes such as neuronal apoptosis and axonal degeneration, leading to impaired cognitive and motor function.Importantly, different structural domains of p75NTR have divergent effects. The extracellular domain (p75ECD) exhibits neuroprotective properties in AD models, in contrast with the pro-apoptotic activity associated with the full-length receptor. Therapeutic targeting of p75NTR with small-molecule ligands and ROCK inhibitors has shown efficacy in preclinical models, and some candidates have progressed to clinical trials. However, several challenges hinder clinical translation: (1) the mechanisms underlying p75NTR upregulation are not fully understood; (2) its downstream signaling network is highly complex; and (3) existing biomarker systems remain limited.A comprehensive understanding of p75NTR's role in neurodegeneration may clarify pathological mechanisms and reveal novel therapeutic targets. Achieving this will require multidisciplinary collaboration to bridge the gap between basic research and clinical applications.}, }
@article {pmid41865815, year = {2026}, author = {Liu, X and Gao, Z and Xu, J}, title = {Beyond Fluorescence: A Critical Look at AI-Powered Brightfield Analysis for T-Cell Killing Assays.}, journal = {SLAS discovery : advancing life sciences R &amp; D}, volume = {}, number = {}, pages = {100307}, doi = {10.1016/j.slasd.2026.100307}, pmid = {41865815}, issn = {2472-5560}, abstract = {This comment evaluates dela Cruz-Chuh et al.'s AI-based label-free workflow for analyzing T-cell mediated tumor killing via brightfield imaging. The study's core strengths include eliminating fluorescent labeling artifacts, achieving comparable consistency to conventional segmentation-based methods, and accommodating phenotypically diverse cancer cells without manual parameter tuning-addressing key bottlenecks in immunotherapy screening. However, critical considerations persist: the binary "killing/non-killing" classification framework may insufficiently resolve low-level or partial cytotoxicity, as evidenced by six false negatives; generalizability to non-adherent hematological malignancies or alternative effector cells remains untested; and the model lacks interpretability regarding morphological features driving cytotoxicity predictions. Additionally, performance across variable imaging platforms or culture conditions is unevaluated, limiting translational reproducibility. Despite these gaps, the workflow advances high-throughput immunotherapy screening efficiency. Future studies incorporating multi-class training, validation across diverse cancer types, and mechanistic decoding of AI-predicted features will strengthen its rigor and broader applicability in drug discovery.}, }
@article {pmid41861969, year = {2026}, author = {Kamar, N and Congy-Jolivet, N and Salhi, S and Darres, A and Colombat, M and Milhes, J and Esposito, L and Guy, P and Hebral, AL and Prudhomme, T and Sallusto, F and Pellegrini, J and Medrano, C and Marion, O and Del Bello, A}, title = {Anti-lymphocyte globulin versus anti-thymocyte globulin in kidney transplant patients with preformed donor specific antibodies.}, journal = {Transplant immunology}, volume = {}, number = {}, pages = {102375}, doi = {10.1016/j.trim.2026.102375}, pmid = {41861969}, issn = {1878-5492}, abstract = {State-of-the-art immunosuppressant therapies recommend the use of induction therapy after kidney transplantation. Anti-interleukin-2 receptor antibody (basiliximab) is used for low-risk patients whereas polyclonal anti-lymphocyte sera (ALS) are recommended for medium/high-risk patients. There are two commercially available rabbit-derived ALS, namely anti-thymocyte globulin (RATG; Thymoglobulin®) and anti-lymphocyte globulin (RATLG; Grafalon®). We retrospectively compared the efficacy and safety of RATG or RATLG induction therapy in high-risk kidney transplant recipients with preformed donor specific antibodies (DSAs; n = 124). Forty-seven recipients received 1.25 mg/kg RATG for 2 to 3 days. Seventy-seven recipients were treated with 9 mg/kg RATLG on day 0 followed by 4 mg/kg RATLG for 2 to 3 days (n = 21) or a single dose of 9 mg/kg RATLG on day 0 (n = 56). Overall there were no significant differences observed between patients treated with RATG and RATLG. Similarly, no difference was observed between patients who had been given a single dose of RATLG and multiple doses of RATLG or RATG. At one year, patient and graft survival rates, acute rejection rate and type of rejection, kidney function, infections and malignancies did not differ between groups. Kidney transplant patients with preformed DSA showed similar clinical outcomes when treated with RATG or RATLG induction therapy. Polyclonal antibodies in high immunological risk kidney transplant patients.}, }
@article {pmid41856848, year = {2026}, author = {Wang, R and Chen, W}, title = {Comment on: "Clinical safety of ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis: Open-label extension of a phase 2/3 randomized controlled study".}, journal = {Journal of the neurological sciences}, volume = {}, number = {}, pages = {125791}, doi = {10.1016/j.jns.2026.125791}, pmid = {41856848}, issn = {1878-5883}, }
@article {pmid41858070, year = {2026}, author = {Zhang, Z and Fan, R and Jing, S and Liu, S and Liu, L and Que, W and Lu, D and Gan, Y and Xiao, F}, title = {Plasma proteomic trajectories before the onset of neurodegenerative diseases.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/17582024.2026.2646760}, pmid = {41858070}, issn = {1758-2032}, abstract = {BACKGROUND: The study aimed to identify indicative proteins associated with the occurrence and mortality of three neurodegenerative diseases (NDDs) and track the changes of proteins before the onset of NDDs.<br><br>RESEARCH DESIGN AND METHODS: We analyzed plasma proteomic data from UK Biobank. Cox regression analyses were utilized to detect the relationship between plasma proteins and the risk of development and all-cause mortality of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Predictive models were established based on related proteins using Lasso regression.<br><br>RESULTS: We identified 14 disease-associated proteins for AD, 35 for PD, and one for ALS. The trajectory of plasma proteins before the onset of NDDs was portrayed. Neuroinflammation and the remodeling of the extracellular matrix might be common pathways for NDDs.<br><br>CONCLUSIONS: Our results highlighted that the landscape of plasma protein changes before the onset of NDDs.}, }
@article {pmid41858090, year = {2026}, author = {Ellis, AC and Dobak, S and Pearson, K and McGuire, R and Sutton, T}, title = {Registered Dietitians' perspectives on nutrition management of persons living with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/17582024.2026.2646759}, pmid = {41858090}, issn = {1758-2032}, abstract = {AIM: Persons with amyotrophic lateral sclerosis (PALS) are at high risk for malnutrition, which is a negative prognostic factor for disease progression and survival. This study explored the perspectives of Registered Dietitians (RDs) providing nutrition care to PALS, focusing on barriers and facilitators to optimal patient care.<br><br>METHODS: RDs from U.S. multidisciplinary ALS clinics participated in six virtual focus groups. Recordings were transcribed verbatim and independently coded by two researchers for deductive content analysis.<br><br>RESULTS: RDs highlighted the importance of using clinical judgment to assess nutrition status and individualizing recommendations to respect patient autonomy. The multidisciplinary team model was identified as a strong facilitator to optimal patient care, while insurance coverage for nutrition-related supplies was a common barrier. RDs reported having little prior knowledge of ALS before assuming their current roles and described the need to upskill through self-teaching and on-the-job experience.<br><br>CONCLUSIONS: Results emphasize the importance of clinical judgment with respect to patient autonomy in providing nutrition care to PALS. The barriers and facilitators identified across multiple levels provide insight for future interventions to improve patient care.}, }
@article {pmid41858403, year = {2026}, author = {Chun, S and Woon Kim, G and Bit Kim, H}, title = {Association between on-scene cardiopulmonary resuscitation duration and outcomes in out-of-hospital cardiac arrest patients.}, journal = {World journal of emergency medicine}, volume = {17}, number = {2}, pages = {137-145}, pmid = {41858403}, issn = {1920-8642}, abstract = {BACKGROUND: Prolonged on-scene Advanced Life Support (ALS) in out-of-hospital cardiac arrest (OHCA) patients may enhance return of spontaneous circulation (ROSC), but the optimal duration of cardiopulmonary resuscitation (CPR) without initial prehospital ROSC remains unclear. We investigated the association between on-scene CPR duration and outcomes using nationwide data. METHODS: This prospective, multi-regional study (2015-2022) included medical cause OHCA patients who underwent Smart ALS (SALS). Data from emergency medical services (EMS) records, SALS logs, and hospital outcomes were analyzed. Logistic regression models were developed for prehospital ROSC, survival to discharge, and good neurological outcome (Cerebral Performance Category [CPC] 1-2). RESULTS: Among 98,569 patients, 34,989 were SALS-eligible and 16,052 received SALS. Predictors of ROSC included younger age, male sex, public arrest, witnessed arrest, bystander CPR, shockable rhythm, and shorter response/scene times. Longer on-scene CPR reduced probabilities of ROSC, survival, and neurological recovery at hospital discharge. Model AUROCs were 0.697 (95%CI 0.676-0.717) for ROSC, 0.836 (95%CI 0.810-0.861) for survival, and 0.925 (95%CI 0.904-0.946) for neurological outcome. CONCLUSION: On-scene CPR duration is a critical prognostic factor in OHCA. The proposed models highlight on-scene predictors that may inform decisions about CPR continuation and support individualized resuscitation strategies. External validation in other EMS systems is warranted.}, }
@article {pmid41858506, year = {2026}, author = {Hier, DB and Carrithers, MD and Rodríguez-Fernández, JM and Kummer, B}, title = {Editorial: The digitalization of neurology-volume II.}, journal = {Frontiers in digital health}, volume = {8}, number = {}, pages = {1806851}, doi = {10.3389/fdgth.2026.1806851}, pmid = {41858506}, issn = {2673-253X}, }
@article {pmid41858744, year = {2026}, author = {Jessee, S and Malhotra, N and Sen, M}, title = {Is the Supreme Court veering rightward? The ebb and flow of representation.}, journal = {PNAS nexus}, volume = {5}, number = {3}, pages = {pgag060}, pmid = {41858744}, issn = {2752-6542}, abstract = {Conducting novel surveys that allow the first direct comparisons between Supreme Court decisions and public preferences, Jessee et al. find that the Court moved sharply to the right between 2020 and 2021 and attribute this change to the replacement of Justice Ruth Bader Ginsburg with Justice Amy Coney Barrett. We extend Jessee et al.'s analysis by presenting additional data gathered between 2022 and 2025. We find that the Supreme Court maintained its conservative position in 2022 but then moderated in 2023 following the backlash to the decision in Dobbs v. Mississippi (2022), which repealed Roe v. Wade (1973). We show that despite the composition of the Court remaining stable and the identity of the median voter being unchanged between 2021 and 2025, there is an ebb and flow to the representativeness of Court decisions, with the institution sometimes further to the right of the public and then sometimes shifting closer to the average voter. However, despite these important periodic shifts, the Court has, since 2021, generally remained in a more conservative position relative to the ideological positioning of the American electorate. Our findings have important implications for the legitimacy of the Court and the stability of the rule of law.}, }
@article {pmid41858792, year = {2026}, author = {Raber, J and Sharpton, TJ}, title = {Diet, gut microbiome, and cognition in neurodegeneration: a review and methodological framework.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1771904}, pmid = {41858792}, issn = {1663-4365}, abstract = {The gut microbiome influences brain function through the gut-brain axis via synthesis of neurotransmitters, production of metabolites affecting epithelial barrier integrity and immune modulation and signaling through the vagus nerve. In humans, microbiome diversity reflects healthy aging and predicts survival, while dysbiosis is increasingly implicated in neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS. Fecal transplant studies in germ-free mice demonstrate that microbiome alterations are sufficient to induce cognitive and neuropathological phenotypes, supporting causality in preclinical models. Genetic risk factors and environmental exposures affect both neurodegeneration risk and microbiome composition. In this review, we synthesize evidence from human cohorts and preclinical models on the gut-brain axis in cognitive health and disease. We then present a methodological framework for diet-microbiome-cognition research, addressing causal inference through mediation analysis, supervised approaches for deriving diet scores, validation strategies, and individual heterogeneity. This framework can guide development of microbiome-targeted dietary interventions to improve cognitive outcomes.}, }
@article {pmid41859232, year = {2026}, author = {Sharbafshaaer, M and Pirozzi, MA and Caiazzo, G and Canale, F and Silvestro, M and Russo, A and Tessitore, A and Esposito, F and Trojsi, F}, title = {Subcortical microstructural impairment in amyotrophic lateral sclerosis: clinical correlates of neurite orientation dispersion and density imaging (NODDI) changes.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1757470}, pmid = {41859232}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving widespread network disruption beyond the motor cortex. Deep gray matter (DGM) nuclei, crucial for motor and cognitive integration, remain underexplored in vivo. This study applied neurite orientation dispersion and density imaging (NODDI) to evaluate DGM microstructure and its relationship with clinical disability in ALS.<br><br>METHODS: Diffusion-weighted MRI data were acquired from 23 ALS patients and 24 age- and sex-matched healthy controls. Orientation dispersion index (ODI), neurite density index (NDI), and free water fraction (FWF) were extracted from the bilateral thalamus, caudate, putamen, pallidum, hippocampus, and amygdala using the Destrieux atlas. Group comparisons and partial correlations were adjusted for age, sex, and disease duration.<br><br>RESULTS: No significant group differences in DGM volumes or NODDI-derived metrics survived correction for multiple comparisons. Within the ALS group, several nominal (uncorrected) associations were observed between DGM microstructural metrics and ALSFRS-R subscores. Reduced respiratory subscores were associated with higher ODI in the left thalamus (&#x3c1; = 0.57, p = 0.0047, uncorrected). Fine-motor subscores showed nominal positive associations with ODI in the left (&#x3c1; = 0.48, p = 0.021, uncorrected) and right amygdala (&#x3c1; = 0.51, p = 0.012, uncorrected). Gross motor subscores were nominally associated with NDI in the right thalamus (&#x3c1; = 0.58, p = 0.004, uncorrected), left thalamus (&#x3c1; = 0.42, p = 0.047, uncorrected), left caudate (&#x3c1; = 0.52, p = 0.011, uncorrected), and right caudate (&#x3c1; = 0.57, p = 0.033, uncorrected). None of these associations survived false discovery rate correction and should therefore be interpreted as exploratory.<br><br>DISCUSSION: These findings suggest subtle and predominantly exploratory associations between DGM microstructural properties and clinical measures in ALS. NODDI derived metrics, particularly ODI and NDI, may provide sensitive indices of subcortical microstructural variation, warranting further investigation in larger cohorts.}, }
@article {pmid41860162, year = {2026}, author = {Mak, SS and McManus, P and Greer, S and Haws, K and Carlson, CJ and Chandler, HK and Osinubi, O and Ash, GI}, title = {Deployment of an Activity Monitoring Program to Complement a Clinical Intervention for Veterans With Gulf War Illness: Qualitative Study.}, journal = {JMIR human factors}, volume = {13}, number = {}, pages = {e82177}, doi = {10.2196/82177}, pmid = {41860162}, issn = {2292-9495}, mesh = {Humans ; *Veterans/statistics &amp; numerical data/psychology ; *Persian Gulf Syndrome/therapy ; Male ; Qualitative Research ; Middle Aged ; Female ; Adult ; Feasibility Studies ; United States ; }, abstract = {BACKGROUND: Many veterans who served in the Gulf experience Gulf War Illness (GWI), a chronic multisymptom condition associated with fatigue, pain, gastrointestinal problems and respiratory issues, mood/cognitive issues, and sleep difficulties. These symptoms contribute to decreased function, increased mental health needs, and poor quality of life. The Veterans Affairs War Related Illness and Injury Study Center in New Jersey developed a 26-week virtual health coaching intervention to support symptom management for veterans with GWI. In 2023, a consumer-grade smartwatch was added as part of an activity monitoring program to complement this program.<br><br>OBJECTIVE: The purpose of this project was to assess the feasibility and acceptability of including a smartwatch-based activity monitoring component to complement a virtual health coaching program for veterans with GWI.<br><br>METHODS: Twenty-four veterans enrolled in the health coaching program were invited to participate in the activity monitoring component. Participants attended a virtual orientation to set up the smartwatch, and verbal consent to share data through a Health Insurance Portability and Accountability Act (HIPAA)-compliant platform was obtained. Program feasibility was assessed by evaluating wear-time percentage and duration of use. Acceptability was assessed using two items from a monthly survey and through a midprogram semistructured interview. Quantitative data were summarized descriptively, and qualitative data were analyzed using a coding scheme adapted from Sekhon et al's Theoretical Framework for Acceptability (TFA).<br><br>RESULTS: Twenty veterans agreed to participate in the program (mean age 49 years; 7/20, 35% female; 19/20, 94% non-Hispanic White; 11/20, 55% first-time smartwatch users). Twelve participants (60%) wore the watch for the full 26 weeks. Among participants who completed 26 weeks, median daily wear-time completeness exceeded 80% for 25 weeks. Most participants (12/20, 60%) reported that wearing the smartwatch helped them achieve their wellness goals, and the majority (16/20, 80%) said they would recommend using the smartwatch for activity monitoring to other veterans. Qualitative findings supported acceptability across TFA domains. One adverse event was reported (minor skin irritation that resolved after changing the smartwatch band to a hypoallergenic watch band).<br><br>CONCLUSIONS: Within this clinical program, pairing a smartwatch with virtual health coaching for veterans with GWI was feasible and acceptable. Activity monitoring integrated into an existing intervention may support symptom self-management and augment patient education and engagement. As no prior activity monitoring programs specific to veterans with GWI have been described, these findings could inform future program development and implementation within this population.}, }
@article {pmid41860208, year = {2026}, author = {Pirdankar, OH and Nene, AS and Thakur, R and Shah, S and Shenoy, P and Badole, P}, title = {Intravitreal Anti-vascular Endothelial Growth Factor in Retinopathy of Prematurity: A Bibliometric Analysis.}, journal = {Journal of pediatric ophthalmology and strabismus}, volume = {}, number = {}, pages = {1-10}, doi = {10.3928/01913913-20251106-02}, pmid = {41860208}, issn = {1938-2405}, abstract = {Retinopathy of prematurity (ROP) is one of the leading cause of blindness in premature infants. A bibliometric analysis on intravitreal anti-vascular endothelial growth factor (VEGF) in ROP was conducted. A comprehensive search of the article on the Scopus database was conducted with the terms related to "anti-vascular endothelial growth factor and retinopathy of prematurity." Only original research and review articles published in the English language were considered. VOSviewer version 1.6.20 was used for the visualization and analysis of the data. Publication trend, productive countries, researchers' details, commonly cited documents, source and influential journals, and keyword occurrence were analyzed. A total of 329 studies were considered, of which 270 were original articles and 59 were review articles. The highest numbers of publications were seen in the year 2022. The United States, China, Turkey, India, and Taiwan were the top 5 countries that published research on the use of anti-VEGF in ROP. The most documents were published by Wei-Chi Wu (22) and Chi-Chun Lai (14), and Falavarjani et al's article had the most citations (737). A total of 2,504 keywords were identified. All keyword analysis revealed the occurrence of "retinopathy of prematurity" and "human" as a keyword was 290 and 286 times, respectively. Most articles and citations were found in Retina. The use of anti-VEGF in ROP is constantly evolving and bibliometric analysis highlights a research trend and influential authors and journals that have published significant work on it. This article can serve as a guide to conduct a literature review for future researchers.}, }
@article {pmid41860259, year = {2026}, author = {Burt-Oberecken, N and Megat, S and Rouaux, C}, title = {[Protective effect of a CREB3 gain-offunction variant in amyotrophic lateral sclerosis].}, journal = {Medecine sciences : M/S}, volume = {42}, number = {3}, pages = {234-237}, doi = {10.1051/medsci/2026027}, pmid = {41860259}, issn = {1958-5381}, }
@article {pmid41860888, year = {2026}, author = {Bao, S and Bajet, A and Martínez, R and Müller-Trede, J and Engeler, I and Hafenbrädl, S}, title = {Commentary: On the Equal-Opportunity Jerk "Defense": Rudeness Complicates Sexism Attributions but Comes at a Cost.}, journal = {Psychological science}, volume = {}, number = {}, pages = {9567976261418939}, doi = {10.1177/09567976261418939}, pmid = {41860888}, issn = {1467-9280}, abstract = {Sexism is a pervasive and persistent problem. In their 2022 article "The 'Equal-Opportunity Jerk' Defense: Rudeness Can Obfuscate Gender Bias" (Psychological Science, Vol. 33, pp. 397-411), Belmi et al. argued that sexism can be obfuscated and go unpunished if perpetrators also act rudely toward men: the "equal-opportunity jerk defense." We introduce a simple Bayesian model that accounts for Belmi et al.'s findings and corroborated their predictions and implications in five preregistered experiments (N = 6,968 U.S. adults recruited via Prolific). We replicated that being rude toward men decreased perceived sexism but importantly found that it came at the cost of increased punishment (Study 1). Moreover, rudeness primarily decreased actors' perceived sexism, whereas their actions were still perceived as sexist (Study 2). Sexism ratings were sensitive to prior beliefs about the prevalence of sexism and to the diagnosticity of observed sexist behavior (Supplementary Studies S1-S2), in line with a broader Bayesian perspective. Bias in sexism ratings thus need not implicate fallacious cognitive processes or an "illusion of gender blindness."}, }
@article {pmid41861112, year = {2026}, author = {Fu, P and Zhang, X and Zhou, Y and Zheng, J and Sun, A and Zhuang, K and Bao, W and Gao, G}, title = {Embedded CRISPRi Enhances Gene-Silencing Efficiency in Drosophila.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e15849}, doi = {10.1002/advs.202515849}, pmid = {41861112}, issn = {2198-3844}, support = {32500494//National Natural Science Foundation of China/ ; 32370631//National Natural Science Foundation of China/ ; //priority academic program development of jiangsu higher education institutions/ ; }, abstract = {CRISPR interference (CRISPRi), leveraging catalytically inactive Cas9 (dCas9), has transformed transcriptional silencing. However, its application in Drosophila melanogaster has been constrained by inconsistent efficiency and limited repression amplitude. Here, we present embedded CRISPR interference (emCRISPRi), an advanced gene-silencing platform that integrates transcriptional repression domains (Mxi and TRD) into a structurally flexible region of dCas9. This design significantly enhances silencing efficiency, enabling robust repression of coding genes and cis-regulatory elements, particularly at transcription start site (TSS)-proximal regions. emCRISPRi demonstrates improved gene-silencing activity compared to RNA interference (RNAi) at several tested loci and facilitates strong phenotypic rescue via unmodified cDNA. Its versatility is demonstrated through the dissection of Hippo pathway interactions and the mitigation of TDP-43-induced neurotoxicity in an amyotrophic lateral sclerosis (ALS) model. These findings position emCRISPRi as a transformative tool for functional genomics, enhancer studies, and disease modeling in Drosophila, with significant potential for cross-species adaptation and therapeutic innovation.}, }
@article {pmid41861506, year = {2026}, author = {Oka, S and Yamazaki, T and Takefuji, Y}, title = {Breaking the spline: Why distributed lag non-linear models miss thresholds in environmental psychiatry.}, journal = {Psychiatry research}, volume = {360}, number = {}, pages = {117104}, doi = {10.1016/j.psychres.2026.117104}, pmid = {41861506}, issn = {1872-7123}, abstract = {This critique evaluates Monti et al.'s investigation into associations between air pollution, apparent temperature, and schizophrenia severity. While their findings indicate significant short‑ and medium‑term effects of PM10 and thermal stress on PANSS scores, several methodological limitations warrant caution. Their study relies on residential exposure assignments, which may not capture individual mobility or indoor environments, potentially introducing substantial exposure misclassification. Despite appropriately modeling delayed and non-linear effects, the DLNM's reliance on predefined spline structures may oversimplify the complex, synergistic interactions among atmospheric variables. Seasonal discrepancies-such as the absence of PM10 effects in autumn-winter-may reflect unmodeled dependencies or limited pollutant data, particularly for PM2.5 and black carbon. To address these constraints, future research should incorporate flexible, data‑driven approaches, particularly those capable of uncovering latent structures within environmental mixtures. Unsupervised feature‑clustering methods can identify correlated pollutant groupings and reduce dimensional noise, while rank‑based correlation metrics provide robust assessment of non‑linear dependencies that are often obscured by parametric spline specifications. These non‑parametric techniques can complement DLNM by capturing multivariate synergies and interaction patterns that rigid basis structures may overlook. Overall, integrating such approaches is essential for advancing analytical capacity and improving risk assessment for vulnerable psychiatric populations.}, }
@article {pmid41851044, year = {2026}, author = {Takeda, T and Ishikawa, A and Kokubun, S and Saito, Y and Isose, S and Ito, K and Arai, K and Kuwabara, S and Honda, K}, title = {Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlag017}, pmid = {41851044}, issn = {1554-6578}, abstract = {Loss of upper and lower motor neurons (MNs) is a defining pathological feature underlying the clinical manifestations of amyotrophic lateral sclerosis (ALS). However, the differences in MN loss and TDP-43 pathology between these areas in ALS patients remain unclear. This study included 7 patients with ALS and 3 controls from consecutive autopsies. The cell density and regional density of TDP-43-positive inclusions in 4 upper MN areas and their anatomically corresponding lower MN areas were measured. The numbers of large cells with loss of nuclear TDP-43 and cytoplasmic delta-like-1 homolog (DLK1) were counted. The results showed severe MN loss in both upper and lower MN areas. However, TDP-43-positive inclusions differed markedly, that is they were rare in upper MNs but abundant in lower MN. In upper MN areas, TDP-43 density was not associated with the residual rate of MNs, whereas in lower MN areas, the density in MNs was associated with the cell residual rate. Significantly higher numbers of MNs lacking nuclear TDP-43 and cytoplasmic DLK1 were observed in the upper and lower MN regions in ALS vs controls. These findings suggest that these morphological changes may be closely related to motor neuron vulnerability and may be mechanistic contributors to ALS development.}, }
@article {pmid41851249, year = {2026}, author = {Leinders, S and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Geukes, SH and Schippers, A and Verberne, MSW and van den Boom, MA and van der Vijgh, BH and Crone, NE and Denison, T and Ramsey, NF and Vansteensel, MJ}, title = {Implanted brain-computer interface functionality during nighttime in late-stage amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-44228-7}, pmid = {41851249}, issn = {2045-2322}, support = {UH3NS114439/NS/NINDS NIH HHS/United States ; ADV 320708/ERC_/European Research Council/International ; UGT7685//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; U01DC016686/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain-computer interfaces (BCIs) hold promise as assistive communication technology for people with severe paralysis. Although such BCIs should be available 24/7, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an electrocorticography-BCI user with amyotrophic lateral sclerosis. We investigated nocturnal dynamics of neural signal features used for BCI control. Additionally, we assessed nocturnal performance of a decoder trained on daytime data, by quantifying the number of unintentional BCI activations at night. Finally, we developed a nightmode functionality and assessed its performance. Mean and variance of low and high frequency band power were significantly higher at night than during the day. When applied to night data, daytime decoders caused unintentional BCI activations in 100% of nights (245 unintended click-commands and 13 unintended caregiver-calls per hour). The specifically developed nightmode functionality, however, functioned error-free in 79% of nights over a period of ± 1.5 years, allowing the user to reliably call the caregiver. Reliable nighttime use of a BCI requires strategies to adjust to circadian and sleep-related signal changes. This demonstration of a reliable nightmode and its long-term use by an individual with amyotrophic lateral sclerosis underscores the importance of 24/7 BCI reliability.}, }
@article {pmid41851271, year = {2026}, author = {Hodgson, RE and Huang, WP and Lang, R and Kumar, V and An, H and Stender, EGP and Chalakova, ZP and Driver, MD and Sanchez Avila, A and Ellis, BCS and Day, E and Rayment, JA and Baeg, K and Strange, A and Moll, T and Wright, GSA and van Vugt, JJFA and ,  and Allen, SP and Locker, N and Pitout, I and Fletcher, S and Onck, PR and Duss, O and Cooper-Knock, J and Shelkovnikova, TA}, title = {Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection.}, journal = {Nature cell biology}, volume = {}, number = {}, pages = {}, pmid = {41851271}, issn = {1476-4679}, support = {MR/W004615/1//Research Councils UK (RCUK)/ ; MR/W028522/1//RCUK | Medical Research Council (MRC)/ ; BB/V014110/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; PhD studentship//Motor Neurone Disease Association (MNDA)/ ; 969-799//Motor Neurone Disease Association (MNDA)/ ; PhD studentship//MND Scotland (Motor Neuron Disease Scotland)/ ; }, abstract = {The paraspeckle is a disease-relevant biomolecular condensate assembled from long non-coding RNA (lncRNA) NEAT1_2 ribonucleoprotein particles. Paraspeckle biogenesis is suppressed in normal tissues, yet it can be rapidly upregulated under stress. Here we demonstrate that a neurodegeneration-linked RNA-binding protein TDP-43 inhibits NEAT1_2 ribonucleoprotein particle condensation into the paraspeckle, in a concentration-dependent manner, which requires its intact polymerization and RNA binding. This effect is counterbalanced by core paraspeckle proteins such as FUS. Below disruptive concentrations, TDP-43 can be recruited into paraspeckles, forming non-liquid clusters. Under stress, TDP-43 sequestration into de novo nuclear condensates alleviates paraspeckle suppression and increases their dynamism. NEAT1_2 middle-part and 3'-end UG repeats mediate paraspeckle regulation by TDP-43 cotranscriptionally and post assembly, respectively. The deletion of the 3'-end UG repeat increases paraspeckle stability and cytoprotection in stressed human neurons. Consistently, longer 3'-end UG repeats are linked to shorter survival in the neurodegenerative disease amyotrophic lateral sclerosis. Thus, TDP-43 is a critical regulator of paraspeckle condensates linked to cytoprotection.}, }
@article {pmid41851470, year = {2026}, author = {Michaelis, T and Lindestam Arlehamn, CS and Johansson, E and Frazier, A and Williams, GP and Berry, JD and Cudkowicz, M and Goyal, NA and Fournier, C and Snyder, A and Kwan, JY and Crook, J and Phillips, EJ and Mallal, SA and Ravits, J and Marder, KS and Sidney, J and Sulzer, D and Sette, A}, title = {Author Correction: Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41586-026-10388-9}, pmid = {41851470}, issn = {1476-4687}, }
@article {pmid41852184, year = {2026}, author = {Gagliardi, D and Villella, C and Zanovello, M and Iacobelli, V and Corti, S and Comi, GP and Fratta, P and Houlden, H and Tucci, A and Ronchi, D}, title = {High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78195}, pmid = {41852184}, issn = {1531-8249}, support = {//Italian Ministry of Health/ ; MR/Z506503/1//UK Medical Research Council/ ; MR/S006753/1//UK Medical Research Council/ ; }, abstract = {OBJECTIVE: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.<br><br>METHODS: We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40&#x2009;years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance.<br><br>RESULTS: We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.<br><br>INTERPRETATION: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026.}, }
@article {pmid41852280, year = {2026}, author = {Isik, FI and Pickford, R and Timmins, HC and Piguet, O and Halliday, GM and Kiernan, MC and Kim, WS}, title = {Systemic dysregulation of apolipoproteins in amyotrophic lateral sclerosis serum.}, journal = {FEBS open bio}, volume = {}, number = {}, pages = {}, doi = {10.1002/2211-5463.70232}, pmid = {41852280}, issn = {2211-5463}, support = {IM-202303-00957//FightMND/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Increasing evidence implicates systemic lipid perturbation in ALS pathogenesis. However, the extent and nature of apolipoprotein changes underlying lipid perturbations in ALS remain largely unknown. To address this, we performed a comprehensive analysis of major apolipoproteins involved in lipid metabolism and examined their association with lipoprotein membrane lipids in sporadic ALS (n = 32) and age-matched healthy controls (n = 32), using ELISA and liquid chromatography-mass spectrometry. Compared with controls, serum levels of apoB, apoCI, apoCII, apoCIII and apoE were significantly elevated in ALS, whereas apoAI and apoAII were unchanged. Distributional analyses demonstrated a relative decrease in apoAI and an increase in apoB in ALS, resulting in an elevated apoB/apoAI ratio, a marker of atherogenic risk, alongside a reduced apoAI/apoE ratio. Correlation analyses revealed strengthened interrelationships among apolipoproteins in ALS, suggesting altered regulatory coordination. At the lipid level, phosphatidylcholine (PC) was increased, whereas sphingomyelin (SM) was reduced in ALS serum. Notably, the strong associations of apoB to both PC and SM observed in controls were absent in ALS. Biomarker analyses identified apoE as the strongest discriminator between ALS and control groups. Collectively, these findings demonstrate a coordinated disruption of apolipoproteins and lipoprotein-associated lipids in ALS serum, with likely functional consequences for lipoprotein metabolism. This study provides new insights into lipid dysregulation in ALS pathobiology and supports the emerging view that ALS encompasses not only neurodegenerative processes but also systemic metabolic reprogramming.}, }
@article {pmid41852613, year = {2026}, author = {Montesanti, S and Bradley, N and Demedeiros, S and McKay, R}, title = {Designing for implementation: a cognitive task analysis of intimate partner violence screening in hospital trauma care in Alberta, Canada.}, journal = {Frontiers in health services}, volume = {6}, number = {}, pages = {1743548}, pmid = {41852613}, issn = {2813-0146}, abstract = {BACKGROUND: Intimate partner violence (IPV) has serious health consequences, yet routine IPV screening remains inconsistently implemented in hospital trauma centres. Despite evidence supporting screening, implementation challenges persist. This study used Cognitive Task Analysis (CTA) to examine how trauma care providers perceive and enact IPV screening, with attention to cognitive processes, barriers, and facilitators to implementation.<br><br>METHODS: We conducted CTA group interviews with nine trauma care providers from two trauma centers in Edmonton, Alberta, Canada. Participants included trauma surgeons, nurse practitioners, social workers, and patient care managers. Using a structured interview guide and concept mapping techniques, we elicited knowledge structures, decision-making processes, and perceived constraints related to IPV screening. We applied an interpretive qualitative approach to uncover underlying themes related to cognitive work and task complexity. Grounded theory techniques, such as open and axial coding, were used in conjunction with CTA to analyze how participants reasoned through clinical scenarios. We paid close attention to how providers assessed cues, coordinated across roles, shifted priorities, and navigated organizational constraints. This hybrid approach allowed us to bridge systems-level implementation science with cognitive insights, drawing conceptually on CFIR and Proctor et al.'s implementation outcomes to generate actionable knowledge for IPV screening interventions in trauma care settings.<br><br>RESULTS: Themes were synthesized into six overarching cognitive domains: trauma care workflow, team collaboration and knowledge, critical situations and decision-making, IPV screening practices and challenges, understanding patient experiences, and institutional support. These were further illustrated through refined concept maps that visually represented participants' mental models, task sequences, and decision-making strategies.<br><br>CONCLUSION: Trauma care providers are well-positioned to identify IPV, yet screening is constrained by limited institutional support, unclear procedures, and poor integration into trauma workflows. Findings highlight the need for system-level strategies that align IPV screening with the cognitive and organizational realities of trauma care. By applying CTA, this study informs the design and implementation of context-sensitive IPV screening interventions that are more acceptable, appropriate, and feasible in hospital trauma settings. Furthermore, this study informs implementation strategies for integrating IPV screening interventions into trauma care, with particular implications for improving the acceptability, appropriateness, feasibility, and sustainability of evidence-based practices.}, }
@article {pmid41853322, year = {2026}, author = {Elshaer, A and Thomas, L}, title = {Investigating inequality in Advanced Life Support courses: a retrospective, single-centre, survey-based pilot study.}, journal = {Resuscitation plus}, volume = {28}, number = {}, pages = {101283}, pmid = {41853322}, issn = {2666-5204}, abstract = {BACKGROUND: With more International Medical Graduates (IMGs) joining the United Kingdom's medical workforce, the demand for Advanced Life Support (ALS) courses has increased. Whilst differential attainment among IMGs is well-documented, little is understood about this phenomenon in ALS courses. This study explores the relationship between ALS course participants' background and course outcomes.<br><br>METHODS: Doctors who attended ALS courses at a UK course centre were retrospectively recruited to participate in a 28-question online survey about their language, education and clinical backgrounds, as well as their ALS course experience and outcomes. Quantitative and qualitative analyses were carried out, and recommendations were thematically summarised.<br><br>RESULTS: Of 419 invited healthcare professionals, 38 doctors (9%) completed the survey. 27 (71.1%) of the respondents graduated outside the UK, 32 (84.2%) studied medicine in English, and 15 (39.5%) were native English speakers. Passing the Cardiac Arrest Simulation Tests (CAS-Test) was statistically associated with more previous scenario-based simulation experience. Thematic analysis of responses suggested that biased treatment, language barriers, communication anxiety, inadequate undergraduate training, vulnerability, rigid professionalism and psychological insecurity were obstacles to IMGs attaining course outcomes. Suggestions for improvement focused on enhancing course accessibility, learning materials, the educational environment, assessment, and faculty development.<br><br>CONCLUSIONS: This exploratory study investigates IMGs' self-reported challenges and proposes interventions to promote the inclusivity of ALS courses. Further prospective research is required to evaluate the nature and generalisability of these findings and the applicability of the offered recommendations.}, }
@article {pmid41853978, year = {2026}, author = {Piotrowski, SL and Allnutt, MA and Johnson, K and Tanaka, T and Ferrucci, L and Morris, H and Hardy, J and ,  and Ryten, M and ,  and Logroscino, G and Troncoso, J and Beach, TG and Serrano, GE and Cruchaga, C and Dickson, DW and Ross, OA and Chiò, A and ,  and ,  and Houlden, H and ,  and Dalgard, CL and Ding, J and Gibbs, JR and Traynor, BJ and Scholz, SW and Jacobson, S}, title = {Herpesvirus genome integration in whole-genome sequences of dementia and control cohorts.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {3}, pages = {e71047}, doi = {10.1002/alz.71047}, pmid = {41853978}, issn = {1552-5279}, support = {1ZIAAG000935/AG/NIA NIH HHS/United States ; P30AG019610/AG/NIA NIH HHS/United States ; P30AG072980/AG/NIA NIH HHS/United States ; U24AG021886/AG/NIA NIH HHS/United States ; P50AG016574/AG/NIA NIH HHS/United States ; U19AG071754/AG/NIA NIH HHS/United States ; R01AG087165/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; 1ZIANS003154/NS/NINDS NIH HHS/United States ; U54-NS110435/NS/NINDS NIH HHS/United States ; P50NS072187/NS/NINDS NIH HHS/United States ; 211002//Arizona Department of Health Services/ ; 4001 0011 05-901//Arizona Biomedical Research Commission/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; //Ted Turner and family/ ; //Little Family Foundation/ ; //Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy body dementia program/ ; }, mesh = {Humans ; *Dementia/virology/genetics ; *Genome, Viral/genetics ; *Herpesvirus 6, Human/genetics ; *Virus Integration/genetics ; Cohort Studies ; Whole Genome Sequencing ; Aged ; Female ; Male ; *Herpesviridae/genetics ; Alzheimer Disease/virology/genetics ; }, abstract = {INTRODUCTION: The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized.<br><br>METHODS: Over 7500 total whole-genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool.<br><br>RESULTS: Low PathSeq scores for human herpesvirus 6 (HHV-6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV-6 genome integration.<br><br>DISCUSSION: This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV-6 may play a role in a subset of these patients.<br><br>HIGHLIGHTS: Over 7500 whole-genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV-6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.}, }
@article {pmid41854033, year = {2026}, author = {Fragkoudi, A and Stern, C and Pollock, D and Barker, TH and Semendric, I and Labra, J and Vucic, S and Whitehouse, J and Munn, Z}, title = {Identifying priorities for a national motor neurone disease (amyotrophic lateral sclerosis) guideline: results from an Australian online survey.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/09638288.2026.2643544}, pmid = {41854033}, issn = {1464-5165}, abstract = {PURPOSE: To identify the priorities of people living with motor neurone disease (MND), their carers, asymptomatic genetic carriers, and healthcare professionals (HCPs) in Australia, to inform the development of a national MND care guideline.<br><br>METHODS: An anonymous online survey was distributed via MND organisations and groups to the Australian MND community.<br><br>RESULTS: Two hundred and fourteen individuals completed the survey. Of those, 44.8% (n&#xa0;=&#xa0;96) were HCPs, with the remaining consisting of people living with MND, genetic carriers, and carers. The following areas were rated as extremely important and should be included in the guideline: diagnosis, service delivery models, clinical care management, caregiver support, and palliative care; while views on genetic testing and cognitive assessment were mixed. Participants highlighted a need for holistic care which considered emotional/psychological and physical aspects of MND. People with MND and their carers want the Australian MND care guideline to highlight proactive and coordinated support prioritising quality of life, while maintaining independence for as long as possible.<br><br>CONCLUSIONS: Identifying priorities is a fundamental step that will shape the forthcoming Australian MND care guideline. This methodology ensures the voices of those with lived experience and interest holders are incorporated from the outset.}, }
@article {pmid41854301, year = {2026}, author = {Walker, TB and Trowbridge, JW and McMahon, S and Marzano, NR and Rice, L and Yerbury, JJ and Ecroyd, H and McAlary, L}, title = {Small heat shock proteins HspB1 and HspB5 differentially alter the condensation and aggregation of the TDP-43 low-complexity domain.}, journal = {Protein science : a publication of the Protein Society}, volume = {35}, number = {4}, pages = {e70539}, doi = {10.1002/pro.70539}, pmid = {41854301}, issn = {1469-896X}, support = {//Motor Neurone Disease Australia/ ; //FightMND/ ; APP1194872//National Health and Medical Research Council/ ; }, mesh = {Humans ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Protein Aggregates ; *HSP27 Heat-Shock Proteins/metabolism/chemistry/genetics ; *alpha-Crystallin B Chain/metabolism/chemistry/genetics ; Molecular Chaperones/metabolism ; Protein Domains ; Phosphorylation ; Heat-Shock Proteins ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein that regulates processes of mRNA metabolism, during which it undergoes condensation mediated by its C-terminal low-complexity domain (TDP-43[LCD]). TDP-43 aggregation and condensation are associated with neurodegenerative disease. However, the proteostasis mechanisms that regulate these processes remain elusive. Some evidence has shown that the molecular chaperone small heat shock protein HspB1 binds to and regulates the cytoplasmic phase separation of TDP-43, indicating that other small heat shock proteins may have similar effects. Here, we demonstrate divergent behaviors for HspB1 and its homolog HspB5 on TDP-43[LCD] condensation and aggregation. In addition to inhibiting TDP-43[LCD] aggregation, HspB1 partitions into TDP-43[LCD] condensates and increases the dynamic exchange of TDP-43[LCD] within condensates and with the surrounding solution. Phosphorylation-mimicking mutations within HspB1 enhance these effects. HspB5 inhibits TDP-43[LCD] aggregation more effectively than HspB1 and partitions into TDP-43[LCD] condensates, where it delays the pathological transition of the condensate to a gel/solid. We identify the N- and C-terminal regions of HspB1 and HspB5 to be crucial for the chaperone effects, and highlight the role of sequence diversity within these regions in defining small heat shock protein function. These findings demonstrate that HspB1 and HspB5 are regulators of TDP-43 phase separation and aggregation and may be potential therapeutic targets in mitigating toxic TDP-43 aggregation in neurodegenerative disease.}, }
@article {pmid41854370, year = {2026}, author = {Morojele, NK and London, L and Saban, A and Myers, B and Harker, N and Mokwena, K and Zingela, Z and Nkosi, S and Ayieko, P and Kapiga, S}, title = {Implications of COVID-19 Restrictions on the Ethics and Methods of a Multi-Site Study on Alcohol and Other Drug (AOD) Use Treatment among Men in South Africa.}, journal = {Journal of empirical research on human research ethics : JERHRE}, volume = {}, number = {}, pages = {15562646261427563}, doi = {10.1177/15562646261427563}, pmid = {41854370}, issn = {1556-2654}, abstract = {Public health measures for medical emergencies generate methodological and ethical challenges for human research. Using Emanuel et al.'s framework, we assessed the ethical integrity of the research methods used in a men's alcohol and other drug (AOD) use disorder study following their revision due to COVID-19 restrictions in South Africa. Following the amendments, the study's social value, favorable risk-benefit ratio, and respect for participants increased. Collaborative partnership, scientific validity, fair participant selection, independent review, and informed consent improved in terms of successful stakeholder engagements and interviewing procedures, but were compromised due to a cellphone access eligibility criterion and complicated consenting procedures. Methodological and ethical challenges of research during health emergencies can be navigated with flexibility and innovation.}, }
@article {pmid41854409, year = {2026}, author = {Shukla, A and Upadhyay, A and Qadeer, M and Thakur, AD and Raj, R}, title = {Eco-friendly Immersion-Coating Strategy for Scalable and Durable Superhydrophobic Aluminum Surfaces.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.langmuir.5c05945}, pmid = {41854409}, issn = {1520-5827}, abstract = {Superhydrophobic (SHPB) surfaces have strong potential to mitigate corrosion, fouling, and icing, yet conventional fabrication methods rely on fluorinated modifiers, toxic reagents, or multistep protocols that limit scalability and conformal coverage on complex geometries. Here, we report an eco-friendly, scalable, and fluorine-free immersion-coating strategy for developing SHPB aluminum (SHPB-Al) surfaces using an ionic liquid (IL, 1-ethyl-3-methylimidazolium chloride) and lauric acid (LA) as nontoxic precursors. The central novelty lies in generating the requisite hierarchical roughness via an ionic liquid adsorption-driven surface modification mechanism, rather than through conventional material-removal or etching processes, thereby minimizing substrate damage and preserving structural integrity. Specifically, the two-step protocol first forms an IL-derived adsorbed substrate layer that induces hierarchical topography and hydrophilicity, followed by lauric acid functionalization to reduce surface energy and induce superhydrophobicity. Systematic optimization of the precursor concentration and dip duration identifies an optimum condition that achieves a static contact angle (SCA) of ≈165° with contact angle hysteresis (CAH) of <5°. Microscopy and surface analyses confirm the presence of hierarchical textures and robust chemical grafting. Durability tests under harsh chemical, thermal, mechanical, and environmental conditions reveal minimal performance loss (SCA > 150° and CAH < 10°), underscoring the coating's reliability. Droplet dynamics exhibit ≥15 successive rebounds, a coefficient of restitution of ≈0.9, and contact times as short as ≈10 ms, demonstrating ultralow adhesion. Building on these insights, we introduce an improvised one-step IL-LA codeposition method that simplifies the fabrication route while retaining high performance (SCA of ≈160° and CAH of ≈5°) and prolonged durability under environmental exposure. Together, this fluorine-free immersion-coating framework offers durable, scalable, and nontoxic routes for producing SHPB-Als, enabling conformal coatings on complex geometries such as heat-exchanger fins and paving the way for industrial deployment in harsh service environments.}, }
@article {pmid41854827, year = {2026}, author = {Calvache Anaya, JA and Urdiales Merino, A and Druetta, NN and Sanz Rigo, M and Cardona Monjo, AM}, title = {Nonlinear and Asymmetric Refractive Sensitivity to Effective Lens Position Errors in Pseudophakic Eye Models.}, journal = {Ophthalmic &amp; physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists)}, volume = {}, number = {}, pages = {}, pmid = {41854827}, issn = {1475-1313}, abstract = {PURPOSE: To perform a theoretical analysis of refractive sensitivity to effective lens position (ELP) errors in pseudophakic eyes using an explicit vergence-based optical model, and to quantify how this sensitivity depends on axial length (AL) and corneal power across a wide biometric range.<br><br>METHODS: A paraxial two-lens thin-lens model of the pseudophakic eye was developed, explicitly parameterised by AL, total corneal power (TCP), intraocular lens (IOL) power and effective lens position (ELP). Refraction was calculated at the corneal plane using vergence propagation. For a fixed reference ELP, the emmetropic IOL power was derived analytically for each combination of AL and TCP, and subsequently held constant while ELP was perturbed by &#xb1;1.0&#x2009;mm. Simulations were performed for ALs from 19 to 31&#x2009;mm and corneal powers from 38 to 50 dioptres. Refractive changes were approximated using families of quadratic regression models as functions of AL.<br><br>RESULTS: Refractive sensitivity to ELP errors was dominated by AL. Short eyes exhibited large refractive changes per millimetre of ELP error, whereas long eyes showed markedly reduced sensitivity. The relationship between refractive error and ELP displacement was nonlinear, resulting in asymmetric refractive effects for equal-magnitude anterior and posterior ELP deviations. TCP continuously modulated refractive sensitivity indirectly through its influence on the emmetropic IOL power required for a given optical configuration.<br><br>CONCLUSIONS: Refractive sensitivity to ELP errors in pseudophakic eye models is inherently nonlinear and asymmetric. This sensitivity is primarily governed by AL, with TCP acting as a secondary but systematic modulator through its effect on emmetropic IOL power. By explicitly separating optical sensitivity from ELP prediction, this vergence-based framework provides a physical basis for understanding ELP-related refractive variability across the biometric spectrum.}, }
@article {pmid41856038, year = {2026}, author = {Nguyen, L}, title = {Repeat expansion RNA elicits toxicity through hybrid G-quadruplexes with promoter DNA.}, journal = {Neuron}, volume = {114}, number = {6}, pages = {969-971}, doi = {10.1016/j.neuron.2026.02.018}, pmid = {41856038}, issn = {1097-4199}, mesh = {*G-Quadruplexes ; Humans ; *Promoter Regions, Genetic/genetics ; C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Repeat Expansion/genetics ; *RNA/genetics ; *DNA/genetics ; *Proteins/genetics ; }, abstract = {In this Neuron issue, Liu et al.[1] show that the C9orf72 expanded G4C2 repeat RNA forms hybrid G-quadruplexes with CG-rich promoter regions, which impedes RNA polymerase II. This process causes global transcriptional dysregulation in C9orf72 amyotrophic lateral sclerosis patient-derived cells.}, }
@article {pmid41856386, year = {2026}, author = {Sadler, SM and Volker, DK and Garguilo, D and Gould, D}, title = {An Analysis of United States Olympic and Paralympic Committee National Governing Body Policies Related to Body Pressures, Body Image Concerns, and Eating Pathology.}, journal = {Psychology of sport and exercise}, volume = {}, number = {}, pages = {103124}, doi = {10.1016/j.psychsport.2026.103124}, pmid = {41856386}, issn = {1878-5476}, abstract = {Athletes are often exposed to body pressures in sport environments, which can contribute to body image concerns and eating pathology, with lasting consequences for performance and well-being. Although research has highlighted the harmful impacts of these concerns, and has called for a broader investigation into the sources of athletes' experiences of these concerns, little is known about the role of sport organizations in influencing athletes' body pressures, body image concerns, and eating pathology. Using a descriptive qualitative research design within a post-positivist paradigmatic approach, the current study explored the frequency and content of body- and eating-related policies within the United States Olympic &amp; Paralympic Committee's (USOPC) 51 national governing bodies, examining differences in policy frequency and content by sport type. National governing body websites were searched for policy documents aligned with Viollet et al.'s (2023) definition of sport policy. Following reflexive content analysis (Nicmanis, 2024) of 156 body- and eating-related policies, five overarching categories were identified: (a) uniform requirements, (b) athlete body image and nutrition-related supports, (c) organizational strategies to prevent body- and eating-related concerns, (d) body- and eating-related maltreatment, and (e) athletes' responsibilities related to nutrition and body weight. Findings highlight the inconsistent and often vague nature of existing national governing body policies, underscoring the need for standardized and comprehensive policies. Practical recommendations include developing both proactive and reactive body- and eating-related policies, providing clear and specific guidance, and critically examining gendered appearance standards communicated through policy to create a more inclusive sport culture that reduces athletes' experiences of body pressures, body image concerns, and eating pathology.}, }
@article {pmid41845095, year = {2026}, author = {Gurunandan, K and Greve, A and Wilmot, E and Henson, RN}, title = {Does signed prediction error drive declarative memory? Evidence from variable choice paradigms.}, journal = {Memory &amp; cognition}, volume = {}, number = {}, pages = {}, pmid = {41845095}, issn = {1532-5946}, support = {EP/Y016815/1//Engineering and Physical Sciences Research Council/ ; SUAG/046/G101400/MRC_/Medical Research Council/United Kingdom ; POS_2023_2_0034//Eusko Jaurlaritza/ ; }, abstract = {Prediction error (PE) is the discrepancy between predictions and new information. For a binary reward outcome, PE may be signed (positive if the outcome was better than predicted and negative if the outcome was worse than predicted) or unsigned (absolute value of "surprise"). Using a "variable choice" paradigm, De Loof et al. (PLOS ONE, 131, Article e0189212, 2018) examined the role of PE in one-shot learning of unknown translations of known words and showed that associative memory for the translation was greater when (financial) reward was more unexpected and lesser when an expected reward was not received (i.e., signed PE); an effect that they replicated in several subsequent studies. However, other work on PE in declarative memory has assumed that memory is greater when an outcome is more unexpected, without any explicit reward (i.e., unsigned PE). We replicated De Loof et al.'s paradigm with and without financial reward, and found that memory was explained slightly better by unsigned PE (Experiments 1A-1B). However, we also identified a potential confound in the paradigm that could explain the results without any role of PE, as confirmed by simulations. We therefore designed a modified version of the paradigm that circumvents this confound (Experiment 2). Results were inconsistent with the PE account. We conclude that variable choice paradigms may not be well-suited to investigate the role of PE in one-shot declarative learning, and that the purported role of signed PE in declarative memory requires further investigation.}, }
@article {pmid41845971, year = {2026}, author = {Dahlhaus, R and Braun, RJ}, title = {The role of TDP-43 fragments in regular cellular functions and homeostatic failure.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {107349}, doi = {10.1016/j.nbd.2026.107349}, pmid = {41845971}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons, leading to severe muscle weakness, loss of voluntary movement, and respiratory failure. A widely noted feature of the disease is the presence of TDP-43 proteinopathies. Under homeostatic conditions, the RNA/DNA-binding protein TDP-43 mainly resides in the nucleus, where it functions to regulate gene expression, controlling not only RNA transcription and splicing, but also stability and transport to the cytoplasm. Upon the arrival at ribosomes, TDP-43 may further moderate translation, acting as a global repressor of protein synthesis. However, in over 95% of ALS cases, TDP-43 mislocalies from the nucleus to the cytoplasm, where it enriches in cytoplasmic inclusions that are marked by the presence of misfolded, ubiquitinated, phosphorylated and fragmented protein species of TDP-43. Although recent studies have tried to untangle the relationship between TDP fragments on the one hand, and cytotoxicity as well as neurodegeneration on the other, the results are still a matter of debate. Here, we review our current understanding of the different TDP fragments derived from proteolytic cleavage as well as alternative splicing, addressing the different N-terminal and C-terminal species and evaluating differences in rodent and primate models. We focus our analysis on the potential homeostatic functions of TDP fragments in the context of viral infections and myelination control, which are potentially pivotally interconnected. The findings illustrate several facets of fragmented TDP-43 protein species in scenarios of enhanced cellular stress. Gaining a detailed understanding could help to reveal new treatment options for ALS and other TDP-43 proteinopathies.}, }
@article {pmid41846014, year = {2026}, author = {Yang, L and Fan, W and Wang, Z and Wu, M and Chen, Y and Cheng, J and Zhou, F and Guo, Z}, title = {The role of IRF5 in Microglia-Mediated neuroinflammation in ALS.}, journal = {Neuroscience letters}, volume = {}, number = {}, pages = {138580}, doi = {10.1016/j.neulet.2026.138580}, pmid = {41846014}, issn = {1872-7972}, abstract = {The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implicated in the disease mechanisms of various conditions. However, its mechanism in ALS remains unclear. This study found that IRF5 expression was significantly increased in hSOD1-G93A transgenic ALS mice and cell models, primarily localized in activated microglia. Silencing IRF5 altered microglial polarization, suppressed the release of inflammatory factors, enhanced phagocytic function, and reduced motor neuron apoptosis in a co-culture system. Mechanistic studies suggested that IRF5 may regulate microglial function through the NF-κB signaling pathway. This study reveals the key role of IRF5 in microglia-mediated neuroinflammation and neuronal damage in ALS, indicating that targeting IRF5 could represent a promising treatment strategy for this disease.}, }
@article {pmid41846418, year = {2026}, author = {Ahire, C and Yadav, R and Bhamare, UU and Kaur, G and Palkar, MB}, title = {From Refractory Epilepsy to Neurodegeneration: Emerging Mechanistic and Clinical Insights Into the Ketogenic Diet.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {40}, number = {6}, pages = {e71609}, doi = {10.1096/fj.202503317R}, pmid = {41846418}, issn = {1530-6860}, mesh = {*Diet, Ketogenic/methods ; Humans ; Animals ; *Neurodegenerative Diseases/diet therapy/metabolism ; *Drug Resistant Epilepsy/diet therapy/metabolism ; }, abstract = {The ketogenic diet (KD), a high-fat, low-carbohydrate intervention, is well established for drug-resistant epilepsy and is increasingly explored in neurodegenerative disorders. KD reduces neuronal hyperexcitability through enhanced γ-aminobutyric acid (GABA)ergic transmission and modulation of neurotransmitter balance, underlying its efficacy in refractory epilepsy. Beyond seizure control, emerging evidence suggests KD may influence disease processes in conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. Preclinical studies indicate that KD can modulate mitochondrial bioenergetics, oxidative stress, neuroinflammation, neurotransmitter signaling, and gut-brain interactions, though these effects are highly context-dependent and primarily derived from cellular and animal models. Clinical data remain limited, heterogeneous, and short-term, with small cohorts and variable outcome measures. Sustaining adherence and assessing long-term safety remain significant challenges in patient populations. This review summarizes recent experimental and clinical findings, highlighting the molecular and cellular mechanisms through which KD exerts neuroprotective effects. We also evaluate translational evidence and discuss the potential utility of KD as an adjunctive intervention in neurological disease management.}, }
@article {pmid41846510, year = {2026}, author = {Raby, KL}, title = {Synthesizing five decades of research on sensitive caregiving: A commentary on Nivison et al. (2026).}, journal = {Journal of child psychology and psychiatry, and allied disciplines}, volume = {}, number = {}, pages = {}, doi = {10.1111/jcpp.70146}, pmid = {41846510}, issn = {1469-7610}, abstract = {This commentary highlights the contributions of Nivison et al.'s (2026) umbrella meta-analysis synthesizing five decades of research on sensitive caregiving and child development. Integrating findings from numerous meta-analyses, the authors demonstrate that caregiver sensitivity is meaningfully associated with multiple domains of child development. Notably, associations with cognitive and language development are at least as large as those with attachment security and behavior problems, expanding traditional conceptualizations of sensitivity's developmental significance. The findings further indicate substantial consistency across child, parent, and family demographic characteristics, while suggesting amplified benefits in socioeconomically disadvantaged contexts. This commentary underscores key gaps in the literature, including the need for meta-analytic investigations of children's peer competence, self-regulation, and physical health outcomes, as well as the need for refined measurement of caregiving dimensions. Although causal inferences require randomized intervention evidence, the synthesis provides compelling support for sensitive caregiving as a central determinant of healthy development and offers a roadmap for future research and policy.}, }
@article {pmid41846565, year = {2026}, author = {Denby, K and Connelly, EDS and Glerup, H and Østgård, R and Egsgaard, AL and Vedsted, P and Appel, CW}, title = {Translation and cross-cultural adaptation of the Identification of Spondyloarthritis Questionnaire (IBIS-Q) into Danish for patients with inflammatory bowel disease.}, journal = {Scandinavian journal of gastroenterology}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/00365521.2026.2645081}, pmid = {41846565}, issn = {1502-7708}, abstract = {OBJECTIVES OF THE ARTICLE: Spondyloarthritis (SpA) affects 10-30% of patients with inflammatory bowel disease (IBD). An early diagnosis is essential as a delayed diagnosis of SpA increases the risk of disability and reduces quality of life. However, few screening tools for patients with IBD exist and none are available in Danish. To support early identification of spondyloarthritis symptoms in Danish patients with IBD, this study aimed to translate and cross-culturally adapt the Identification of Spondyloarthritis Questionnaire (IBIS-Q) into Danish and to assess face validity of the Danish version.<br><br>MATERIALS AND METHODS: Following Beaton et&#xa0;al.'s six step forward-backward translation guideline, the IBIS-Q was translated and cross-culturally adapted into Danish. This was done through an iterative process with an expert committee of translators, clinicians, methodologists and with inclusion of the IBIS-Q developers. Face validity was assessed through semi-structured interviews with 24 adults with and without arthritis-related symptoms.<br><br>RESULTS: Participants generally found the questionnaire easy to understand, and face validity was confirmed. The semantic equivalence of painful and sore in a Danish context was a central topic of discussion within the expert committee. However, only minor modifications were made, including the addition of an introductory paragraph and changing the questionnaire's title.<br><br>CONCLUSIONS: Following an international, standardised guideline, the IBIS-Q was successfully translated and cross-culturally adapted into Danish, and face validity was confirmed. The IBIS-Q is the first available questionnaire to assess Danish patients with IBD for SpA symptoms. Psychometric validation of the measurement properties of IBIS-Q is recommended prior to implementation.}, }
@article {pmid41847237, year = {2026}, author = {Zarco-Martín, MT and Andreo-López, MC and Yagui-Beltrán, MS and Fernández-Soto, ML}, title = {Sarcopenia in amyotrophic lateral sclerosis: a key predictor of respiratory dysfunction and disease progression.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1713253}, pmid = {41847237}, issn = {2296-861X}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness and respiratory decline. Sarcopenia remains underexplored in terms of prevalence and their relationship with disease progression. We aimed to determine the prevalence of sarcopenia in ALS patients, assess the predictive value of morphofunctional assessment tools for sarcopenia, and explore their relationship with respiratory function and disease progression.<br><br>METHODS: A cross-sectional study was conducted with 40 ALS patients at the ALS Multidisciplinary Unit, San Cecilio University Hospital in Granada. Sarcopenia was defined based on the European Working Group of Sarcopenia in Older People 2(EWGSOP2) and malnutrition was diagnosed using GLIM criteria. Morphofunctional status was assessed using: Phase Angle (PA) and body composition by Bioelectrical Impedance Vector Analysis, muscle strength through Handgrip Strength (HGS). Respiratory function was evaluated using Forced Vital Capacity (FVC). Associations between sarcopenia, body composition, respiratory function, and disease severity were analyzed using logistic regression models. Receiver operating characteristic analyses were performed to identify optimal predictive cut-off values.<br><br>RESULTS: Sarcopenia was identified in 25% of ALS patients. Compared with non-sarcopenic individuals, sarcopenic patients exhibited significantly lower muscle mass indices, PA, and HGS, along with higher extracellular water percentage (%ECW). Malnutrition was more frequent in sarcopenia group (90% vs. 25%, p&#x202f;<&#x202f;0.001). Respiratory impairment was more pronounced in sarcopenic patients, with reduced FVC and elevated pCO&#x2082; (p&#x202f;=&#x202f;0.02), and a greater need for non-invasive mechanical ventilation (NIMV) (70% vs. 10%, p&#x202f;=&#x202f;0.001). VC correlated positively with body cell mass index (BCMI) (r&#x202f;=&#x202f;0.450), skeletal muscle mass index (SMI) (r&#x202f;=&#x202f;0.413), and ALSFRS-R score (r&#x202f;=&#x202f;0.731; all p&#x202f;<&#x202f;0.05). Lower PA, BCMI, and ALSFRS-R scores, together with higher %ECW and partial pressure of carbon dioxide (pCO&#x2082;), predicted sarcopenia risk. Reduced BCMI, HGS, Short Physical Performance Battery (SPPB) and sarcopenia were associated with the need of NIMV. BCMI (cut-off:8.05&#x202f;kg/m[2]; AUC:0.889) and ALSFRS-R (cut-off:33 points; AUC:0.884) were the most accurate predictors of sarcopenia and ventilatory support, respectively.<br><br>CONCLUSION: This study is the first to assess sarcopenia prevalence in ALS patients using standardized diagnostic criteria. The findings highlight the relationship between sarcopenia, malnutrition, and respiratory decline. PA, BCMI, and respiratory parameters emerge as potential tools for sarcopenia and NIMV risk stratification.}, }
@article {pmid41847382, year = {2026}, author = {Talbot, SR and Scorrano, F and Gaburro, S and Lainee, P and van Gaalen, MM}, title = {From observation to optimization: behavioral metrics that matter in KPI based home cage monitoring.}, journal = {Frontiers in behavioral neuroscience}, volume = {20}, number = {}, pages = {1694689}, pmid = {41847382}, issn = {1662-5153}, abstract = {Most in vivo scientists would agree that digital biomarkers collected via home-cage monitoring generate valuable data. However, few can tell precisely how valuable. The gap between enthusiasm and evidence has slowed the adoption of digital biomarkers in preclinical research. This framework paper addresses that gap by providing explicit key performance indicators (KPIs), organized into scientific, operational, welfare, and financial categories. We show how return-on-investment calculations differ across pharmaceutical companies, contract research organizations (CROs), and academic institutions. Furthermore, we demonstrate the approach through a worked example in an Amyotrophic Lateral Sclerosis (ALS) mouse model that reduces full-time equivalent (FTE) requirements by half. When successfully integrated, digital biomarkers can generate richer datasets, reduce the number of animals, improve welfare, and enhance translational value. However, successful implementation requires clear performance metrics to justify investment and measure success. We also discuss what these technologies cannot do, because understanding limitations matters as much as understanding benefits.}, }
@article {pmid41850140, year = {2026}, author = {Gao, Y and Sun, Z and Wei, Q and She, C and Wang, Y and Chen, J and Wang, M and Gui, X and Xia, X and Liu, Y and Wang, X}, title = {Employing an integrated computational simulation strategy to identify high-affinity ligands for TDP-43 amyloid proteins.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {137}, number = {}, pages = {118634}, doi = {10.1016/j.bmc.2026.118634}, pmid = {41850140}, issn = {1464-3391}, abstract = {Developing high-affinity ligands targeting TDP-43 amyloid species is a potential therapeutic approach for amyotrophic lateral sclerosis (ALS). Here, we propose an integrated computational simulation strategy, which integrates multiple virtual screening methods, molecular dynamics simulations and binding free energy evaluations. Using this strategy, we successfully identified TDPL1, a high-affinity ligand for TDP-43 amyloid proteins. In vitro affinity assays confirmed the computational predictions. Based on the MD simulation results, we further investigated the binding mode between TDPL1 and TDP-43 amyloid proteins. Additionally, steered molecular dynamics simulations were employed to assess the impact of TDPL1 on the stability of β-sheet interactions within the TDP-43 amyloid structure. Our data demonstrate that TDPL1 not only binds effectively to TDP-43 amyloid proteins but also possesses the potential to disrupt the stability of amyloid aggregates. These findings provide a molecular foundation for the future development of diagnostic agents or targeted therapeutics for ALS and related diseases.}, }
@article {pmid41850233, year = {2026}, author = {Guise, AJ and Ferber, KL and Young, D and Edwards, AL and Sabouri, S and Fraser, KB and Milliman, E and Plowey, ED and Zoghbi, J and Fradette, SM and Graham, DL}, title = {Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics.}, journal = {Cell reports. Medicine}, volume = {7}, number = {3}, pages = {102648}, doi = {10.1016/j.xcrm.2026.102648}, pmid = {41850233}, issn = {2666-3791}, mesh = {Humans ; *Proteomics/methods ; *Biomarkers/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics ; Superoxide Dismutase-1/genetics ; Male ; Female ; Middle Aged ; Adult ; Membrane Glycoproteins/cerebrospinal fluid ; Aged ; }, abstract = {Tofersen, the first approved genetically targeted therapy for amyotrophic lateral sclerosis (ALS), demonstrates significant lowering of plasma neurofilament in adults carrying mutations in the superoxide dismutase 1 (SOD1) gene; however, additional biomarkers of treatment response in ALS are lacking. Here, we analyze longitudinally collected cerebrospinal fluid (CSF) samples from the phase 3 VALOR clinical trial to identify candidate tofersen treatment-response biomarkers in SOD1-ALS via quantitative proteomics. We observe significant modulation from baseline abundance for 56 proteins in tofersen-treated participants relative to placebo, including CSF GPNMB, which is significantly and continuously elevated across all post-baseline timepoints. We orthogonally confirm this observation by GPNMB immunoassay in independent tofersen-treated cohorts. Taken together, these data identify pharmacodynamic-response biomarkers of tofersen treatment that can be measured as early as 4 weeks post-treatment in SOD1-ALS patients and demonstrate the utility of leveraging unbiased proteomic screening integrated with targeted validation methods to identify pharmacodynamic-response biomarkers in clinical trial patient samples.}, }
@article {pmid41850301, year = {2026}, author = {Glaubitz, R and Harst, L and Ehm, F and Tesch, F and Barlinn, J and Krause, F and Schwarz, R and Malzahn, J and Werblow, A and Sinz, C and Randig, I and Riedel, T and Kutschker, C and Fiebig, S and Kubitza, J and Cording, M and Wolff, J and Schmitt, J}, title = {Testing a model-based approach for planning and regional coordination of hospital service group offerings: A model project in the East Saxony healthcare cluster.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2771-8616}, pmid = {41850301}, issn = {1439-4421}, abstract = {The hospital reform passed in 2024 will lead to regional and nationwide changes in the German hospital landscape. A joint project to examine the effects of the hospital reform on health care structures in the East Saxony region was initiated by the Center for Evidence-Based Health Care (ZEGV) at Dresden University Hospital, the regional health care coordinators of the four districts in the East Saxony care cluster and the city of Dresden, a statutory health insurance provider (AOK PLUS), and other regional stakeholders. In addition, the aim was to promote cooperation between the stakeholders for the purpose of future regionally coordinated planning for inpatient care. The project involved the application and validation of a model displaying a hospital's relevance for stationary care provision (care relevance model), which was developed in cooperation with the GKV-Spitzenverband (National Association of Statutory Health Insurance Funds) and is based on the performance data of German hospitals in accordance with § 21 KHEntgG (Hospital Remuneration Act). Thirty of the 36 hospital locations in the project region agreed to participate in the project. Both in a questionnaire-based self-assessment provided by the clinics and during a joint cluster conference, the tension between the need for cooperation and individual interests became clear. At this point, the care relevance model developed can scientifically support the dialogue between the stakeholders and thus support inpatient planning.Im Zuge der im Jahr 2024 verabschiedeten Krankenhausreform wird es zu regionalen und deutschlandweiten Veränderungen der Krankenhauslandschaft kommen. Vor diesem Hintergrund wurde ein gemeinsames Projekt des Zentrums für Evidenzbasierte Gesundheitsversorgung (ZEGV) der Hochschulmedizin Dresden mit den Regionalkoordinator:innen für Gesundheit der vier Landkreise im Versorgungscluster Ostsachsen und der Stadt Dresden, der AOK PLUS und weiteren regionalen Akteuren initiiert, um die Auswirkungen der Krankenhausreform auf die Versorgungsstrukturen in der Region Ostsachsen zu untersuchen. Zudem sollte die Kooperation zwischen den Akteuren zum Zweck einer zukünftigen regional abgestimmten Planung für die stationäre Versorgung gefördert werden. Im Projekt erfolgte die Anwendung und Validierung eines Versorgungsrelevanzmodells, welches in Kooperation mit dem GKV-Spitzenverband entwickelt wurde und auf den Leistungsdaten deutscher Krankenhäuser nach § 21 KHEntgG basiert. Dreißig von 36 Krankenhausstandorten in der Projektregion konnten für eine Teilnahme am Projekt gewonnen werden. Sowohl in einer fragebogengestützten Selbstauskunft der Kliniken als auch im Rahmen der zusammenführenden Clusterkonferenz wurde das Spannungsfeld zwischen Kooperationsnotwendigkeiten und Partikularinteressen deutlich. An dieser Stelle kann das entwickelte Versorgungsrelevanzmodell den Dialog zwischen den Akteuren wissenschaftlich begleiten und so die stationäre Planung unterstützen.}, }
@article {pmid41850981, year = {2026}, author = {Pu, Y and Cao, X}, title = {KLHL6: a proteostatic guardian against T-cell exhaustion.}, journal = {Trends in immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.it.2026.02.003}, pmid = {41850981}, issn = {1471-4981}, abstract = {Cheng et al.'s recent study identifies the Cullin3-RING E3 ubiquitin ligase complexes (CRL3) adaptor protein Kelch-like protein 6 (KLHL6) as a proteostasis regulator whose downregulation in chronically stimulated T cells leads to the accumulation of thymocyte selection-associated high mobility group box protein and phosphoglycerate mutase family member 5, driving T-cell dysfunction. This work positions T-cell exhaustion as a proteostatic disorder and highlights KLHL6 as a promising target for cancer immunotherapy.}, }
@article {pmid41842529, year = {2026}, author = {Zhao, J and Ji, X and Leng, L and Wang, M and Li, Y and Wang, W and Sun, Y}, title = {Integrating terrain and spectral attributes for automated water-land classification using airborne LiDAR without any prior information.}, journal = {Applied optics}, volume = {65}, number = {7}, pages = {2053-2062}, doi = {10.1364/AO.579495}, pmid = {41842529}, issn = {1539-4522}, abstract = {Accurate differentiation between water and land is crucial for flood monitoring, land-use planning, and ecological protection. Airborne laser scanning (ALS) provides high-resolution three-dimensional topographic and intensity data, offering a robust foundation for these applications. However, existing classification approaches largely depend on manually defined thresholds or supervised learning, with limited attention to the underlying synergies among multidimensional features, thereby constraining both accuracy and automation. To address these limitations, this study introduces an unsupervised classification framework based on multi-feature fusion, where four fusion indicators are derived from 14 geometric and radiometric features, enabling fully automated water-land classification. Experiments on two ALS datasets from central Dublin demonstrate that the proposed method substantially outperforms SLIER, fuzzy logic, and elevation-threshold approaches, achieving overall accuracies of 98.3% and 97.3%, with Kappa coefficients of 0.903 and 0.914. Beyond improving classification accuracy and reducing computational complexity, the fusion indicators also enhance digital elevation model (DEM) reconstruction by repairing voids in water regions and refining boundary delineation, thereby reinforcing the value of ALS data for environmental monitoring and disaster management.}, }
@article {pmid41843813, year = {2026}, author = {Meyer, T and Ticozzi, N and Weber, M and Ravits, J and Lingor, P and Kuźma-Kozakiewicz, M and Boentert, M and Grehl, T and Corcia, P and Povedano Panadés, M and Maier, A and Ingre, C and Cetin, H and Weydt, P and Lunetta, C and van den Berg, L and Ludolph, AC and Brenner, D and Turner, MR and Genge, A}, title = {ALS motor phenotypes: a revised 'OPM' classification.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2026.2644277}, pmid = {41843813}, issn = {2167-9223}, abstract = {BACKGROUND: Defining motor phenotypes in amyotrophic lateral sclerosis (ALS) is important for individualized care and optimal therapeutic trial design. The "ALS-OPM" classification is based on the onset region (O), the propagation of motor symptoms (P), and the degree of clinical upper (UMN) and/or lower (LMN) motor neuron dysfunction (M).<br><br>METHODS: An international ALS expert focus group was held in September 2025, followed by a consensus process through which revisions of the OPM classification were finalized.<br><br>RESULTS: Onset (O1-4) identifies first motor symptoms as relating to the head (O1), distal/proximal arm (O2d/p), respiratory/axial trunk (O3r/a), or distal/proximal leg (O4d/p). Onset symptoms are defined by weakness or slowed, poorly coordinated voluntary movements in the muscles of the head, arm, trunk, or leg, including dysarthria, dysphagia, dysphonia, dyspnea, and axial instability. Propagation (P1(n)) or absence of propagation (P0(n)) of motor symptoms from the onset region to another body region are designated, where n denotes the number of months from onset to propagation or assessment. The degree of UMN dysfunction (slowed, poorly coordinated voluntary movements, hyperreflexia and/or spastic muscle tone, emotional lability) and/or LMN dysfunction (weakness with associated muscle atrophy) is classified as follows: balanced UMN and LMN dysfunction (M0); dominant (M1d) or pure UMN dysfunction (M1p); dominant (M2d) or pure LMN dysfunction (M2p); and dissociated UMN/LMN dysfunction (M3), in which the arms and legs predominantly show LMN and UMN involvement, respectively.<br><br>CONCLUSION: The revised ALS-OPM classification aims to make it routine, practical and feasible to capture phenotype in clinical practice and therapeutic trials.}, }
@article {pmid41350059, year = {2026}, author = {Sarker, SC and Chen, J and Wang, C and He, S and Yu, H and Li, X and Cui, H}, title = {ALS target-site mutations and overexpression synergistically enhance mesosulfuron resistance in Lolium perenne.}, journal = {Pesticide biochemistry and physiology}, volume = {216}, number = {Pt 2}, pages = {106802}, doi = {10.1016/j.pestbp.2025.106802}, pmid = {41350059}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Lolium/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; Mutation ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; }, abstract = {The invasive weed Lolium perenne (perennial ryegrass) poses a considerable threat to winter wheat crops in China and is hardly controlled by acetolactate synthase (ALS) inhibitors after years of application. In this study, four L. perenne populations from different locations in Henan were collected to evaluate the mechanisms of target site resistance to mesosulfuron-methyl. The resistant index (RI) of these four populations ranged from 122.73 to 149.26 compared to the susceptible population. ALS gene sequencing revealed three specific target site mutations: Pro-197-Thr, Asp-376-Glu, and Trp-574-Leu. Among these, Trp-574-Leu has not been previously reported in L. perenne. Three simultaneous double mutations were found in the same individual: Pro-197-Thr and Asp-376-Glu (Group I); Pro-197-Thr and Trp-574-Leu (Group II); and Asp-376-Glu and Trp-574-Leu (Group III). The gene expression levels of the double mutant groups were significantly higher than those of the susceptible plants. The I50 values obtained from the ALS enzyme assays showed that all three double mutant groups demonstrated a 136.75 to 149-fold increase compared to the enzyme activity of susceptible plants. Molecular docking analysis of mutant ALS proteins with mesosulfuron-methyl indicated that the mutant proteins had a reduced binding affinity to the herbicide. This reduced affinity was due to the disruption of hydrogen bonds and other key interactions, which contributed to increased herbicide resistance. Double target site mutations in a single ALS gene are a crucial mechanism for conferring high levels of mesosulfuron-methyl resistance in L. perenne.}, }
@article {pmid41350075, year = {2026}, author = {Wu, G and Chen, Y and Yao, Y and Huang, W and Wu, K}, title = {Integrating network toxicology and molecular docking to uncover mechanisms of novel herbicide-induced neurodegeneration.}, journal = {Pesticide biochemistry and physiology}, volume = {216}, number = {Pt 2}, pages = {106821}, doi = {10.1016/j.pestbp.2025.106821}, pmid = {41350075}, issn = {1095-9939}, mesh = {*Herbicides/toxicity/chemistry ; *Molecular Docking Simulation ; Humans ; *Neurodegenerative Diseases/chemically induced/metabolism ; Protein Interaction Maps ; }, abstract = {Rising global reliance on novel herbicides has outpaced understanding of their potential neurotoxicity. This study employs an integrative network-toxicology pipeline to clarify how five widely used compounds, including mesotrione, topramezone, flufenazopyr, glufosinate-ammonium and beflubutamid-M, may contribute to Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis pathogenesis. We first predicted toxic liabilities in eMolTox, SwissADME and ProTox, then harvested 310 human targets via PubChem, ChEMBL, STITCH and Swiss Target Prediction. Intersection with 3668-3429 disease genes (GeneCards/ OMIM) revealed 91-176 shared targets per disorder. PPI networks constructed in STRING and refined with Cytoscape (MCODE, cytoHubba) and novel NodeIdentifyR algorithm converged on eleven high-impact hub genes: EGFR, GSK3B, SRC, AKT1, MAPT, CASP3, MMP9, MTOR, PTK2, BCL2L1 and MAPK8. GO and KEGG enrichment analyses highlighted apoptosis, PI3K-Akt and MAPK signaling dysregulation. Single-cell and bulk transcriptomic atlases confirmed aberrant expression of these hubs in patient brains; Molecular docking demonstrated low-nanomolar affinities of all herbicides for multiple hub proteins, with mesotrione and topramezone displaying the broadest binding spectra and SRC emerging as a common high-affinity site. Molecular dynamics simulations supported stable binding in a representative herbicide-protein complex. Additionally, in vivo and in vitro experiments using Glufosinate-ammonium exposure corroborated the computational findings, underscoring the robustness of our approach. Together, these results establish a systems-level framework linking environmental herbicide exposure to neurodegeneration and nominate tractable targets for surveillance and therapeutic intervention.}, }
@article {pmid41350201, year = {2026}, author = {Hokkoku, K and Inoue, M and Yamada, S and Namba, H and Matsukura, K and Mukai, T and Chiba, T and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {Reply to the letter by Marimbun et al. on fasciculation awareness in ALS.}, journal = {Journal of the neurological sciences}, volume = {480}, number = {}, pages = {125677}, doi = {10.1016/j.jns.2025.125677}, pmid = {41350201}, issn = {1878-5883}, }
@article {pmid41350294, year = {2025}, author = {Williams, SE and Luisi, K and Liang, C and Cane, A and Begier, E}, title = {Methodological Issues in Taquet et al.'s analysis preclude any conclusions regarding AS01 adjuvant's specific role in dementia prevention.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {255}, pmid = {41350294}, issn = {2059-0105}, abstract = {Taquet et al. evaluated the impact of AS01-adjuvanted vaccines on subsequent dementia diagnosis[1]. The authors conclude: "No difference was observed between the two AS01-adjuvanted vaccines, suggesting that the AS01 adjuvant itself plays a direct role in lowering dementia risk". Although the study offers promising evidence, the inference regarding the role of AS01 adjuvant in dementia prevention is not convincingly supported by the presented data or other published literature[2].}, }
@article {pmid41350409, year = {2025}, author = {Cheng, S and Zhong, C and Zhu, H and Mu, K and Jiang, H and Zhong, P and Ma, Z and Liu, X and Wang, Z and Liu, R and Ding, Y}, title = {Structural mechanisms and insights on multiple nanobodies binding diverse SOD1 epitopes.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {30}, pmid = {41350409}, issn = {2399-3642}, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/immunology/genetics ; *Single-Domain Antibodies/chemistry/metabolism/immunology ; Humans ; *Epitopes/chemistry/immunology/metabolism ; Protein Binding ; Amyotrophic Lateral Sclerosis ; Models, Molecular ; Crystallography, X-Ray ; Protein Conformation ; }, abstract = {Copper/zinc superoxide dismutase (SOD1) is a crucial metalloenzyme that mitigates oxidative stress by scavenging superoxide anion radicals. Mutations and aggregation of SOD1 are closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). Targeting pathogenic SOD1 with nanobodies presents a promising therapeutic approach. We report the first high-resolution crystal structures of SOD1 in complex with three distinct nanobodies (Nb1, Nb2, and Nb3) and their multimeric assemblies (1:2 and 1:3 stoichiometries), revealing distinct binding epitopes primarily mediated by their complementarity determining regions (CDRs) through hydrogen bonds, salt bridges, and hydrophobic interactions. Structural and biophysical analyses using isothermal titration calorimetry (ITC) and fluorescence-detection size-exclusion chromatography (FSEC) demonstrated that all three nanobodies bind SOD1 simultaneously with nanomolar affinities (KD values ranging from 23.2 nM to 529 nM). Notably, engineered multimeric tandem nanobodies (Nb1-Nb2-Nb3) achieved higher affinity (KD = 4.39 nM) compared to single nanobodies, as validated by ITC. Characterization via dynamic light scattering (DLS) further revealed colloidal stability of SOD1-nanobody complexes. These results provide the first atomic-resolution insights into multi-nanobody targeting of SOD1 without steric interference, establishing a foundation for developing high-affinity tools to detect and manipulate SOD1 in ALS and related neurodegenerative diseases.}, }
@article {pmid41350806, year = {2025}, author = {Nakamura, R and Tohnai, G and Atsuta, N and Matsuda, Y and Morimoto, S and Ito, D and Katsuno, M and Izumi, Y and Morita, M and Iwata, I and Yabe, I and Nakazato, T and Hattori, N and Hirayama, T and Kano, O and Tamura, A and Suzuki, N and Aoki, M and Shibuya, K and Kuwabara, S and Oda, M and Hashimoto, R and Aiba, I and Ishihara, T and Onodera, O and Yamashita, T and Ishiura, H and Bokuda, K and Shimizu, T and Ikeda, Y and Hasegawa, K and Tanaka, F and Yokota, T and Kanai, K and Noto, YI and Kaji, R and Watanabe, H and Konishi, T and Hasegawa, M and Fukaya, H and Niwa, JI and Doyu, M and Okada, Y and Nakamura, S and Ozawa, F and Okano, H and Nakatochi, M and Sobue, G and , }, title = {A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1720}, pmid = {41350806}, issn = {2399-3642}, support = {23FC0201//Ministry of Health, Labour and Welfare (Ministry of Health, Labour and Welfare, Japan)/ ; JP23ek0109492, JP23ak0101111, JP23ak0101124, JP24wm0425009//Japan Agency for Medical Research and Development (AMED)/ ; JP24ak0101216, JP24ak0101222, JP25wn0625519, JP25ak0101216, JP25ak0101222, JP25ek0109617//Japan Agency for Medical Research and Development (AMED)/ ; JP23ek0109538//Japan Agency for Medical Research and Development (AMED)/ ; JP23bm1123046, JP23kk0305024, JP23bm1423002//Japan Agency for Medical Research and Development (AMED)/ ; JP24bm1423003//Japan Agency for Medical Research and Development (AMED)/ ; JP23bm1123046, JP23kk0305024, JP23bm1423002//Japan Agency for Medical Research and Development (AMED)/ ; JP19km0405216//Japan Agency for Medical Research and Development (AMED)/ ; 19K07973//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07359//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07509//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K06523//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07359//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K07973//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07509//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K06835//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07359//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K07509//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 25K10781//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H05278//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K06523//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K06975//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H02988//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K06975//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K24249//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H05278//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 16H06277//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H04923//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H03350//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Genome-Wide Association Study ; Age of Onset ; Female ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Aged ; Genetic Predisposition to Disease ; Adult ; *GPI-Linked Proteins/genetics ; Japan ; }, abstract = {Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10[-8]); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10[-9]). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.}, }
@article {pmid41351663, year = {2025}, author = {Amirian, R and Merati, A and Babamohamadi, M and Mirahmadi, Y and Esfahani, ML and Rahmani, S and Izadi, Z and Rezazadeh, D}, title = {Navigating the Autophagy Maze: ATG and Their Impact on Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {260}, pmid = {41351663}, issn = {1559-1182}, mesh = {*Autophagy/genetics/physiology ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Signal Transduction ; }, abstract = {Autophagy, a tightly regulated process essential for maintaining cellular homeostasis, plays a critical role in the pathogenesis and progression of neurodegenerative diseases (NDs). These disorders-marked by diverse mechanisms and clinical heterogeneity-pose significant challenges in developing effective therapies. Central to the autophagic machinery are autophagy-related genes (ATGs), whose functions and variants are increasingly recognized as pivotal in modulating disease-specific pathways. This review explores the intricate roles of ATGs in NDs, emphasizing the need for a comprehensive understanding of molecular signaling networks, protein-protein interactions, and regulatory checkpoints that may serve as therapeutic targets. We highlight recent advancements in disease modeling, autophagy assays, and biomarker identification that facilitate the translation of ATG-related discoveries into clinical practice. Furthermore, we underscore the importance of interdisciplinary collaboration across academia, industry, clinical medicine, and regulatory bodies to harness the therapeutic potential of autophagy. This article aims to serve as a detailed roadmap for understanding the role of ATGs in NDs and to illuminate promising avenues for future research and therapeutic development.}, }
@article {pmid41352634, year = {2026}, author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B}, title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.}, journal = {Brain, behavior, and immunity}, volume = {132}, number = {}, pages = {106201}, doi = {10.1016/j.bbi.2025.106201}, pmid = {41352634}, issn = {1090-2139}, mesh = {Humans ; *Endogenous Retroviruses/genetics/physiology ; *Neurodegenerative Diseases/virology/genetics ; Alzheimer Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Parkinson Disease/virology ; Frontotemporal Dementia/virology ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.<br><br>METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.<br><br>RESULTS: Twenty-six studies (N ranges: 6-485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95&#xa0;% CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.<br><br>CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.}, }
@article {pmid41352688, year = {2026}, author = {Chikuchi, R and Kato, Y and Tomatsu, A and Nishisaki, S and Kawakami, Y and Yoshimura, T and Li, J and Iguchi, Y and Onodera, K and Hashimoto, R and Aiba, I and Nakamura, R and Tohnai, G and Atsuta, N and Sobue, G and Okada, Y and Katsuno, M and Yokoi, S}, title = {The TDP-43[I383V] heterozygous mutation results in increased TDP-43 expression and altered neuronal activity in ALS patient-derived iPSC motor neurons.}, journal = {Neuroscience research}, volume = {222}, number = {}, pages = {105003}, doi = {10.1016/j.neures.2025.105003}, pmid = {41352688}, issn = {1872-8111}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; Mutation/genetics ; Rats ; Heterozygote ; Coculture Techniques ; Cells, Cultured ; }, abstract = {TAR-binding protein 43 (TDP-43) is a pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). To elucidate the pathogenesis of ALS, we generated induced pluripotent stem cells (iPSCs) from lymphoblastoid cell line (LCL) cells of an ALS patient with the TDP-43[I383V] heterozygous mutation. Furthermore, we generated isogenic wild-type iPSCs from wild-type LCL cells using scarless genome editing with CRISPR/Cas9. A modified iPSC-derived motor neuron culture method utilizing BrainPhys neuronal medium and rat astrocyte co-culture effectively promoted and maintained neuronal activity. Under these conditions, the TDP-43[I383V] heterozygous mutation resulted in increased TDP-43 protein expression through prolonged stabilization. Moreover, mutant iPSC-derived motor neurons showed increased numbers of pre-synapses and altered neuronal activity. These results suggest that the modified motor neuron culture method can help elucidate abnormalities in TDP-43 expression, synapse formation, and neuronal activity caused by the heterozygous TDP-43[I383V] mutation. The model developed in this study has the potential to facilitate the analysis of the early pathological phenotype of ALS.}, }
@article {pmid41352714, year = {2025}, author = {Maas, D and Spindler, A and Zappi, I and Shapiro, J and Lo Sicco, KI}, title = {Response to Vaz de Faria et al's ''Forehead atrophy in frontal fibrosing alopecia: An ultrasonographic and histopathological study of 10 patients".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.10.159}, pmid = {41352714}, issn = {1097-6787}, }
@article {pmid41352717, year = {2025}, author = {Doche, I and Vaz de Faria, JR}, title = {Response to Maas et al, "Response to Vaz de Faria et al's "Forehead atrophy in frontal fibrosing alopecia: An ultrasonographic and histopathological study of 10 patients"".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.12.015}, pmid = {41352717}, issn = {1097-6787}, }
@article {pmid41352930, year = {2026}, author = {Queral-Beltran, A and Lacorte, S and Tauler, R}, title = {GC-orbitrap-HRMS with ROIMCR and MSident targeted and non-targeted analysis of persistent organic pollutants in fish-based certified reference materials.}, journal = {Analytica chimica acta}, volume = {1383}, number = {}, pages = {344892}, doi = {10.1016/j.aca.2025.344892}, pmid = {41352930}, issn = {1873-4324}, mesh = {Animals ; *Gas Chromatography-Mass Spectrometry/standards/methods ; *Fishes ; *Persistent Organic Pollutants ; Reference Standards ; }, abstract = {The use of fish-based reference materials allows the validation of analytical methods used for the monitoring of persistent organic pollutants (POPs) in environmental samples. Thus, the aim of this work has been to apply and validate the Regions of Interest Multivariate Curve Resolution (ROIMCR) procedure, in a first instance, to quantify POPs using two fish-based certified reference materials (CRM) provided by the Institute of Reference Materials (IRMM); and also to identify, with the MSident program, the presence of more POPs in the same samples. Samples were extracted and analyzed by gas chromatography coupled to an Orbitrap mass spectrometer (GC-HRMS). A targeted analysis was performed to quantify the four certified POPs: hexachlorobenzene (HCBz) and hexachlorobutadiene (HCBu) in ERM®-CE100 and pentachlorobenzene (PeCB) and α, β, γ, and δ-hexachlorocyclohexane (HCH) in ERM®-CE103. Quantitative estimations obtained with ROIMCR method were compared with those obtained using the instrument vendor's Xcalibur software. Two tailed t-tests were performed and good agreement was observed between the two approaches and with the certified values. A non-targeted analysis approach was then performed to characterize other unknown POPs present in the samples. Data processed with the ROIMCR method in the non-targeted acquisition mode was complemented with the MSident chemical identification procedure, which allowed the annotation of several polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), phthalates, and polychlorinated biphenyls (PCBs). The presence of some of these compounds was confirmed with the analysis of validation standard mixture samples containing 43 POPs. The ROIMCR methodology herein proposed allows, in a first instance, the quantitative analysis of multiple unknown contaminants present in the analyzed fish-based certified samples by using GC-HRMS data and also, combined with the MSident program, enables a qualitative analysis which could provide a comprehensive assessment of POP pollution patterns in fish or other environmental samples.}, }
@article {pmid41353609, year = {2026}, author = {Van Beckhoven, D and Serrien, B and Demeester, R and Van Praet, J and Messiaen, P and Darcis, G and Henrard, S and De Munter, P and Libois, A and Deblonde, J}, title = {Reply to Satapathy et al.'s comment on "Dual cross-sectional and longitudinal perspective on the continuum of HIV care to disentangle natural epidemic evolution from real progress, Belgium 2014-2022".}, journal = {HIV medicine}, volume = {27}, number = {2}, pages = {328-331}, doi = {10.1111/hiv.70163}, pmid = {41353609}, issn = {1468-1293}, }
@article {pmid41354105, year = {2026}, author = {Mendes Araújo, L and Chianca, T and Persaud, C and Hartung, P and Soares, Y and Almirón, G and João, R}, title = {Respiratory strength training for patients with amyotrophic lateral sclerosis: A meta-analysis of randomized controlled trials.}, journal = {Respiratory medicine}, volume = {251}, number = {}, pages = {108560}, doi = {10.1016/j.rmed.2025.108560}, pmid = {41354105}, issn = {1532-3064}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; Randomized Controlled Trials as Topic ; *Breathing Exercises/methods ; Male ; Middle Aged ; Respiratory Muscles/physiopathology ; *Resistance Training/methods ; Female ; Treatment Outcome ; Aged ; Maximal Respiratory Pressures ; }, abstract = {INTRODUCTION: Respiratory strength training (RST) has been considered as a possible add-on treatment for amyotrophic lateral sclerosis (ALS). However, the benefits of RST are still controversial. We performed a meta-analysis of randomized controlled trials (RCTs) on the efficacy of RST in patients with ALS.<br><br>METHODS: PubMed, Embase and Cochrane Central were searched for RCTs comparing the use of RST with sham therapy or minimal device load in patients with ALS. The main outcomes were maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP) and the ALS functioning rating scale (ALSFRS-R) score. Statistical analysis was performed using R software and heterogeneity was assessed with I[2] statistics.<br><br>RESULTS: Four RCTs were included with a total of 138 patients. RST was used to treat 69 (50&#xa0;%) patients. The mean age was 60.2&#xa0;&#xb1;&#xa0;10.4 years, with 82 (62.3&#xa0;%) male patients. Follow-up ranged from 2 to 8 months. Subgroup analysis of expiratory muscle training protocols showed a statistically significant improvement in MEP (MD 20.22 cmH2O; 95&#xa0;% CI 2.66-37.77; p&#xa0;=&#xa0;0.04). In overall analyses, there was no difference between groups regarding MEP (MD 9.40 cmH2O; 95&#xa0;% CI -11.57-30.37; p&#xa0;=&#xa0;0.25), MIP (MD 3.26 cmH2O; 95&#xa0;% CI -9.23-15.75; p&#xa0;=&#xa0;0.38), FVC (MD 4.05 %predicted; 95&#xa0;% CI -0.91-9.01; p&#xa0;=&#xa0;0.08) and ALSFRS-R score (MD 0.01 points; 95&#xa0;% CI -0.29-0.32; p&#xa0;=&#xa0;0.85).<br><br>CONCLUSION: In this meta-analysis of RCTs including patients with ALS, expiratory muscle training was associated with increased MEP compared with sham or minimal load. However, no statistically significant associations were found for overall RST in MIP, FVC, MEP, and ALSFRS-R.}, }
@article {pmid41354564, year = {2025}, author = {Mouhi, S and Pio, T and Andersen, J}, title = {Revisiting oligodendrocytes in amyotrophic lateral sclerosis using human multicellular stem cell models.}, journal = {Trends in cell biology}, volume = {}, number = {}, pages = {}, pmid = {41354564}, issn = {1879-3088}, support = {F31 NS135955/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, muscle wasting, and eventual paralysis. The clinical and genetic complexity along with rapid disease progression has hindered efforts to model the disease and develop effective treatments. Rodent models and human tissue studies point to dysfunction in oligodendrocyte lineage cells early in disease, although the underlying mechanisms remain unclear. Advances in stem cell research have introduced novel platforms to investigate cells in the oligodendrocyte lineage and their interactions with neurons and other glial cells in complex human genetic backgrounds. This Review summarizes the literature implicating oligodendrocyte lineage cells in ALS and discusses both the potential and limitations of in vitro-derived cultures to shed light on their vulnerabilities and cellular interactions.}, }
@article {pmid41354852, year = {2025}, author = {Oraha, J and Wagner, R and Bergh, S and Lee, NJ and Kirik, D and Petersén, &#xc5;}, title = {Differential effects of overexpression of mutant huntingtin and TDP-43 in agouti-related protein neurons in the arcuate nucleus of the hypothalamus in mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {253}, pmid = {41354852}, issn = {2051-5960}, mesh = {Animals ; *DNA-Binding Proteins/genetics/metabolism ; *Neurons/metabolism/pathology ; *Agouti-Related Protein/metabolism/genetics ; Male ; *Arcuate Nucleus of Hypothalamus/metabolism/pathology ; Female ; Mice ; Mice, Transgenic ; *Nerve Tissue Proteins/genetics/metabolism ; Huntingtin Protein ; Humans ; Mutation/genetics ; *Nuclear Proteins/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {The spectrum of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Huntington disease (HD) are fatal neurodegenerative disorders with no major disease-modifying therapies. Recent work has shown that the hallmark pathological proteins TAR DNA binding protein of 43 kDa (TDP-43) in FTD/ALS and mutant huntingtin (mHTT) in HD may be interlinked. Furthermore, these disorders share early features of altered metabolism and psychiatric symptoms that have been suggested to arise from pathology in the hypothalamus, an important brain region involved in the regulation of metabolism and emotions. Agouti-related protein (AgRP)-expressing neurons localised exclusively to the arcuate nucleus (ARC) of the hypothalamus are key modulators of body weight regulation and food seeking behaviour, and they have recently been implicated in anxiety- and anhedonic-like processes. The aim of this study was to investigate the effects of overexpression of TDP-43 or mHTT in AgRP-expressing neurons on metabolic, behavioral and neuropathological features in mice. Flex-switch adeno associated viral vectors expressing human wild-type TDP-43, mHTT or green fluorescent protein to serve as a control, were injected into male and female AgRP-Cre mice to target the ARC using stereotactic surgery. We demonstrate targeted overexpression of transgenes including formation of mHTT inclusions in the ARC of the hypothalamus. Overexpression of mHTT led to a significant reduction in AgRP fibres in the hypothalamus 21 weeks post-injection, as well as higher food consumption in female mice. Overexpression of TDP-43 did not lead to the development of any metabolic or behavioral phenotypes in the mice. Our data suggest that AgRP neurons in the ARC are protected from the toxic effects resulting from overexpression of TDP-43 whereas they display some sensitivity to mHTT overexpression resulting in mHTT inclusion formation, reduction in AgRP fibers and sex-specific effects on food consumption. Taken together, other hypothalamic neuronal populations may be more important for the development of non-motor features resulting from overexpression of TDP-43 and mHTT in the hypothalamus.}, }
@article {pmid41354869, year = {2025}, author = {Tahedl, M and Kleinerova, J and McKenna, MC and Siah, WF and Hardiman, O and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Tan, EL and Hutchinson, S and Bede, P}, title = {Putative mitochondrial components of frontotemporal lobar degeneration: topological correlations between mitochondrial density and atrophy in FTLD/FTD phenotypes.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {11}, pmid = {41354869}, issn = {1432-1459}, support = {(HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; Male ; Female ; Atrophy/pathology ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/metabolism/genetics ; Middle Aged ; Aged ; *Mitochondria/pathology/metabolism ; *Frontotemporal Dementia/pathology/diagnostic imaging ; Phenotype ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Prospective Studies ; }, abstract = {BACKGROUND: Frontotemporal lobar degeneration encompasses a spectrum of clinically, radiologically, and molecularly heterogeneous conditions. Clinical phenotypes are defined based on predominant neuropsychological manifestations and the selective involvement of specific brain regions determines the core symptoms, disability profiles, and care needs. While the unique anatomical patterns of cortical and subcortical degeneration along the FTLD/FTD spectrum are well recognised, the molecular basis of this selective vulnerability remains unclear.<br><br>METHODS: A large prospective neuroimaging study has been undertaken to explore topological associations between phenotype-specific atrophy patterns and physiological mitochondrial density along the FTLD/FTD spectrum. Patients with behavioural variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA), C9orf72-positive ALS-FTD, C9orf72-negative ALS-FTD, and a cohort of healthy controls (HC) were included. FTD phenotypes were first contrasted to healthy&#xa0;controls and the resulting voxelwise maps were correlated to physiological mitochondrial density maps.<br><br>RESULTS: We have identified voxelwise associations between atrophic change and physiological mitochondrial density. The resulting correlation coefficients over the entire GM mask revealed weak topological associations with r&#x2009;=&#x2009;0.217 in C9NEG ALS-FTD, r&#x2009;=&#x2009;0.251 in C9POS ALS-FTD, r&#x2009;=&#x2009;0.213 in bvFTD, r&#x2009;=&#x2009;0.182 in nfvPPA, and r&#x2009;=&#x2009;0.292 in svPPA at p FWE&#x2009;<&#x2009;0.001. Our region-of-interest analyses revealed moderate-to-strong regional associations between mitochondrial density and focal degenerative change with r values above 0.65 in multiple brain regions in all five FTD subgroups. Brain regions exhibiting the most significant associations between volume loss and mitochondrial density in each FTD subgroup are the very regions that define the core clinical manifestations of the given phenotype.<br><br>DISCUSSION: Cortical and subcortical brain regions with high physiological mitochondrial density are particularly vulnerable to neurodegenerative change in FTD. While these anatomical associations do not indicate direct causation, mitochondrial metabolism may represent an important component in the cascade of focal degeneration.}, }
@article {pmid41355168, year = {2025}, author = {Cline, LL and Biggs, R and Butler, JS and Nichols, C}, title = {A Systems-Approach to Addressing the US Rural Veterinarian Shortage Through Collaborative Problem-Solving Training and Education.}, journal = {New directions for student leadership}, volume = {2025}, number = {188}, pages = {97-105}, doi = {10.1002/yd.70028}, pmid = {41355168}, issn = {2373-3357}, mesh = {Humans ; *Problem Solving ; *Education, Veterinary/organization &amp; administration ; *Leadership ; *Veterinarians/supply &amp; distribution ; *Rural Population ; United States ; Oklahoma ; Cooperative Behavior ; Workforce ; }, abstract = {The shortage of rural veterinarians in the United States poses significant challenges to food security, public health, and the agricultural economy. This article explores two systems-based training strategies to address this issue through two case studies: the Integrated Beef Cattle Program (IBCP) in the College of Veterinary Medicine (CVM) at Oklahoma State University (OSU) and the development of adaptive leadership and collaborative problem-solving capacity among rural veterinarians at Pat Dye Clinics. Grounded in Heifetz et al.'s (2009) adaptive leadership framework and Kirton's (2011) Adaption-Innovation Theory (A-I theory), these initiatives demonstrate how leadership development and cognitive diversity can enhance recruitment, retention, and resilience in rural veterinary practice. Findings suggest that integrating leadership learning in veterinary education and professional development can serve as a critical leverage point for systemic change.}, }
@article {pmid41355171, year = {2026}, author = {Lağap, AC and Harma, M}, title = {Does Your Love Lift Me Higher? A Direct Replication of the Energising Role of Secure Relationships.}, journal = {International journal of psychology : Journal international de psychologie}, volume = {61}, number = {1}, pages = {e70144}, doi = {10.1002/ijop.70144}, pmid = {41355171}, issn = {1464-066X}, mesh = {Humans ; Female ; Male ; *Motivation ; *Love ; Adult ; *Object Attachment ; Young Adult ; *Interpersonal Relations ; Adolescent ; }, abstract = {Previous work has revealed that priming people with significant others increases feelings of security and energy, and in turn, boosts exploration motivations. In this preregistered study, we directly replicated Luke et al.'s (2012) Study 2 (N = 281). We found similar results as the replicated study regarding increased security feelings and exploration motivations on the self-report measures after the priming. However, we did not find any support for the increased energy feelings after the attachment security priming. In addition, contrary to Luke et al.'s (2012) results, energy feelings did not mediate the relationship between security priming and exploration motivations. A discussion of null findings, along with the limitations of self-reports and potential misinterpretation of the mediational analyses, follows. We also discuss possible future implications of the current findings.}, }
@article {pmid41355735, year = {2025}, author = {Pal, P and Carrer, M and Weiss, L and Jaime, OG and Cheng, C and Shmara, A and Boock, V and Bosch, D and Youssef, M and Fazeli, Y and Afetian, M and Grossman, TR and Hicks, MR and Jafar-Nejad, P and Kimonis, V}, title = {Antisense oligonucleotides targeting valosin-containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.}, journal = {Clinical and translational medicine}, volume = {15}, number = {12}, pages = {e70530}, pmid = {41355735}, issn = {2001-1326}, support = {1297770//Muscular Dystrophy Association/ ; //Cure VCP Disease Inc. Ionis Pharmaceuticals, Inc./ ; }, mesh = {Animals ; *Valosin Containing Protein/genetics/metabolism/antagonists &amp; inhibitors ; Mice ; *Oligonucleotides, Antisense/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; Muscle, Skeletal/pathology ; Muscular Dystrophies, Limb-Girdle/genetics ; Frontotemporal Dementia/genetics ; Myositis, Inclusion Body ; Osteitis Deformans/genetics ; }, abstract = {BACKGROUND: Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease presents with variable combinations of inclusion body myopathy, early-onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology.<br><br>MAIN TOPICS COVERED: In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5&#xa0;&#xb5;M and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39-56]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanised VCP severe A232E pathogenic gene variant (VCP A232E mice) with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95% CI [27-32]) knockdown of VCP protein compared with control ASO. The ASO-mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TAR DNA binding protein 43 (TDP-43) expression, hallmarks of VCP related MSP1. In addition, ASO-treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared with mice treated with control ASO.<br><br>CONCLUSIONS: These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP related MSP1.<br><br>KEY POINTS: VCP multisystem proteinopathy 1 is caused by gain-of-function pathogenic variants of the VCP gene. VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). The ASOs reduced VCP, TDP-43, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.}, }
@article {pmid41356579, year = {2025}, author = {Seyam, MK and Shaik, RA and Miraj, M and Alzahrani, NS and Shaik, AR and Ajmera, P and Kalra, S and Miraj, SA and Shawky, GM and Nurani, KM and A, P}, title = {Effect of mobile phone applications on medication adherence among patients with coronary artery diseases: A scoping review.}, journal = {World journal of cardiology}, volume = {17}, number = {11}, pages = {114140}, pmid = {41356579}, issn = {1949-8462}, abstract = {Patients with cardiovascular disease rely on medication to achieve favorable long-term clinical results. Poor adherence has been linked to a relative increase in mortality of 50%-80% as well as higher health care costs. This scoping review thus aimed to explore the evidence of the effects of mobile health care apps on medication adherence in patients with cardiovascular diseases. A comprehensive data search and extraction was done in line with the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. A total of 10 studies were included for the review. The mean pooled improvement in adherence was found to be 18% and the most effective tool was the digital therapeutics app discussed in Li et al's study. Smartphones and apps enhance coronary artery disease management by promoting medication compliance. Challenges include data security and smartphone usage among the elderly. Tailored apps or voice assistants offer potential solutions.}, }
@article {pmid41356587, year = {2025}, author = {Liu, HR and Weng, JL}, title = {Interpreting fractional flow reserve-guided percutaneous coronary intervention vs coronary artery bypass grafting outcomes.}, journal = {World journal of cardiology}, volume = {17}, number = {11}, pages = {113225}, pmid = {41356587}, issn = {1949-8462}, abstract = {Kataveni et al's meta-analysis offers an important contemporary synthesis of randomized evidence comparing fractional flow reserve-guided percutaneous coronary intervention and coronary artery bypass grafting (CABG) in multivessel coronary artery disease (CAD). The pooled analysis found no significant difference in all-cause mortality or stroke, yet CABG was superior in reducing myocardial infarction, major adverse cardiac events, and repeat revascularization. These results confirm CABG's durability even in the era of physiological lesion assessment and second-generation drug-eluting stents. From a traditional Chinese medicine (TCM) perspective, multivessel CAD corresponds to syndromes such as "heart vessel obstruction" and "Qi and blood stagnation", in which local blockage is compounded by systemic imbalance. While revascularization addresses the structural impediment to blood flow, TCM approaches, including herbal medicine, acupuncture, and lifestyle therapy, aim to improve microcirculation, reduce inflammation, and support recovery, potentially mitigating recurrent ischemic events. This commentary argues that future research should integrate optimal revascularization strategies with rigorously evaluated TCM interventions to address both the anatomical and systemic dimensions of CAD and improve long-term patient outcomes.}, }
@article {pmid41359166, year = {2025}, author = {Gondim, FAA and Fernandes, JMA and Dutra Junior, AM and Thomas, FP}, title = {Four families with slowly progressive ALS due to p.Val120Leu SOD1 variant in Northeast Brazil.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2025.2597943}, pmid = {41359166}, issn = {2167-9223}, abstract = {Objective: SOD1 mutations are the second most prevalent variants in amyotrophic lateral sclerosis (ALS). Epidemiological data about SOD1 mutations are scarce in Brazil. Here, we report the clinical and genetic findings of four Brazilian families with p.Val120Leu SOD1 variant. Methods: This study is part of an epidemiological study of the prevalence of ALS conducted in the State of Ceará, Brazil. We reviewed the medical records of families with p.Val120Leu (c.358G > C, exon 5) SOD1 variant seen at the Walter Cantídio University Hospital, Federal University of Ceará, Brazil. Results: We identified 15 patients from 4 families with p.Val120Leu SOD1 variant among 251 ALS patients. Of these, six were personally examined and had ALS confirmed and five had confirmatory genetic testing (four homozygous and one heterozygous). C9orf72 testing was normal in the heterozygous patient. In two families, three older heterozygous patients (genetically tested) had no signs or symptoms of ALS. The mean age of symptom onset was 46.7 ± 13.4 years. Features of ALS in the four families were very similar, with prolonged disease duration and upper and lower motor neuron involvement, fulfilling the Revised El Escorial, Awaji, and Gold Coast diagnostic criteria. All examined living patients had limb onset and a few bulbar symptoms. Conclusion: p.Val120Leu SOD1 variant leads to slowly progressive ALS with incomplete penetrance. Our findings are similar to a previous report of ALS due to p.Asp90Ala SOD1 variant.}, }
@article {pmid41359202, year = {2025}, author = {Guerra-Hernández, J and Mauro-Gutiérrez, F and Rodríguez-Puerta, F and Pascual, A}, title = {Scaling and sampling dependencies of forest canopy height mapping towards jurisdictional biomass reporting using airborne LiDAR and small-area estimation.}, journal = {Carbon balance and management}, volume = {21}, number = {1}, pages = {12}, pmid = {41359202}, issn = {1750-0680}, support = {2023.15225.TENURE.008//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; PID2022-140104OA-I00//Spanish Ministry of Science and Innovation/ ; }, abstract = {Consolidated airborne laser scanning (ALS) programs, satellite imagery and spaceborne structural measurements have enabled major advances in canopy height mapping that translate towards the forest carbon biomass arena. However, we must carefully evaluate the cost of using fine-grained canopy height products to predict biomass under calibration models scoped at the scale of inventory plots. In this study, we estimated biomass using field plots and ALS metrics before predicting biomass over a jurisdiction of ~ 15,500 km[2] in Spain using 10 m, 25 m, 44 m, and 100 m as prediction scales. We altered the scale of ALS-based biomass predictors in 10 sub-jurisdictions intensively surveyed by the Spanish National Forest Inventory (NFI) before estimating mean and total biomass using three options: (i) traditional NFI design-based (DB) estimation, (ii) a model-based (MB) approach using scale-varying canopy height metrics from ALS and NFI plots, and (iii) an small-area estimation (SAE) implemntation designed for sub-jurisdictional domains. Higher uncertainties - relative standard errors (SE) - were found for DB, particularly at sub-jurisdictional and stratum levels. We observed a consistent increase in uncertainty for MB estimation from the finest 10 m scale up to 100 m. In MB estimation, the maximum relative bias reached 11% for 10-m predictions compared to the baseline estimate at the NFI sampling native resolution. The bias associated with the prediction scale ranged from + 5% (25 m) to -8% (100 m). The mean biomass estimates for SAE generally ranged between DB and MB but at lower uncertainty to the former, especially as the NFI sampling becomes scarcer and not enough for solid inference of biomass mean. The SEA statistics helped to disentangle biomass comparisons between ALS-based inference and the traditional NFI estimation that do not incorporate remote sensing data.}, }
@article {pmid41359433, year = {2025}, author = {Zulhairy-Liong, NA and Edgar, S and Ellis, M and Zhu, D and Lai, K and Capelle, DP and Sabirin, S and Pek, EW and Nair, P and Ang, CM and Kennerson, ML and Shahrizaila, N and Ahmad-Annuar, A}, title = {Novel and rare variants in amyotrophic lateral sclerosis genes identified in Malaysian patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2582832}, pmid = {41359433}, issn = {2167-9223}, abstract = {There is limited information on the genetic architecture of amyotrophic lateral sclerosis (ALS) in Southeast Asian populations. To address this knowledge gap, we performed 1) SOD1 (exon 1-4), FUS (exon 13-15), TARDBP (exon 6) and ATXN2 repeat expansion screening in 201 multi-ethnic Malaysian (Malay, Chinese, Indian and others) ALS patients, 2) C9orf72 repeat expansion testing in 179 subset patients, and 3) a panel of 61 ALS-associated genes screening in 112 subset cases using either whole genome (n = 21) or exome (n = 91) sequencing datasets. Among the patients, the observed mutational frequencies in key ALS genes were: SOD1 3.0% (6/201), C9orf72 2.2% (4/179), ATXN2 2.0% (4/201), FUS 1.5% (3/201), and TARDBP 1.5% (3/201). Of the 112 cases that underwent WGS/WES, 6.3% (7/112) comprised of pathogenic and likely pathogenic variants in FIG4 (p.Lys657Serfs*2), FUS (p.Arg485Profs*32), TARDBP (p.Ile383del), NEK1 (p.Ile633Asnfs*28), GRN (c.599-1G > C), CYP27A1 (p.Met1Thr) and SPAST (p.Glu449Gly). Additionally, 42.9% (48/112) had at least one variant of uncertain significance (VUS) in 34 genes. Notably, in the 24 genes classified as 'definitive' by the ClinGen ALS Spectrum Disorders Gene Curation Expert Panel, five patients (4.5%, 5/112) harbored more than one likely pathogenic variant and/or VUS. However, burden analysis revealed no significant differences in clinical characteristics between patients with varying numbers of variants. Our findings highlight the utility of next-generation sequencing in elucidating the genetic basis of ALS in Malaysian and Southeast Asian ethnic groups, including the identification of several novel variants of clinical interest as well as increasing diagnostic yield up to 47.7%.}, }
@article {pmid41359530, year = {2025}, author = {Rees, L and Lam, CF and Du, QS and Yu, A and Wong, MN and Xie, H}, title = {Exploring the duality of voice habit: Testing and extending theory and measurement.}, journal = {The Journal of applied psychology}, volume = {}, number = {}, pages = {}, doi = {10.1037/apl0001326}, pmid = {41359530}, issn = {1939-1854}, support = {//National Natural Science Foundation of China/ ; //Hong Kong General Research Fund/ ; }, abstract = {Scholars increasingly recognize the existence of voice habit, wherein employees speak up automatically without considering relevant situational factors, being able to control their impulse to voice, and exerting effort in deciding whether to voice. However, a lack of theory testing and an absence of a psychometrically valid measure have called into question its theoretical usefulness as well as its construct validity. Moreover, contrary to Lam et al.'s (2018) theorizing on the interpersonal costs and intrapersonal benefits of voice habit, research on the reticence bias suggests the opposite: Habitual voicers may gain interpersonal benefits by experiencing higher supervisor liking, but they may also suffer intrapersonal costs by experiencing voice regret. Integrating these divergent insights with theorizing on voice habit, we predict that voice habit may elicit supervisor liking when supervisors perceive habitual voicers as having higher prosocial motives or behavioral integrity, even though habitual voicers may experience regret in work units with a weaker voice climate. Results from a multiwave, multisource field study with 435 employees and 135 supervisors using a 12-item validated scale of voice habit support our hypotheses. Our work provides a direct test and extension of the recently proposed theorizing on voice habit and introduces a psychometrically valid measure for future research use. Our findings also empirically support the dual nature of voice habit, highlighting both its potential functional interpersonal outcomes in relation to supervisors and its potential dysfunctional intrapersonal outcomes for habitual voicers. (PsycInfo Database Record (c) 2025 APA, all rights reserved).}, }
@article {pmid41359535, year = {2026}, author = {Bollen, C and van Grunsven, J}, title = {In defense of the double empathy problem hypothesis: An urgently needed alternative to fallacies and injustices in mainstream autism research.}, journal = {Psychological review}, volume = {133}, number = {2}, pages = {507-514}, doi = {10.1037/rev0000605}, pmid = {41359535}, issn = {1939-1471}, support = {//Netherlands Organisation for Scientific Research/ ; }, mesh = {Humans ; *Empathy ; *Autistic Disorder/psychology ; *Autism Spectrum Disorder/psychology ; *Psychological Theory ; }, abstract = {In their theoretical note, "The Double Empathy Problem: A Derivation Chain Analysis and Cautionary Note," Livingston et al. (2024) took a critical look at the double empathy problem hypothesis (DEPH). While they acknowledge that the DEPH offers promising insights, and while their critical note seems, at times, to be written with an eye to furthering and expanding DEPH, the main point they ultimately drive home is that DEPH has a "precarious theoretical and evidence base" and that, given this (allegedly) shaky foundation, applying DEPH "into real-world applications may have unintended and potentially harmful consequences for autistic people and those with similar conditions" (Livingston et al., 2024, p. 10). In this theoretical note, we take a critical look at Livingston et al.'s critique of DEPH, arguing that their warning note is problematic both from an ethical and philosophy of science point of view. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid41360043, year = {2026}, author = {Chis-Ciure, R}, title = {The unbearable hardness of inferring being: Comment on "preliminaries to artificial consciousness" by Evers et al.}, journal = {Physics of life reviews}, volume = {56}, number = {}, pages = {87-90}, doi = {10.1016/j.plrev.2025.12.004}, pmid = {41360043}, issn = {1873-1457}, mesh = {*Consciousness ; Humans ; Brain/physiology ; }, abstract = {This commentary commends Evers et al.'s multidimensional heuristic for structuring artificial consciousness research while arguing it cannot, as stated, adjudicate the nomological possibility of phenomenal consciousness, which is at stake in current debates. Behavioral-cognitive "profiles" lack a justified principle linking function to experience, and the awareness case study illustrates how externally specified goals can just as well underwrite as-if (pseudo-intentional) control rather than original intentionality. Moreover, the proposed heuristic overlooks that substrate similarity is currently indispensable for justifiably inferring the presence of consciousness beyond the validated case of the adult human brain. Given all this, the framework seems to provide a blueprint for building a more sophisticated philosophical zombie; it does not-and cannot-tell us whether anyone is there.}, }
@article {pmid41360752, year = {2026}, author = {Ma, JY and Wang, X and Cai, Y and Wang, G and Lu, M and Feng, K and Zhao, Y and Wu, X and Zhang, X and Wu, H and Yu, W and Ma, M and Ge, Z and Zhang, Y}, title = {Anionic Liposomes as Optimal Membrane Fusion Carriers Enabling in Situ Multiplexed Detection of Extracellular Vesicle MicroRNAs.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {10}, pages = {e19758}, pmid = {41360752}, issn = {2198-3844}, support = {2022YFA1205802//National Key Research and Development Program of China/ ; 2022YFC2406504//National Key Research and Development Program of China/ ; 82572399//National Natural Science Foundation of China/ ; 82302370//National Natural Science Foundation of China/ ; BF2024062//Frontier Technologies R&amp;D Program of Jiangsu/ ; BK20230836//Natural Science Foundation of Jiangsu Province/ ; KYCX24_0471//Postgraduate Research &amp; Practice Innovation Program of Jiangsu Province/ ; CXJH_SEU 25140//SEU Innovation Capability Enhancement Plan for Doctoral Students/ ; }, mesh = {*Extracellular Vesicles/genetics/metabolism ; Humans ; *Liposomes/chemistry ; *MicroRNAs/analysis/genetics ; Liquid Biopsy/methods ; *Membrane Fusion ; Anions/chemistry ; Biomarkers, Tumor ; }, abstract = {Extracellular vesicle (EV) microRNAs (miRNAs) are promising liquid biopsy biomarkers for non-invasive diagnosis, monitoring, and therapeutic evaluation of cancer. However, sensitive EV miRNA detection is hindered by complex pre-analytical processing. Here, the authors present an anionic liposome (AL) assisted membrane fusion strategy enabling one-step multiplexed quantification of EV miRNAs directly from plasma without EV isolation or RNA extraction, termed EValarm (Anionic Liposome Assisted miRNAs Monitoring for Extracellular Vesicles). Liposomes encapsulating probes are prepared using a microfluidic chip, achieving catalytic signal amplification after target recognition of miRNA. Systematic lipid screening identified ALs as optimal carriers, exhibiting minimal background and superior sensitivity compared to cationic and neutral liposomes. The AL-based assay delivered accuracy comparable to quantitative PCR with a streamlined workflow. Applied to 106 clinical samples from lymphoma patients and healthy controls, integration with artificial intelligence achieved high accuracy (AUC > 0.99). In summary, this study demonstrates a platform enabling direct and sensitive plasma EV miRNA detection, offering strong potential for clinical translation in cancer liquid biopsy.}, }
@article {pmid41361184, year = {2025}, author = {Taquet, M and Todd, JA and Harrison, PJ}, title = {Reply to: Methodological Issues in Taquet et al.'s analysis preclude any conclusions regarding AS01 adjuvant's specific role in dementia prevention.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {256}, pmid = {41361184}, issn = {2059-0105}, }
@article {pmid41361196, year = {2025}, author = {Zhao, R and Bai, Y and Zhang, S and Zhu, J and Liu, H and Ni, G}, title = {An open dataset of multidimensional signals based on different speech patterns in pragmatic Mandarin.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {1934}, pmid = {41361196}, issn = {2052-4463}, mesh = {Humans ; *Speech ; Electroencephalography ; *Language ; Brain-Computer Interfaces ; Electromyography ; China ; Brain/physiology ; }, abstract = {Speech is essential for human communication, but millions of people lose the ability to speak due to conditions such as amyotrophic lateral sclerosis (ALS) or stroke. Assistive technologies like brain-computer interfaces (BCIs), can convert brain signals into speech. However, these technologies still face challenges in decoding accuracy. This issue is especially challenging for tonal languages like Mandarin Chinese. Furthermore, most existing speech datasets are based on Indo-European languages, which hinders our understanding of how tonal information is encoded in the brain. To address this, we introduce a comprehensive open dataset, which includes multimodal signals from 30 subjects using Mandarin Chinese across overt, silent, and imagined speech modes, covering electroencephalogram (EEG), surface electromyogram (sEMG), and speech recordings. This dataset lays a valuable groundwork for exploring the neural encoding of tonal languages, investigating tone-related brain dynamics, and improving assistive communication strategies. It supports cross-linguistic speech processing research and contributes to data-driven neural speech decoding technology innovations.}, }
@article {pmid41361897, year = {2025}, author = {Rosenfeld, J and Abrahams, S and McHutchinson, C and Ajroud-Driss, S and Weber, M and Paganoni, S and Mitsumoto, H and Genge, A and Grosskreutz, J and Van Den Berg, L and Andrews, J and Kiernan, MC}, title = {Utility of patient subgrouping in ALS clinical trials: a World Federation of Neurology white paper.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2593308}, pmid = {41361897}, issn = {2167-9223}, abstract = {The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.}, }
@article {pmid41362129, year = {2025}, author = {Ma, T and Zhu, H and Zhu, J and Zhao, J and Zhao, X}, title = {Evaluation of pathogenicity, host resistance, biological properties and chemical control of Xanthomonas fragariae Strain JD1 causing angular leaf spot on strawberry.}, journal = {Plant disease}, volume = {}, number = {}, pages = {}, doi = {10.1094/PDIS-10-25-2070-RE}, pmid = {41362129}, issn = {0191-2917}, abstract = {Angular leaf spot (ALS), caused by the quarantine pathogen Xanthomonas fragariae, is a major bacterial disease threatening global strawberry production. In China, its continued spread across multiple regions poses a significant and persistent epidemiological threat to the strawberry industry. Recently, ALS has emerged as a great threat to strawberry industry in the Jiande, Zhejiang province (located at 29°N, 119°E). This study reports the first isolation and characterization of X. fragariae strain JD1 from symptomatic strawberry leaves in Jiande, Zhejiang Province. The identification of strain JD1 was confirmed through species-specific PCR, analysis of colony characteristics, and phylogenetic clustering based on 16S rRNA and HrpB gene sequences. Pathogenicity assays revealed strain JD1 resulted in water-soaked lesions progressing to necrotic patches on leaves, along with systemic colonization of crown tissues showing water-soaked, reddish-brown lesions without cavity formation. Additionally, resistance evaluation across six strawberry cultivars revealed that 'Yue Xiu' was the most susceptible, followed closely by 'Jiande Hong', 'Hong Yu', 'Li Fen', and 'Hong Yan', while 'Fen Yu' exhibited the highest resistance. Biological characterization showed that strain JD1 grows optimally at 25°C and pH 7.0, with significant inhibition observed at 35°C and under acidic (pH 4) or alkaline (pH 9) conditions. In bactericide screening, tetramycin and benziothiazolinone were identified as highly effective against JD, followed by sintracin acetate aqueous with minor efficacy, whereas kasugamycin and quinoline copper showed limited or no efficacy. Collectively, these findings not only emphasize the threat posed by X. fragariae strain JD1 to strawberry production but also provide critical insights that inform integrated management strategies, including the use of resistant cultivars, environmental controls, and targeted bactericides, for controlling ALS.}, }
@article {pmid41364388, year = {2025}, author = {Levine, AA and Rucker, JA and Cockerham, A and Cartner, J and Chambers, JD}, title = {U.S. health plan coverage of Neuromuscular Disease Therapies: An assessment of policy availability and restrictions.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251405815}, doi = {10.1177/22143602251405815}, pmid = {41364388}, issn = {2214-3602}, abstract = {BACKGROUND: Health plan policies managing neuromuscular disease (NMD) therapies may impose burdensome requirements on patients and providers. While prior research has explored payer restrictions for rare NMD treatments, limited evidence exists on policies specifically governing therapy initiation and reauthorization.<br><br>OBJECTIVES: To examine initial and reauthorization coverage policies for therapies targeting five NMDs-Duchenne muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, generalized myasthenia gravis, and Lambert-Eaton myasthenic syndrome-across all U.S. state Medicaid programs and leading commercial health plans.<br><br>METHODS: We constructed a database of coverage decisions issued by 50 states and DC Medicaid programs and 35 major commercial insurers, including both fee-for-service and managed care organizations. We analyzed (1) policy availability and coverage frequency, (2) initial coverage requirements (e.g., subgroup restrictions, step therapy, prescriber type), (3) reauthorization criteria, and (4) approval durations.<br><br>RESULTS: Of 1204 potential decisions, 908 (75%) had publicly available policies. Of these, 558 (46%) included reauthorization criteria. Among covered therapies, 96% imposed restrictions beyond FDA label indications. Requirements varied by payer type, NMD, and therapy. Average approval durations were 6 months for initial coverage and 10 months for reauthorization.<br><br>CONCLUSIONS: Many plans lacked publicly accessible policies, and most covered therapies were subject to restrictive requirements. These barriers-such as step therapy, narrow prescriber criteria, and short approval periods-may delay treatment and disrupt care continuity. Findings underscore the need for greater transparency and reform in prior authorization and pharmacy benefit design to support timely access to NMD therapies.}, }
@article {pmid41364409, year = {2025}, author = {Matur, Z and Deveci, &#x15e; and Erdal, Y}, title = {Correlations of cerebrospinal fluid neurofilament light chain levels with clinical and electromyography findings in amyotrophic lateral sclerosis.}, journal = {Irish journal of medical science}, volume = {}, number = {}, pages = {}, pmid = {41364409}, issn = {1863-4362}, abstract = {BACKGROUND: This study aimed to examine correlations between cerebrospinal fluid neurofilament light chain (CSF NfL) levels, and clinical and electrophysiological findings in amyotrophic lateral sclerosis (ALS). Compare CSF NfL and total protein levels between ALS and other central nervous system (CNS) neurodegenerative disorders.<br><br>METHODS: This retrospective study analyzed 46 ALS patients (Gold Coast criteria) and 33 non-ALS neurodegenerative controls. We documented time from symptom onset to diagnosis, revised ALS Functional Rating Scale (ALSFRS-R) scores at CSF sampling, initial involvement regions (bulbar/cervical/lumbosacral), and extent of lower motor neuron (LMN) involvement.<br><br>RESULTS: ALS patients had significantly higher CSF NfL levels than non-ALS controls (4221&#x2009;&#xb1;&#x2009;2585 vs. 3004&#x2009;&#xb1;&#x2009;2788 pg/mL, p&#x2009;=&#x2009;0.025). In the ALS group, CSF NfL levels showed significant inverse correlation with ALSFRS-R scores (r = -0.332, p&#x2009;=&#x2009;0.024), and patients demonstrating involvement in all four-region on needle electromyography exhibited the highest CSF NfL levels. Among the ALS cohort 18 patients (39%) had died by the last follow-up, and patients who died during the study exhibited significantly higher baseline CSF NfL levels (median: 5115 pg/mL) compared to surviving patients (median: 3276 pg/mL; p&#x2009;=&#x2009;0.007).<br><br>CONCLUSIONS: Our study demonstrated that CSF NFL levels were significantly elevated in ALS compared to other neurodegenerative disorders. Higher CSF NFL concentrations correlated with more rapid functional decline, more extensive LMN degeneration, and poorer survival outcomes.}, }
@article {pmid41365006, year = {2026}, author = {Hamzeloo, M and Bogenschütz, L and Hackländer, RPM and Bermeitinger, C}, title = {Evaluating the generalizability of the normative odor rating across cultures: Evidence from a German-speaking sample.}, journal = {Acta psychologica}, volume = {262}, number = {}, pages = {106056}, doi = {10.1016/j.actpsy.2025.106056}, pmid = {41365006}, issn = {1873-6297}, mesh = {Humans ; Male ; Female ; *Odorants ; Adult ; Young Adult ; *Olfactory Perception/physiology ; *Cross-Cultural Comparison ; Germany ; *Recognition, Psychology/physiology ; Adolescent ; Language ; *Smell/physiology ; }, abstract = {Olfactory perception varies across cultures, yet the cross-cultural generalizability of normative odor ratings remains underexplored. This study investigates the generalizability of normative odor ratings to a German-speaking sample by assessing 24 odors across eight dimensions-familiarity, frequency, pleasantness, irritability, context availability, discriminability, age of acquisition, and verbalizability-in 124 German-speaking participants (Mage = 22.36, SD = 3.24). Building on Moss et al.'s (2016) methodology with English-speaking participants, we examined the consistency of these dimensions, the influence of odor familiarity, and the role of odor-specific properties versus individual differences. Results revealed significant intercorrelations among the dimensions, except for age of acquisition, which negatively correlated with others, confirming the importance of early exposure in olfactory perceptual saliency and linguistic accessibility. For high-familiar odors, strong correlations with Moss et al.'s ratings were found for familiarity (r = 0.805), frequency (r = 0.799), pleasantness (r = 0.792), context availability (r = 0.794), discriminability (r = 0.967), and verbalizability (r = 0.844), and age of acquisition (r = 0.750), but not for irritability (r = 0.495). Low-familiar odors showed only a moderate correlation for verbalizability (r = 0.530), highlighting the role of exposure in cross-cultural consistency. Variance across odors significantly exceeded variance across participants, indicating reliable differentiation by odor properties. These findings suggest that normative odor ratings show strong cross-sample consistency across the two samples, particularly for familiar odors. This study supports the utility of normative ratings in olfactory research while highlighting the role of familiarity and context in cross-cultural perception.}, }
@article {pmid41365015, year = {2026}, author = {Svendsen, O and Stevens, MWR and Hamamura, T and Harpas, I and Radunz, M and King, DL}, title = {Reporting quality standards in gaming disorder treatment evidence: A systematic review.}, journal = {Acta psychologica}, volume = {262}, number = {}, pages = {106063}, doi = {10.1016/j.actpsy.2025.106063}, pmid = {41365015}, issn = {1873-6297}, mesh = {Humans ; *Video Games ; *Psychotherapy/standards ; Randomized Controlled Trials as Topic/standards ; *Internet Addiction Disorder/therapy ; *Research Design/standards ; }, abstract = {BACKGROUND: The treatment evidence base for gaming disorder (GD) has grown steadily over the past two decades. A systematic review by King et al. (2017) of 30 studies reported that GD treatment studies tended to favor psychotherapy approaches, but the research was limited by poor reporting standards as assessed by the Consolidated Standards of Reporting Trials (CONSORT) framework. This systematic review aimed to conduct a follow up evaluation of the reporting quality of subsequent GD treatment studies.<br><br>METHODS: A literature search of six databases yielded 51,056 records, which resulted in 31 eligible studies after screening. Each study's reporting quality was assessed using the CONSORT statement, and then these assessments were compared to King et al.'s (2017) review.<br><br>RESULTS: This review identified several methodological improvements since 2017: 61&#xa0;% of studies were randomized controlled trials (vs. 40&#xa0;% in 2017), 90&#xa0;% included control groups (vs. 63&#xa0;%), and follow-up duration increased to 6.1&#xa0;months (vs. 3.5&#xa0;months; p&#xa0;=&#xa0;.032). Reporting improved for participant flow (87.1&#xa0;% vs. 43.3&#xa0;%; p&#xa0;=&#xa0;.001) and group-level statistics (74.2&#xa0;% vs. 36.7&#xa0;%; p&#xa0;=&#xa0;.003), but some areas showed no improvement.<br><br>DISCUSSION: There have been several improvements in GD treatment study design and reporting, including controls, randomization and follow up, reflecting an increasing number of higher quality trials for the condition. Most of the studies with higher reporting quality (i.e., scoring &#x2265;30/46 on the CONSORT framework) were psychotherapy-based. Future research should employ designs with longer follow-ups, broader assessment of outcomes, and standardized ICD-11-aligned tools. Pharmacological treatments, including novel pharmacotherapies for other addictions (e.g., Naltrexone), are underexplored and lack high quality evidence.}, }
@article {pmid41365127, year = {2026}, author = {Kulappu Arachchige, SN and Abeykoon, AMH and Stevenson, MA and Kanci Condello, A and Shil, PK and Tulman, ER and Szczepanek, SM and Silbart, LK and Underwood, GJ and Noormohammadi, AH and Geary, SJ and Wawegama, NK and Browning, GF}, title = {Assessment of tracheal mucosal thicknesses is a preferable method for evaluation of the immunogenicity of Mycoplasma gallisepticum vaccines in poultry.}, journal = {Vaccine}, volume = {72}, number = {}, pages = {128063}, doi = {10.1016/j.vaccine.2025.128063}, pmid = {41365127}, issn = {1873-2518}, mesh = {Animals ; *Mycoplasma gallisepticum/immunology ; *Bacterial Vaccines/immunology/administration &amp; dosage ; *Poultry Diseases/prevention &amp; control/immunology/microbiology ; *Mycoplasma Infections/prevention &amp; control/veterinary/immunology ; *Trachea/pathology/immunology ; Chickens ; Vaccines, Attenuated/immunology/administration &amp; dosage ; *Mucous Membrane/pathology ; *Immunogenicity, Vaccine ; Vaccine Efficacy ; Poultry ; Vaccination ; Air Sacs/pathology ; }, abstract = {Live-attenuated vaccines are commonly used to control chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum in poultry. A previous review found that measures of tracheal lesions are better indicators of the validity of a vaccine efficacy test than air sac lesions. Here we extend those observations by comparing the raw tracheal mucosal thickness (TMT) and gross air sac lesion score (ALS) data from published vaccine efficacy studies to provide insights into standardising methods for evaluation of M. gallisepticum vaccine efficacy by identifying the most discriminative and reproducible parameter to demonstrate the efficacy of vaccines and the validity of immunogenicity tests. Our analyses revealed that a higher proportion of trials detected a ≥ 80 % effectiveness of challenge based on TMT, with a significantly lower number of biological replicates, than ALS. Furthermore, a significantly higher proportion of vaccinated-and-challenged groups had a proportion protected of ≥80 %, a reduction in lesions of ≥30 % and a mitigated fraction of ≥0.80, with a significantly lower number of biological replicates, compared to the positive-control group when analyses were based on TMT rather than ALSs. These findings indicate that TMT is a more discriminative and reproducible parameter to assess the efficacy of a vaccine and the validity of an efficacy test, and hence that this should be the primary outcome variable used to evaluate M. gallisepticum vaccine efficacy studies. Furthermore, the ability of TMT to discriminate these groups with fewer biological replicates enhances animal welfare by reducing the number of animals needed for efficacy studies.}, }
@article {pmid41366746, year = {2025}, author = {Huang, J and Liu, Y and Li, M and He, R and Tang, Z and Lei, Y and Zha, Y and Wei, J}, title = {Safety and efficacy of botulinum toxin injection for sialorrhea in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {496}, pmid = {41366746}, issn = {1471-2377}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, with 80% of ALS patients experiencing bulbar weakness at some stage of the disease. ALS patients with bulbar weakness often suffer from troublesome sialorrhea. Botulinum toxin injection, as a neuromuscular blocker, has been widely used in the treatment of sialorrhea. This paper evaluates the safety and efficacy of botulinum toxin injections for the treatment of sialorrhea in ALS patients through a systematic review and meta-analysis.<br><br>METHODS: A systematic review and meta-analysis was conducted by searching eight databases, including PubMed, EMBASE, and CNKI, up to April 13, 2025. Eligible randomized controlled trials and quasi-experimental studies were analyzed using Review Manager 5.4 and Stata software.<br><br>RESULTS: Thirteen studies (2 RCTs, 11 quasi-experimental studies) with 130 ALS patients were included. Botulinum toxin significantly reduced sialorrhea and improved quality of life (Z&#x2009;=&#x2009;10.98, p&#x2009;<&#x2009;0.00001; RD&#x2009;=&#x2009;0.82, 95% CI: 0.67&#x2013;0.97). The treatment effect was independent of toxin type (p&#x2009;=&#x2009;0.48), injection site (p&#x2009;=&#x2009;0.17), and ultrasound guidance use (p&#x2009;=&#x2009;0.44).<br><br>CONCLUSION: Botulinum toxin appears to be a safe and effective option for managing sialorrhea in ALS patients, regardless of injection technique. However, given that most included studies were observational, further validation through high-quality RCTs is warranted.<br><br>TRIAL REGISTRATION: This meta-analysis has been registered with Prospero, and the registration number is CRD420251029441. The registration period is April 9, 2025.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-025-04515-8.}, }
@article {pmid41366786, year = {2025}, author = {Saracino, D and Cipriano, L and Houot, M and Querin, G and Rinaldi, D and Rametti-Lacroux, A and Wallon, D and Gerardin, E and Couratier, P and Boncoeur, MP and Lebouvier, T and ,  and Colliot, O and Pradat, PF and Migliaccio, R and Le Ber, I}, title = {Quantifying multimodal longitudinal brain changes in presymptomatic C9orf72 disease.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70902}, pmid = {41366786}, issn = {1552-5279}, support = {PRTS2015-2019PREV-DEMALS//ANR/DGOS - Assistance Publique-H&#xf4;pitaux de Paris (Dr Le Ber)/ ; ANR-10-IAIHU-06//Agence Nationale de la Recherche (Dr Le Ber)/ ; 2019-JPW2-0005-01STRATALS//JPND/ANR (Dr Pradat and Dr Le Ber)/ ; ANR-23-IACL-0008,&#x2009;PRAIRIE-PSAI//Agence Nationale de la Recherche as part of the "France 2030" program/ ; ANR-19-P3IA-0001,&#x2009;projectPRAIRIE3IAInstitute//Agence Nationale de la Recherche as part of the "Investissements d'avenir" program/ ; 101136607,&#x2009;projectCLARA//European Union's HORIZON EUROPE Framework Programme/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *Brain/pathology/diagnostic imaging ; *C9orf72 Protein/genetics ; Disease Progression ; *Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; *Gray Matter/pathology/diagnostic imaging ; Longitudinal Studies ; Magnetic Resonance Imaging ; *White Matter/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: The presymptomatic phase of frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72 repeat expansion features widespread structural brain changes. We aimed at fulfilling the unmet need of quantitative magnetic resonance imaging (MRI)-derived measures suitable for disease tracking.<br><br>METHODS: We compared the profile of longitudinal gray (GM) and white matter (WM) changes in 66 presymptomatic carriers and 52 controls over 3-year follow-up and appraised their annualized rate of change (ARC).<br><br>RESULTS: Both putamen (p&#xa0;<&#xa0;0.01) and left insula (p&#xa0;=&#xa0;0.005) volumes declined the most in carriers over 40, with an ARC up to four-fold higher than in controls. Increases in mean diffusivity occurred first in the left uncinate fasciculus, followed by thalamo-cortical bundles (p&#xa0;<&#xa0;0.05), associated with higher neurofilament levels.<br><br>DISCUSSION: Our study highlighted the GM and WM structures showing the greatest longitudinal decline during the preclinical stage, whose ARC may serve as an MRI-derived biomarker for longitudinal surveillance and therapeutic outcome.<br><br>CLINICAL TRIAL REGISTRATION: NCT02590276 and NCT05358431.<br><br>HIGHLIGHTS: We studied longitudinal multimodal MRI changes in presymptomatic C9orf72 disease. Carriers displayed faster atrophy in putamen, insula and cerebellar regions. Mean diffusivity increased mainly in uncinate and thalamo-cortical tracts. These differences were even more significant in older (>&#xa0;40) participants. We proposed targeted annualized rate of change as a quantitative biomarker.}, }
@article {pmid41366852, year = {2025}, author = {Barahona-López, C and Plans-Beriso, E and Diez-Echave, P and Hernández, O and de Larrea, NF and Craciun, O and García-Ovejero, E and Petrova, D and Fernández-Martínez, NF and Arruabarrena-Blanco, E and Babb-de-Villiers, C and Turner, H and Jimenez, RC and Erady, C and Wilson, H and Fernández-Navarro, P and García-Esquinas, EG and Kuhn, I and Sánchez, P and Rodríguez-Artalejo, F and Sánchez, MJ and Moreno, V and Blackburn, L and Pollán, M and Kroese, M and Perez-Gomez, B}, title = {Personalized prevention of neurodegenerative diseases: scoping review and evidence gap map.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70980}, pmid = {41366852}, issn = {1552-5279}, support = {001/WHO_/World Health Organization/International ; 10040946//UKRI/ ; 101057721//Horizon Europe / H2020 Health/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention &amp; control/genetics ; Biomarkers ; *Precision Medicine/methods ; Evidence Gaps ; }, abstract = {Neurodegenerative diseases represent a major public health challenge due to their high prevalence and poor prognosis. Identifying biomarkers to stratify individuals by their risk of developing these diseases may help to define new personalized prevention interventions. The objective of this study was to conduct a scoping review of biomarkers for primary and secondary personalized prevention of neurodegenerative diseases. The search targeted biomarkers in adults or high-risk subpopulations in clinical or public health settings for Alzheimer's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Ultimately, 286 papers were included in the review and the interactive gap map. There is a strong focus on Alzheimer's disease, and most papers included -omics-based biomarkers and/or used artificial intelligence. Genetics/genomics are at the forefront of current scientific research, although there is a notable gap in studying gene-environment interactions, and studies in clinical settings are still scarce. HIGHLIGHTS: Research indicates a strong focus on Alzheimer´s disease and limited research in other diseases. Genetics and genomics are at the forefront of current scientific research. We found biomarkers for predicting progression in mild cognitive decline. There is a notable gap in studying gene-environment interactions. Studies investigating biomarkers in a clinical context are still scarce.}, }
@article {pmid41367793, year = {2025}, author = {Yu, L and Yang, Z and Ming, Z and Zeng, S}, title = {Evaluation of ascending aorta and radial artery elasticity in patients with type 2 diabetes mellitus via velocity vector imaging.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {12}, pages = {12044-12054}, pmid = {41367793}, issn = {2223-4292}, abstract = {BACKGROUND: A decrease in arterial elasticity may contribute to accelerated atherosclerosis, the sequelae of which are the most common causes of death in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to assess ascending aorta (AA) and radial artery (RA) elasticity in T2DM patients via velocity vector imaging (VVI).<br><br>METHODS: We enrolled 50 patients with T2DM and 52 age- and sex-matched nondiabetic individuals as controls. All the participants underwent echocardiography and RA ultrasound examinations. AA elasticity parameters, i.e., ascending aortic mean longitudinal strain (ALS), ascending aortic global circumferential strain (ACS), ascending aortic fractional area change (FAC), and RA elasticity parameters, i.e., radial arterial mean longitudinal strain (RLS) and radial arterial global circumferential strain (RCS), were evaluated with VVI. The differences in arterial elasticity parameters between diabetic and non-diabetic patients were evaluated by a paired t-test. Spearman correlation coefficients were calculated to demonstrate the relationship between arterial elasticity parameters and clinical risk factors and cardiovascular biometrics in T2DM patients.<br><br>RESULTS: We found that the T2DM group presented significantly lower ALS, ACS, FAC, RLS and RCS values than the control group did (all P<0.05). There were significant associations between all arterial elasticity parameters and glycosylated hemoglobin (HbA1c) and diabetes duration (ALS and HbA1c: r=-0.36, ALS and diabetes duration: r=-0.52, ACS and HbA1c: r=-0.32, ACS and diabetes duration: r=-0.38, FAC and HbA1c: r=-0.36, FAC and diabetes duration: r=-0.32, RLS and HbA1c: r=-0.39, RLS and diabetes duration: r=-0.46, RCS and HbA1c: r=-0.31, RCS and diabetes duration: r=-0.39, respectively; P<0.01). Additionally, the ALS was significantly negatively correlated with fasting plasma glucose (FPG) (r=-0.30, P<0.05).<br><br>CONCLUSIONS: The elasticity of the AA and RA in T2DM patients was impaired. Decreased arterial elasticity was associated with poor blood glucose control and a longer duration of diabetes. Further studies are needed to assess the clinical value of VVI findings for predicting future cardiac events.}, }
@article {pmid41368443, year = {2025}, author = {Shamsi, A and Alrouji, M and AlOmeir, O and Tasqeruddin, S and Dinislam, K and Zuberi, A}, title = {Correction: CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1739705}, doi = {10.3389/fncel.2025.1739705}, pmid = {41368443}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2025.1681891.].}, }
@article {pmid41369024, year = {2025}, author = {Correa-Arrieta, C and Castellar-Leones, S and Ruiz-Ospina, E and Diaz-Ruiz, J and Sanchez-Peñarete, D and Rodriguez-Cruz, W and Bravo-Espejo, J and Uriza-Prias, DM and Ortiz-Corredor, F}, title = {Amyotrophic lateral sclerosis in Colombia: a population-based study of incidence and socioeconomic determinants.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2597944}, pmid = {41369024}, issn = {2167-9223}, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with variable global incidence. In Latin America, limited population-level data hinder accurate burden estimation and public health planning. This study estimated ALS incidence in Colombia from 1984 to 2024, analyzing regional distribution patterns and the demographic and socioeconomic profiles of affected individuals. Methods: This cross-sectional, population-based study analyzed 2185 clinically confirmed ALS cases reported to the Colombian National Institute of Health. Diagnoses were established using El Escorial or Gold Coast criteria. Annual and cumulative incidence rates were estimated using national population data. Demographic, geographic, and socioeconomic variables were classified under international standards, and all statistical analyses were performed using Python (version 3.12). Results: A total of 2185 ALS cases diagnosed between 1984 and 2024 were included. For the most recent decade (2015-2024), the national cumulative incidence was 41.46 per million inhabitants, with a steady increase in annual incidence. Bogotá and Caldas showed the highest cumulative incidence, whereas Chocó and Casanare reported the lowest. The mean age at diagnosis was 59.9 years, with a slight male predominance (male-to-female ratio 1.11:1). Socioeconomic disparities were evident: 18.0% of patients had no formal education, and over 40% were economically inactive at diagnosis. Conclusions: ALS incidence in Colombia is lower than that reported in high-income regions, but shows pronounced geographic and socioeconomic heterogeneity. These findings underscore the need to strengthen diagnostic capacity, improve equitable access to neurology services, and advance research on environmental and genetic determinants of ALS in Latin America.}, }
@article {pmid41370023, year = {2026}, author = {Ding, W and Guo, J and Lu, Y and Li, X}, title = {Nocturnal hypoxemia mediates age-related sleep fragmentation in amyotrophic lateral sclerosis: a polysomnographic case-control study.}, journal = {Acta neurologica Belgica}, volume = {126}, number = {1}, pages = {251-258}, pmid = {41370023}, issn = {2240-2993}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Middle Aged ; Polysomnography ; *Hypoxia/physiopathology/etiology ; Aged ; Case-Control Studies ; *Sleep Deprivation/physiopathology/etiology ; *Aging/physiology ; Adult ; }, abstract = {OBJECTIVE: To evaluate sleep architecture disruptions in amyotrophic lateral sclerosis (ALS) using polysomnography (PSG) and identify clinical/demographic correlates for targeted interventions.<br><br>METHODS: Forty definite/probable ALS patients (revised El Escorial criteria) without primary sleep disorders and 40 age/sex/BMI-matched controls underwent full polysomnography (PSG). Sleep parameters (total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], N1-N3, rapid eye movement [REM] sleep), respiratory indices (AHI, minimum peripheral oxygen saturation (min SpO&#x2082;), SpO&#x2082; range/coefficient of variation [CV]), and clinical metrics (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R], Hospital Anxiety and Depression Scale [HADS]) were compared. Multivariate regression identified independent sleep predictors, and mediation analysis quantified min SpO&#x2082;'s role in age-sleep fragmentation relationships.<br><br>RESULTS: ALS patients showed significantly reduced TST (371.54&#x2009;&#xb1;&#x2009;67.62 vs. 495.13&#x2009;&#xb1;&#x2009;45.69&#xa0;min, p&#x2009;=&#x2009;0.004), SE (69.95&#x2009;&#xb1;&#x2009;13.79 vs. 85.10&#x2009;&#xb1;&#x2009;7.03%, p&#x2009;=&#x2009;0.009), N2 sleep (127.33&#x2009;&#xb1;&#x2009;56.75 vs. 204.28&#x2009;&#xb1;&#x2009;67.16&#xa0;min, p&#x2009;=&#x2009;0.013), N3 sleep (61.70&#x2009;&#xb1;&#x2009;33.67 vs. 91.90&#x2009;&#xb1;&#x2009;44.06&#xa0;min, p&#x2009;=&#x2009;0.021), and REM sleep (66.09&#x2009;&#xb1;&#x2009;35.85 vs. 84.66&#x2009;&#xb1;&#x2009;37.65&#xa0;min, p&#x2009;=&#x2009;0.012) alongside elevated WASO (131.70&#x2009;&#xb1;&#x2009;78.82 vs. 64.26&#x2009;&#xb1;&#x2009;44.18&#xa0;min, p&#x2009;=&#x2009;0.015). Nocturnal oxygenation was impaired (min SpO&#x2082;: 89.3&#x2009;&#xb1;&#x2009;3.1% vs. 93.7&#x2009;&#xb1;&#x2009;2.4%, p&#x2009;<&#x2009;0.001; SpO&#x2082; CV: 3.7&#x2009;&#xb1;&#x2009;1.5% vs. 1.8&#x2009;&#xb1;&#x2009;0.9%, p&#x2009;<&#x2009;0.001), though AHI and REM AHI were comparable (AHI: p&#x2009;=&#x2009;0.087; REM AHI: p&#x2009;=&#x2009;0.134). Age (&#x3b2; = -0.28, p&#x2009;=&#x2009;0.02) and min SpO&#x2082; (&#x3b2;&#x2009;=&#x2009;0.31, p&#x2009;=&#x2009;0.01) independently predicted TST. Mediation analysis confirmed min SpO&#x2082; partially explains age-related TST reduction (indirect effect: -0.14, 95% CI: -0.28 to -&#x2009;0.03; accounting for 43.8% of the total effect).<br><br>CONCLUSION: Our data confirm profound sleep architecture disruption and nocturnal hypoxemia in ALS independent of primary sleep disorders. Critically, we establish min SpO&#x2082; as a partial mediator of age-related sleep fragmentation, suggesting that early management of hypoxemia may improve sleep quality. Larger prospective studies validating these mechanisms and their impact on disease progression are warranted.}, }
@article {pmid41371413, year = {2025}, author = {Spindler, A and Maas, D and Zappi, I and Senna, MM and Shapiro, J and Lo Sicco, KI}, title = {Response to Huang et al.'s ''Real-world efficacy of ritlecitinib in treating alopecia areata across various anatomical sites: potential rapid response predictors".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.10.161}, pmid = {41371413}, issn = {1097-6787}, }
@article {pmid41371952, year = {2026}, author = {Dalton, C and Mojsilovic-Petrovic, J and Safren, N and Snoznik, C and Gebis, KK and Wang, YZ and Sutter, AB and Lamitina, T and Savas, JN and Kalb, RG}, title = {Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {46}, number = {4}, pages = {}, pmid = {41371952}, issn = {1529-2401}, support = {R01 NS124802/NS/NINDS NIH HHS/United States ; S10 OD032464/OD/NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; R01 NS052255/NS/NINDS NIH HHS/United States ; R21 NS087077/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; HEK293 Cells ; *DNA-Binding Proteins/metabolism/genetics/toxicity/chemistry ; Rats ; *Neurons/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Solubility ; *DNA Repair Enzymes/metabolism/genetics ; Caenorhabditis elegans ; }, abstract = {At autopsy, >95% of ALS cases display a redistribution of the essential RNA binding protein TDP-43 from the nucleus into cytoplasmic aggregates. The mislocalization and aggregation of TDP-43 is believed to be a key pathological driver in ALS. Due to its vital role in basic cellular mechanisms, direct depletion of TDP-43 is unlikely to lead to a promising therapy. Therefore, we have explored the utility of identifying genes that modify its mislocalization or aggregation. We have previously shown that loss of rad-23 improves locomotor deficits in TDP-43 Caenorhabditis elegans models of disease and increases the degradation rate of TDP-43 in cellular models. To understand the mechanism through which these protective effects occur, we generated an inducible mutant TDP-43 HEK293 cell line. We find that knockdown of RAD23A reduces insoluble TDP-43 levels in this model and primary rat cortical neurons expressing human TDP-43[A315T] Utilizing a discovery-based proteomics approach, we then explored how loss of RAD23A remodels the proteome. Through this proteomic screen, we identified USP13, a deubiquitinase, as a new potent modifier of TDP-43 induced aggregation and cytotoxicity. We find that knockdown of USP13 reduces the abundance of sarkosyl insoluble mTDP-43 in both our HEK293 model and primary rat neurons, reduces cell death in primary rat motor neurons, and improves locomotor deficits in C. elegans ALS models.}, }
@article {pmid41373461, year = {2025}, author = {Butcher, EL and Arthur, S}, title = {Emerging Roles of Bile Acids in Neuroinflammation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373461}, issn = {1422-0067}, mesh = {Humans ; *Bile Acids and Salts/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Animals ; Gastrointestinal Microbiome ; Signal Transduction ; Biomarkers/metabolism ; Blood-Brain Barrier/metabolism ; Inflammation/metabolism ; Central Nervous System/metabolism ; }, abstract = {Bile acids, once considered mere digestive detergents, have emerged as multifaceted signaling molecules with systemic influence extending far beyond the gastrointestinal tract. Recent discoveries reveal their capacity to modulate immune responses, cross the blood-brain barrier, and interact with central nervous system (CNS) cells through their receptors. Neuroinflammation, a key driver of neurodegenerative and neuroimmune disorders, is increasingly linked to bile acid signaling pathways that regulate glial activation, cytokine production, and neuronal survival. This review compiles the current evidence connecting bile acids to CNS inflammation, highlighting mechanistic insights, disease-specific alterations, and the gut-microbiome-bile acid-brain axis. It also explores the therapeutic potential of bile acid derivatives and receptor modulators, as well as their emerging role as biomarkers in conditions such as Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy. Despite promising advances, critical gaps remain, including the need for bile receptor mapping in human CNS cells, standardized CNS bile acid profiling, and longitudinal metabolomic studies. Bridging these gaps may unlock new strategies for targeting neuroinflammation through bile acid-immune crosstalk.}, }
@article {pmid41373533, year = {2025}, author = {Apolloni, S and Tortoriello, S and Milani, M and Rossi, S}, title = {Extracellular Matrix Remodeling in Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373533}, issn = {1422-0067}, support = {GR-2021-12375436//Ministero della Salute/ ; PNRR project "Rome Technopole - Innovation Ecosystem"//European Union/ ; }, mesh = {Humans ; *Extracellular Matrix/metabolism/pathology ; *Motor Neuron Disease/metabolism/pathology ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {The extracellular matrix (ECM) constitutes a dynamic scaffold composed of both cellular and non-cellular elements that not only ensure tissue integrity but also regulate signaling events crucial for development and homeostasis. While its dysregulation has long been investigated in cancer, fibrosis, and autoimmunity, increasing evidence implicates ECM remodeling in neurodegenerative diseases, including motor neuron diseases (MNDs). Amyotrophic lateral sclerosis and spinal muscular atrophy, the most studied MNDs, both exhibit profound ECM alterations that influence synaptic connectivity, glial reactivity, and neuroinflammation. This review outlines recent data on ECM dynamics in MNDs, highlighting shared and disease-specific mechanisms, their potential as biomarkers, and therapeutic opportunities targeting the ECM environment to preserve neuronal function and slow disease progression.}, }
@article {pmid41373580, year = {2025}, author = {Salvany, S and Hernández, S and Casanovas, A and Gras, S and Piedrafita, L and Bosch-Queralt, M and Schwab, MH and Calderó, J and Esquerda, JE and Tarabal, O}, title = {Chronic Overexpression of Neuronal NRG1-III in Mice Causes Long-Term Detrimental Changes in Lower Motor Neurons, Neuromuscular Synapses and Motor Behaviour.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373580}, issn = {1422-0067}, support = {PID2021-122785OB-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; 202005-30//Marat&#xf3; de TV3 Foundation/ ; }, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; *Neuromuscular Junction/metabolism/pathology ; *Neuregulin-1/genetics/metabolism ; Mice ; Mice, Transgenic ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Motor Activity ; Disease Models, Animal ; Spinal Cord/metabolism/pathology ; Calcium/metabolism ; }, abstract = {Neuregulins (NRGs) are ligands of tyrosine kinase receptors from the ErbB family and play multiple developmental roles. NRG1-ErbB signaling regulates myelination and has been associated with amyotrophic lateral sclerosis (ALS) pathology. Given the potential therapeutic relevance of this pathway for motor neuron (MN) diseases, we employed a transgenic (TG) mouse with persistent neuronal overexpression of neuregulin type III (NRG1-III) to investigate its impact on the neuromuscular system. We performed an analysis of phenotypic changes in this TG model, including motor behavior, neuropathological evaluation by immunocytochemistry and ultrastructural examination of the spinal cord, peripheral nerves, and neuromuscular junctions (NMJs). Calcium dynamics in cultured MNs were also examined. We found that cholinergic C-boutons on TG MNs, where NRG1-III typically accumulates, exhibited upregulation of C-bouton-associated proteins and expansion of the subsynaptic cistern (SSC)-associated endoplasmic reticulum. Calcium imaging revealed altered homeostasis in TG MNs, accompanied by the upregulation of molecules linked to axonal plasticity. At NMJs, regressive changes involving autophagic dysregulation were observed. These alterations were accompanied by increased motor activity in behavioral tests. Overall, our findings indicate that persistently elevated NRG1-III signaling compromises MN connectivity and long-term health, a factor to consider when developing therapeutic strategies for neurodegenerative diseases such as ALS.}, }
@article {pmid41373649, year = {2025}, author = {Mukhija, S and Hering, L and Schreiner, SJ and Lehner, F and Loosli, J and Togni, C and Otto, F and Ziegler, M and Weiss, T and Jung, HH and Briel, N}, title = {Multimodal Biomarker Characterization of the ALS/FTD Spectrum: A Real-World Clinical Dataset Analysis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373649}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/cerebrospinal fluid/blood/metabolism ; *Biomarkers/blood/cerebrospinal fluid ; *Frontotemporal Dementia/diagnosis/blood/cerebrospinal fluid/metabolism ; Male ; Female ; tau Proteins/cerebrospinal fluid/blood ; Middle Aged ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; Neuroimaging ; }, abstract = {Diagnosis and prognosis of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) spectrum remain largely dependent on clinical assessments due to a lack of established fluid biomarkers. While neurofilaments and the cerebrospinal fluid (CSF) phosphorylated-tau/total-tau ratio (pTau:tTau) have been studied, their limitations, including their lack of clinical implementation and low specificity, necessitate multimodal approaches. This study aimed to characterize the biological features of the ALS/FTD spectrum through integration of clinically available parameters. We conducted a retrospective, single-center, cross-sectional study analyzing routinely collected clinical, neuroimaging, CSF, and serum data from 229 samples, including 45 from patients with ALS, 26 from patients with FTD, 158 from patients with other neurodegenerative diseases, and 29 from cognitively healthy controls. We implemented propensity score-weighted comparisons, an F1 score-based optimal cut-point determination for the pTau:tTau ratio, and a regularized XGBoost-based multimodal feature modeling approach. The biomarker and model performance was evaluated by the area under the precision-recall curve (AUC-PR). Feature importance analysis identified characteristic indicators of the ALS/FTD spectrum. Consistent with the prior literature, the pTau:tTau ratio was significantly reduced in ALS/FTD, but the classification performance was modest (AUC-PR 0.32). A multimodal model integrating clinical, biofluid, and neuroimaging features achieved a notably better performance (AUC-PR 0.75). Feature importance analysis revealed an ALS/FTD signature beyond the pTau:tTau ratio characterized by higher global cognition, younger age, an altered Aβ42/pTau ratio, and immunoglobulin changes (CSF IgG:IgA, serum IgG). Integration of clinical routine data centered on tau, amyloid, and immunological pathophysiology as well as temporal disease dynamics provide a contextualized biological characterization of the ALS/FTD spectrum. This approach offers a foundation for hypothesis generation regarding ALS/FTD pathophysiology and biomarker-supported diagnosis.}, }
@article {pmid41373784, year = {2025}, author = {Basavarajappa, BS and Subbanna, S}, title = {From Synaptic Plasticity to Neurotoxicity: Endocannabinoid Influence on Addiction and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373784}, issn = {1422-0067}, mesh = {Humans ; *Endocannabinoids/metabolism ; *Neuronal Plasticity ; Animals ; *Neurodegenerative Diseases/metabolism ; *Substance-Related Disorders/metabolism ; Receptors, Cannabinoid/metabolism ; }, abstract = {The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components-cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes-modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation-pathological features common to Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline.}, }
@article {pmid41375620, year = {2025}, author = {Krysiak, D and Ćwiertnia, M and Wójcik, M and Babik, P and Suchanek, &#x141; and Jaskiewicz, F and Trojak-Piętka, J and Szlagor, M and Pollok-Waksmańska, W and Kawecki, M and Ilczak, T}, title = {Analysis of Medical Response Team Interventions and the Impact of Certified Training on the Treatment of Patients with Hypoglycaemia-A Simulation Study.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375620}, issn = {2077-0383}, abstract = {Background/objectives: The effectiveness of emergency medical procedures administered to a patient in a life-threatening condition depends, to a large degree, on the knowledge and skills of medical response team personnel. Their competencies can be developed through participation in training and then verified during emergency medicine championships. Methods: The research was conducted on the basis of one of the tasks carried out during the '16th International Winter Championships in Emergency Medicine'. The task was completed by 28 Polish emergency response teams from ambulance stations across the country. The teams carried out a simulated scenario related to procedures with a patient with hypoglycaemia. The teams' interventions were assessed in accordance with European Resuscitation Council (ERC) guidelines by judges selected from among academic lecturers and ERC instructors. Results: The research showed that 86% of the teams obtained the maximum number of points for adhering to safety procedures. Further, 61% of the teams obtained the maximum of 6 points for the initial assessment, with the average number of points obtained by the teams being 5.54. The average number of points for the physical examination was 21.04, with only one team obtaining the maximum result of 26 points. Additionally, 57% of the teams obtained the maximum number of 6 points for the medical consultation, with the average obtained by the teams being 5.43. The teams obtained, on average, 8.18 points for the correct treatment of hypoglycaemia, with 68% of the teams obtaining the maximum of 9 points. The research demonstrated a positive correlation between the quality of patient examination and the collection of medical data, and the effectiveness of hypoglycaemia treatment. It was also shown that if the team leader had completed an ALS course, they obtained higher scores for the treatment of hypoglycaemia, although this finding is specific to this scenario. Conclusions: The teams demonstrated generally high performance in a simulated hypoglycaemia scenario. More complete assessment and history-taking were associated with higher treatment scores. Correct treatment was achieved in 79% of ALS-led teams versus 44% of non-ALS teams, although this observation is specific to this simulation and should not be generalised.}, }
@article {pmid41375893, year = {2025}, author = {Gratzer, A and Gdynia, N and Sasse, N and Beese, R and Winterholler, C and Bauer, Y and Schröter, C and Gdynia, HJ}, title = {Rehabilitation in Amyotrophic Lateral Sclerosis: Recommendations for Clinical Practice and Further Research.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375893}, issn = {2077-0383}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition characterized by the degeneration of upper and lower motor neurons. This degeneration leads to a gradual muscle weakness, dysarthria, dysphagia, respiratory insufficiency, and, in some patients, alterations in cognitive and behavioral performance. Regardless of advancements made in pharmacological and gene-targeted interventions, a definitive curative treatment remains elusive. Consequently, rehabilitation plays a pivotal role in preserving autonomy, participation, and overall quality of life. This review outlines the current evidence and clinical approaches related to multidisciplinary rehabilitation in ALS. It covers physical and occupational therapy, respiratory, speech and language, psychological, and palliative care domains. Evidence supports moderate tailored exercise programs, early respiratory therapy, and structured management of mobility deficits, spasticity, pain, dysphagia, and communication impairments as key elements of symptomatic treatment. Psychological and social support, which includes the involvement of caregivers and relatives, enhances emotional well-being and coping resilience. Even with progressive development of gene-targeted and disease-modifying therapies, rehabilitation will stay relevant for maintaining long-term motor function. This review highlights the need for standardized, evidence-based rehabilitation protocols and intensified neurorehabilitation research to strengthen clinical outcomes and quality of life as key therapeutic goals in ALS management.}, }
@article {pmid41375912, year = {2025}, author = {Sancho, J and Ferrer, S and Signes-Costa, J}, title = {Noninvasive Ventilation Effectiveness in Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375912}, issn = {2077-0383}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons; respiratory problems are the leading cause of death and hospital admissions and are secondary to progressive weakness of the respiratory muscles and upper airway. Noninvasive ventilation (NIV) can increase survival, alleviate symptoms, reduce hospital admissions, and improve the quality of life of these patients. The key factor in respiratory management of patients with ALS is achieving effective NIV; ineffective NIV has a negative impact on survival, with a reduction of up to 50% compared to patients with an effective technique. The most common cause of ineffective NIV is air leaks; other causes include upper airway obstruction events, residual hypoventilation, hyperventilation, and upper airway obstruction secondary to an oronasal mask. Regular monitoring of the effectiveness of NIV is essential given its impact on survival; the key tools that detect the main problems are the presence of hypoventilation symptoms, arterial blood gases, nocturnal oximetry and capnography, and built-in ventilator software. Different measures have been proposed to address the ineffectiveness of NIV, such as fitting the mask to reduce air leaks, increasing ventilatory support for residual hypoventilation, decreasing ventilatory support for hyperventilation, or a trial with a nasal mask to address oronasal interface effects. In the case of obstruction, the most common measure is to increase positive expiratory pressure during NIV. These measures enable NIV to be effective in 58% of cases, achieving a survival rate similar to that of patients who have effective NIV from the outset.}, }
@article {pmid41376117, year = {2025}, author = {Ali, YY and Fares, NV and Ayad, MF and Abbas, MM}, title = {Toward Practical and Sensitive Fluorescence Analysis: Factorial Design-Optimized o-Phthalaldehyde Derivatization for Synchronous Spectrofluorimetric Determination of Modafinil in Plasma and Dosage Form.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {40}, number = {12}, pages = {e70383}, doi = {10.1002/bio.70383}, pmid = {41376117}, issn = {1522-7243}, mesh = {*o-Phthalaldehyde/chemistry ; *Modafinil/blood/analysis ; Spectrometry, Fluorescence/methods ; Humans ; Limit of Detection ; Tablets ; Molecular Structure ; Fluorescence ; }, abstract = {The current research discusses a simple, sensitive, and practical spectrofluorimetric method for Modafinil (MDF) analysis. MDF can improve the fatigue symptoms associated with amyotrophic lateral sclerosis. MDF's aliphatic primary amide moiety can undergo base-catalyzed condensation with o-phthalaldehyde to give a highly fluorescent isoindoline derivative measured at 445 nm using synchronous spectrofluorimetry with Δλ of 110 nm. Different factors were studied using a two-level factorial design to reach the optimum conditions for the analysis. The method validation was carried out following the International Conference on Harmonization guidelines. The calibration curve was established to illustrate how relative fluorescence intensity varies with MDF concentration, and linearity was attained over the range of 10-7000 ng mL[-1], with an average recovery of 100.51% ± 0.91%. The limit of detection (LOD) was determined to be 3.21 ng mL[-1] while the quantitation limit (LOQ) was found to be 9.74 ng mL[-1]. The developed method demonstrated its effectiveness in determining MDF in tablets and spiked human plasma with recoveries of 100.43% ± 0.16 and 96.07% ± 1.55, respectively. MoGAPI, AGREE, and BAGI assessments yielded scores of 72, 0.62, and 70, respectively. The results show that the method is user-friendly and can be used in routine applications.}, }
@article {pmid41376376, year = {2025}, author = {Shi, Y and Zhao, T and Peng, L and Wang, P and Huang, X and Xu, F and Tan, Y and Peng, S and Xiong, T and Bai, Y and Liu, X and Wei, C and Zhang, W and Ding, H}, title = {Investigating the shared genetic architecture between post-traumatic stress disorder and neurodegenerative diseases: a large-scale genomewide cross-trait analysis.}, journal = {International journal of surgery (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/JS9.0000000000004347}, pmid = {41376376}, issn = {1743-9159}, abstract = {BACKGROUND: Post-traumatic stress disorder (PTSD), the most prevalent psychopathological consequence following traumatic events, profoundly impacts human life amidst global societal pressures. Emerging twin and family studies suggest that individuals with stress-related disorders face an elevated risk of neurodegenerative diseases, yet the genetic underpinnings of this association remain poorly understood.<br><br>METHODS: Here, we present a comprehensive framework elucidating this genetic basis. Using bivariate causal mixture models (MiXeR), we quantified polygenic overlap between PTSD (N&#xa0;=&#xa0;1,280,933) and four neurodegenerative phenotypes (N&#xa0;=&#xa0;115,803- 487,511), leveraging summary statistics from the largest PTSD genome-wide association study to date. Conditional/conjunction false discovery rate (FDR) analysis identified shared genomic loci.<br><br>RESULTS: MiXeR revealed considerable genetic variant sharing between neurodegenerative diseases and PTSD. Subsequent conjunction FDR analysis pinpointed 15 distinct shared loci. &#x3c1;-HESS local genetic correlation analysis identified seven significant local genetic correlations, with Chr6: 61,880,512-63,552,888 emerging as the most significant shared locus between PTSD and Alzheimer's disease. Cross-trait analyses using MTAG and CPASSOC identified 174 PTSD risk loci associated with at least one psychiatric disorder. Protein-coding genes mapped to known and novel shared loci exhibited specific spatial developmental trajectories. Through a framework incorporating five fundamental TWAS algorithm models, we identified 27 novel susceptibility genes that passed rigorous screening. Polygenic risk score (PRS) stratification in the UK Biobank cohort revealed dose-dependent relationships between PRS and risks of Alzheimer's disease, multiple sclerosis, and Parkinson's disease, with limited support for ALS and PTSD.<br><br>CONCLUSIONS: These findings illuminate the shared genetic architecture between PTSD and neurodegenerative phenotypes, advancing our understanding of their neurobiological interconnections. And enhance statistical power for detecting shared loci, thereby refining the characterization of common genetic mechanisms underlying PTSD and neurodegenerative pathologies.}, }
@article {pmid41377283, year = {2025}, author = {Imtiaz, E and Mahato, RK and Soomro, S and Jadoon, M and Intikhab, S}, title = {Nanomedicine-enhanced delivery of CRISPR-Cas13 for RNA editing in C9orf72-associated ALS.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {12}, pages = {9167-9168}, pmid = {41377283}, issn = {2049-0801}, }
@article {pmid41377708, year = {2025}, author = {Khalid, YA and Saad, MB and Nasreddin, ME}, title = {Assessing junior doctors' knowledge and attitude on advanced life support in Egypt: a cross-sectional study.}, journal = {African journal of emergency medicine : Revue africaine de la medecine d'urgence}, volume = {15}, number = {4}, pages = {100927}, pmid = {41377708}, issn = {2211-4203}, abstract = {INTRODUCTION: Cardiovascular diseases are a leading cause of mortality worldwide, with cardiac arrest survival heavily dependent on timely and effective resuscitation efforts. Junior doctors often serve as first responders in hospitals, yet their advanced life support (ALS) knowledge and training adequacy remain underinvestigated in Egypt. This study assessed the knowledge and attitudes of junior doctors in Egypt regarding basic life support (BLS) and ALS, identified knowledge gaps, and suggests improvements in resuscitation training programs.<br><br>METHODS: A cross-sectional survey was conducted among 184 junior doctors, including house officers, general practitioners, and residents, across multiple healthcare centres in Egypt. Data was collected via an online questionnaire based on European Resuscitation Council guidelines, evaluating demographic factors, BLS/ALS knowledge, and attitudes toward cardiac arrest management. Statistical analysis explored associations between knowledge scores and participant characteristics.<br><br>RESULTS: Participants demonstrated inadequate knowledge with mean BLS and ALS scores of 59 % and 61.8 %, respectively. Significant deficiencies were noted in pediatric resuscitation, cardiac arrest diagnosis, IV access, and capnography interpretation. Residents and those attending ALS workshops scored significantly higher (p < 0.05), while prior clinical exposure did not correlate with higher knowledge scores. Most participants (91.3%) expressed a need for further ALS training.<br><br>DISCUSSION: Junior doctors in Egypt show deficient ALS knowledge with critical gaps that may impact patient outcomes. Structured ALS training and curriculum reforms are urgently needed to enhance emergency preparedness and improve cardiac arrest survival.}, }
@article {pmid41378777, year = {2026}, author = {González-Velasco, &#xd3; and Parlato, R and Yilmaz, R and Decker, L and Menge, S and Freischmidt, A and Yang, X and Tulasi, N and Brenner, D and Andersen, PM and Forsberg, KME and Schlachetzki, JCM and Brors, B and Voith von Voithenberg, L and Weishaupt, JH}, title = {Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {778-784}, doi = {10.1093/brain/awaf460}, pmid = {41378777}, issn = {1460-2156}, support = {AIH23//AI Health Innovation Cluster/ ; YI 209/1-1, AOBJ 680080//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Motor Cortex/metabolism/pathology ; *Mutation/genetics ; Female ; Male ; Middle Aged ; Aged ; *RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately 10% of sporadic ALS cases (sALS). We leveraged DNA and single-cell RNA sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot-spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hotspot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single-cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.}, }
@article {pmid41379273, year = {2025}, author = {Zhang, R and Gao, B and Li, R and Zhou, R}, title = {Meta-analysis of the effects of dance- and movement-based kinesthetic games on cognitive function in older adults with cognitive impairment (CI) under different intervention periods.}, journal = {Aging clinical and experimental research}, volume = {37}, number = {1}, pages = {343}, pmid = {41379273}, issn = {1720-8319}, support = {24YJC890031//he&#xa0;Ministry of Education 's Youth&#xa0;Fund&#xa0;Project&#xa0;for&#xa0;Humanities&#xa0;and&#xa0;Social&#xa0;Sciences/ ; 22PJC094//Shanghai Pujiang Program/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy/psychology ; Aged ; *Cognition/physiology ; *Video Games ; *Dancing ; *Dance Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; *Exercise Therapy/methods ; Female ; }, abstract = {OBJECTIVE: To evaluate the effects of different types and durations of exergame interventions on cognition in elderly individuals with cognitive impairment (CI) through a meta-analysis.<br><br>METHODS: A computerized search was conducted in databases including Cochrane Library, PubMed, Web of Science, Embase, and CNKI from database inception to September 2025. Quality assessment and data extraction were performed on the included studies. Results measures included the MoCA , MMSE, etc. The study designs were randomized controlled trials or qua-si-experimental studies. The Cochrane Handbook's risk of bias tool was used for quality assessment, and Rev Man 5.0 software was employed to conduct meta-analyses on the ef-fects of dance-based and movement-based exergames on cognitive function in elderly CI patients.<br><br>RESULTS: A total of 13 studies involving 433 CI patients were included. Analysis of the 13 studies showed that dance-based exergaming was significantly superior to exercise-based exergaming in cognitive ability (SMD = 0.73, P < 0.01); interventions lasting &#x2265;8 weeks were more effective than those lasting <8 weeks (SMD = 1.01, P = 0.02).<br><br>CONCLUSION: Dance-based exergames significantly improve cognition in elderly individu-als with CI, with better effects observed in long-term interventions. However, more high-quality studies are needed to verify these findings and to supplement analyses on ex-ercise dose effects.}, }
@article {pmid41379346, year = {2026}, author = {Canosa, A and Callegaro, S and Manera, U and Vasta, R and Cabras, S and Di Pede, F and De Mattei, F and Palumbo, F and Iazzolino, B and Dei Giudici, A and Matteoni, E and Zocco, G and Minerva, E and Maccabeo, A and Pellegrino, G and Pascariu, D and Grassano, M and Piombino, P and Testa, M and Polverari, G and Fuda, G and Merulla, I and Casale, F and Gallone, S and Moglia, C and Calvo, A and Pagani, M and Chiò, A}, title = {Brain metabolic connectivity in ALS due to C9ORF72 hexanucleotide expansion: a [[18]F]FDG-PET study.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {53}, number = {4}, pages = {2786-2798}, pmid = {41379346}, issn = {1619-7089}, mesh = {Humans ; *C9orf72 Protein/genetics ; *Fluorodeoxyglucose F18 ; Male ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/metabolism ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Brain/metabolism/diagnostic imaging ; Aged ; *DNA Repeat Expansion ; Adult ; }, abstract = {PURPOSE: Our aim was to investigate brain metabolic connectivity, as assessed via [[18]F]FDG-PET, in ALS patients carrying the C9ORF72 expansion (C9-ALS).<br><br>METHODS: We compared brain metabolism of C9-ALS and patients without mutations of the main ALS-related genes (ctrl-ALS) through the two-sample t-test model of SPM12. Metabolic clusters showing a significant difference between the two groups were used as seed regions for an interregional correlation analysis (IRCA) in each group to evaluate metabolic connectivity.<br><br>RESULTS: As compared to ctrl-ALS, C9-ALS showed a relative hypometabolism in bilateral thalamus and left precentral and postcentral gyri, and a relative hypermetabolism in bilateral cerebellum and brainstem. In the IRCA, a positive correlation was found between the thalamic seed region and the cingulate cortex, including its anterior part. This correlation was broader in C9-ALS than in Ctrl-ALS. A negative correlation between the thalamic seed region and the sensorimotor cortex was only found in C9-ALS. In the IRCA, based on the cerebellar/brainstem cluster, positive correlations with the seed region substantially represented autocorrelation in both groups. Negative correlation, which mainly included frontal cortices, was more extensive in C9-ALS than in Ctrl-ALS.<br><br>CONCLUSION: In the comparison with ctrl-ALS, C9-ALS showed a relatively lower metabolism in the thalami and a relatively higher metabolism in the brainstem and the cerebellum. As compared to ctrl-ALS, C9-ALS showed a predominant involvement of the salience network, which is related to cognitive and behavioural control. The cerebellum might be recruited to cope with cognitive impairment to a greater extent in C9-ALS than in ctrl-ALS.}, }
@article {pmid41379813, year = {2026}, author = {Dashnaw, CM and Gonzalez, M and Abdolvahabi, A and Bassett, PT and Lato, TJ and Balamurali, R and Guberman-Pfeffer, MJ and Shaw, BF}, title = {Heteroaggregation of Wild-Type and ALS Mutant SOD1.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {1}, pages = {90-108}, doi = {10.1021/acschemneuro.5c00632}, pmid = {41379813}, issn = {1948-7193}, mesh = {*Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Mutation/genetics ; *Superoxide Dismutase/genetics/metabolism ; *Protein Aggregates ; }, abstract = {The presence of wild-type (WT) Cu, Zn superoxide dismutase-1 (SOD1) can increase the toxicity of mutant SOD1 proteins linked to amyotrophic lateral sclerosis (ALS). The mechanism of synergy is unclear but might involve interactions between WT and mutant SOD1 in native or non-native states. One unanswered question is will the diverse rates of mutant SOD1 homofibrillization converge in the presence of WT SOD1? To answer this question, we assessed the coaggregation of mutant and WT SOD1 in vitro, including (i) how WT SOD1 affected the formation rate and stability of mutant fibrils and (ii) the proximity of WT and mutant SOD1 in heterofibrils. For most mutations studied, the presence of WT SOD1 slowed nucleation and propagation of mutant fibrils while increasing fibril thermostability. The D90A SOD1 protein was one exception: WT SOD1 had a nearly negligible effect on its rate of nucleation. The cross-seeding of soluble mutant SOD1 with WT fibrils (and of soluble WT SOD1 with mutant fibrils) suggests that both proteins can occupy the same fibril. Mass spectrometry of heterofibrils treated with an NHS-ester cross-linker (∼8 Å) suggested that WT and E100G mutant SOD1 are colocalized in heterofibrils, possibly stacked in an alternating configuration.}, }
@article {pmid41380476, year = {2026}, author = {Gu, Y and Chen, Y and Tang, X and Guo, J and Hu, J and Yang, W and Li, J and Chen, X and Fan, D and Chen, GB and He, J and Ren, Y and Dong, Y and Sato, C and Chen, Y and Zinman, L and Rogaeva, E and Zhang, M}, title = {Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations.}, journal = {EBioMedicine}, volume = {123}, number = {}, pages = {106071}, pmid = {41380476}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality ; DNA Methylation ; *Epigenesis, Genetic ; Polymorphism, Single Nucleotide ; Male ; Female ; Middle Aged ; CpG Islands ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; *Genetic Loci ; Aged ; Genotype ; Epigenomics/methods ; Whole Genome Sequencing ; Multiomics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.<br><br>METHODS: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.<br><br>FINDINGS: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.<br><br>INTERPRETATION: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.<br><br>FUNDING: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).}, }
@article {pmid41380670, year = {2025}, author = {Fujioka, Y and Ishigaki, S}, title = {Decoding ALS from the tail end of RNA.}, journal = {Cell genomics}, volume = {5}, number = {12}, pages = {101102}, pmid = {41380670}, issn = {2666-979X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Polyadenylation/genetics ; RNA, Messenger/genetics/metabolism ; Transcriptome/genetics ; Brain/metabolism ; }, abstract = {In this issue of Cell Genomics, McKeever et al.[1] generate a single-nucleus transcriptomic atlas of ALS/FTLD brain and reveal widespread alternative polyadenylation changes. Their findings highlight 3' end RNA processing as a central integrator of stress responses, cell-type specificity, and disease susceptibility, offering new mechanistic insight and potential therapeutic directions.}, }
@article {pmid41381004, year = {2025}, author = {Maas, D and Spindler, A and Zappi, I and Shapiro, J and Lo Sicco, KI}, title = {Response to Olsen et al's "Summation and recommendations for the safe and effective use of topical and oral minoxidil".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.09.118}, pmid = {41381004}, issn = {1097-6787}, }
@article {pmid41381656, year = {2025}, author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR}, title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {510}, pmid = {41381656}, issn = {2045-2322}, support = {LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Humans ; *Proteomics/methods ; Cell Line, Tumor ; Tandem Mass Spectrometry ; *Proteome ; *Dipeptides/toxicity ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; *Alanine/analogs &amp; derivatives/toxicity ; }, abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.}, }
@article {pmid41381924, year = {2025}, author = {Soares, &#xc1;M and de Paula Cruz, ECO and da Silva, LG and de Sousa, YG and Távora, DGF and de Albuquerque, LAF}, title = {Anatomical references for the transopercular approach to the insula: a 1.5 Tesla magnetic resonance study.}, journal = {Neurosurgical review}, volume = {49}, number = {1}, pages = {63}, pmid = {41381924}, issn = {1437-2320}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Female ; Male ; Adult ; Middle Aged ; *Insular Cortex/anatomy &amp; histology/surgery ; *Cerebral Cortex/anatomy &amp; histology/surgery ; Young Adult ; Aged ; Adolescent ; Brain Mapping/methods ; }, abstract = {OBJECTIVE: This study aimed to establish the topographic relation of the limiting sulci of the insula with structures on the brain surface, in addition to determining a new anatomical point to objectively identify the Berger-Sanai quadrants.<br><br>METHODS: 1.5 Tesla MRI was used to analyze 100 insulas and their relation to the brain surface. The projection of the anterior (ALS), superior (SLS), and inferior (ILS) limiting sulci of the insula onto the brain surface was determined, together with the relations between these sulci and the anterior Sylvian point (ASP), the inferior frontal sulcus (IFS), and the superior temporal sulcus (STS). The central point of the Berger-Sanai quadrants was identified based on the inferior Rolandic point (IRP). The projection of this central point onto the insula and the brain surface were also identified.<br><br>RESULTS: The following measurements were calculated: the mean anteroposterior distance between the ASP and ALS, 3.2&#xa0;mm&#x2009;&#xb1;&#x2009;0.7&#xa0;mm; the mean craniocaudal distance from the ASP to the SLS, 10.5&#xa0;mm&#x2009;&#xb1;&#x2009;1.8&#xa0;mm; the mean craniocaudal distance between the IFS and SLS, 15.5&#xa0;mm&#x2009;&#xb1;&#x2009;2.5&#xa0;mm; the mean craniocaudal distance from the end of the IFS to the SLS, 13.5&#xa0;mm&#x2009;&#xb1;&#x2009;2.9&#xa0;mm; the mean craniocaudal distance between the STS and ILS, 4.0&#xa0;mm&#x2009;&#xb1;&#x2009;1.9&#xa0;mm; the mean craniocaudal distance from the end of the STS to the ILS, 6.1&#xa0;mm&#x2009;&#xb1;&#x2009;2.4&#xa0;mm; and the mean laterolateral distance from the STS to the ILS, 22.7&#xa0;mm&#x2009;&#xb1;&#x2009;3.5&#xa0;mm. The central point of the Berger Sanai quadrants was determined to be over the Sylvian fissure, at a mean distance of 7.3&#xa0;mm&#x2009;&#xb1;&#x2009;1.2&#xa0;mm anterior to the IRP. This point projected over the precentral gyrus in 79% of cases and the posterior short gyrus of the insula in 68%.<br><br>CONCLUSIONS: The data obtained in this study demonstrate a close topographic relationship between easily identifiable structures on the brain surface (ASP, IFS and STS) and the limiting sulci of the insula. We propose a simple, novel way to find the central point of the Berger Sanai quadrants based on their relation with the IRP. The findings determined here can assist neurosurgeons in locating the insula, especially in transopercular approaches.}, }
@article {pmid41383013, year = {2026}, author = {Hor, JH and Ow, JR and Ng, W and Ramasamy, B and Tabaglio, T and Lim, KNH and Bin Muzakar, MI and Lim, VJW and Gurrampati, RR and Rajarethinam, R and Ngo, ST and Ramadass, V and Ling, SC and Lakshmanan, M and Wee, KB and Ng, SY}, title = {BLOC1S1 depletion via splice-switching oligonucleotides improves mitochondrial respiration and rescues ALS phenotypes.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {3}, pages = {1672-1683}, pmid = {41383013}, issn = {1525-0024}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy/pathology ; Animals ; *Mitochondria/metabolism/genetics ; Humans ; Mice ; Disease Models, Animal ; Motor Neurons/metabolism ; Phenotype ; *Oligonucleotides, Antisense/genetics ; Cell Respiration ; Induced Pluripotent Stem Cells/metabolism ; *RNA Splicing ; *Oligonucleotides/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and debilitating neurodegenerative disease, yet the mechanisms underlying disease onset and progression remain poorly understood, particularly in sporadic ALS. Emerging evidence suggests that mitochondrial dysfunction and metabolic dysregulation are central to ALS pathophysiology. A key feature of ALS motor neurons (MNs) is hyper-acetylation of mitochondrial proteins, which disrupt mitochondrial respiration and energy homeostasis. In this study, we identify BLOC1S1 (also known as GCN5L1) as a novel regulator of mitochondrial acetylation in ALS. We demonstrate that BLOC1S1 is significantly upregulated in ALS patient-derived MNs, postmortem motor cortices, and spinal cords of ALS mouse models. Functional studies in induced pluripotent stem cell-derived MNs reveal that BLOC1S1 depletion rescues key disease phenotypes. Therefore, we develop an efficacious splice-switching antisense oligonucleotide that induces nonsense-mediated decay of BLOC1S1 transcripts as a potential therapeutic candidate. Besides mitigating ALS-relevant cellular deficits in MN cultures from diverse genetic backgrounds, it was validated to extend disease-free and overall survival that is associated with improved rotarod performance in an ALS mouse model. These findings establish BLOC1S1 as a critical modifier of disease progression in ALS and highlight its potential as a novel therapeutic target.}, }
@article {pmid41384008, year = {2025}, author = {Gutral, J and Cypryańska, M and Nezlek, JB}, title = {A Polish language version of Wood et al.'s multidimensional Authenticity Scale.}, journal = {Current issues in personality psychology}, volume = {13}, number = {4}, pages = {254-260}, pmid = {41384008}, issn = {2353-561X}, abstract = {BACKGROUND: There is considerable interest among personality psychologists in authenticity. To provide researchers with a tool to study dispositional authenticity among speakers of Polish, we created a Polish language version of Wood et al.'s multidimensional measure of authenticity. Wood et al.'s measure has 12 items and measures three constructs: four items for selfalienation; authentic living; and accepting external influence.<br><br>PARTICIPANTS AND PROCEDURE: Participants were 825 Polish adults (M age = 42.7, SD = 15.4; 50% women) who were recruited by a professional survey company. Participants completed the newly developed measure of authenticity, and for validation purposes, they completed measures of Ryff's model of well-being, self-esteem, satisfaction with life, and stress, the same measures used by Wood et al.<br><br>RESULTS: A confirmatory factor analysis found that the Polish version of the scale had the same three factors as the original measure developed by Wood et al., and the loadings of the items on the factors were consistent with those presented by Wood et al. The three scales of the new measure were reliable. Moreover, relationships between the authenticity scales and the validation measures were similar to those reported by Wood et al.<br><br>CONCLUSIONS: The present results suggest that our proposed Polish language version of Wood et al.'s multidimensional authenticity scale measures a similar set of constructs to those measured by the original English language scale. Therefore, we believe our new measure should be useful for researchers interested in studying dispositional authenticity among Polish language speakers.}, }
@article {pmid41384353, year = {2025}, author = {Yu, H and Zhang, X and Liu, Z and Zhang, L}, title = {Explaining Isoform Selectivity of c-Jun N-Terminal Kinase 3 (JNK3) Inhibitors through Its Development and Structural Insights.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {24}, pages = {25665-25688}, doi = {10.1021/acs.jmedchem.5c01488}, pmid = {41384353}, issn = {1520-4804}, mesh = {*Mitogen-Activated Protein Kinase 10/antagonists &amp; inhibitors/metabolism/chemistry ; Humans ; *Protein Kinase Inhibitors/chemistry/pharmacology ; Structure-Activity Relationship ; Animals ; Models, Molecular ; Protein Isoforms/metabolism/antagonists &amp; inhibitors ; }, abstract = {c-Jun N-terminal kinase 3 (JNK3), a member of the mitogen-activated protein kinase (MAPK) family, is selectively enriched in the brain. It plays a significant role in the pathogenesis of neurodegenerative disorders, glaucoma, amyotrophic lateral sclerosis, and cancer, which makes it a promising drug target. However, the advancement of JNK3 inhibitors has been challenged by limited isoform selectivity. This article explains the pathway regulated by JNK3 and the unique functions of JNK3. A detailed structural analysis of JNK3 complexes with ligands is presented to uncover the molecular basis of binding interactions. The inhibitors are systematically classified according to their chemical scaffolds, and the reason for their isoform selectivity was discussed, providing a structural rationale for the evolution of JNK3 inhibitor design. The perspective concludes with an exploration of the challenges in the discovery of selective JNK3 inhibitors and proposes innovative strategies to surmount these obstacles.}, }
@article {pmid41385026, year = {2025}, author = {Kara, NS and Ozisik, O and Baudot, A and Slachtova, L}, title = {Investigating the Potential Roles of Environmental Exposures on the Pathology of Amyotrophic Lateral Sclerosis by Overlap Analysis.}, journal = {Neurotoxicity research}, volume = {43}, number = {6}, pages = {51}, pmid = {41385026}, issn = {1476-3524}, support = {AMX-19-IET-007//Initiative d'Excellence d'Aix-Marseille Universit&#xe9;/ ; PRIMUS UK 21/MED/012//Univerzita Karlova v Praze/ ; OP JAK MSCA//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Environmental Exposure/adverse effects ; Vehicle Emissions/toxicity ; Pesticides/toxicity ; Toluene/toxicity ; Smoking/adverse effects ; Computational Biology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is essential in ALS pathology. Several neurotoxic exposures, such as smoking, pesticides, and organic solvents, have been implicated as affecting the risk of ALS. However, it is unclear how these exposures impact specific cellular mechanisms and influence ALS risk. We investigated the potential mechanisms of toxicity of diesel exhaust, toluene, pesticides, and smoking on ALS pathology through a bioinformatics approach. We retrieved the gene sets targeted by these environmental exposures, and the gene sets involved in ALS-associated biological processes. We performed overlap analysis to assess the statistical significance of the overlap between the gene sets associated with environmental exposures and those linked to ALS. Response to oxidative stress, synaptic signaling, lipid metabolic process, cellular oxidant detoxification, and regulation of gliogenesis significantly overlapped with the gene sets targeted by each of the four environmental exposures. Contrarily, chaperone-mediated autophagy, DNA repair, and regulation of action potential, significantly overlapped only with the gene sets targeted by diesel exhaust, pesticides, and toluene, respectively. Finally, transport across the blood-brain barrier, vesicle-mediated transport, actin filament-based transport, autophagy, transport to the Golgi and subsequent modification of proteins, metabolism of lipids, regulation of neurotransmitter receptor levels, and axon guidance significantly overlapped only with the gene set targeted by tobacco smoke pollution. This study aims to investigate the molecular relationships between neurotoxic exposures and ALS by overlap analysis, providing a framework that can be applied to investigate other exposure-disease interactions.}, }
@article {pmid41385186, year = {2025}, author = {Mitsiadou, D and Xirodimas, DP and Polanowska, J}, title = {NEDD8, stress granules, and amyotrophic lateral sclerosis: unveiling the therapeutic potential of the NEDP1 protease.}, journal = {Essays in biochemistry}, volume = {69}, number = {5}, pages = {}, pmid = {41385186}, issn = {1744-1358}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; Animals ; *Stress Granules/metabolism ; *NEDD8 Protein/metabolism ; }, abstract = {Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.}, }
@article {pmid41386291, year = {2025}, author = {Andersen, CA and Jenssen, C and Poppleton, A and Leceaga, E and Kosiak, M and Iacob, MS and Skendi, M and Frese, T and Løkkegaard, T and Homar, V and Rüttermann, V and Ewertsen, C}, title = {Point-of-care ultrasound in primary care - EFSUMB core curriculum and training recommendations, a position paper.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2771-2848}, pmid = {41386291}, issn = {1438-8782}, abstract = {English abstract: Frontline physicians working in primary care increasingly use diagnostic ultrasound examinations and simple ultrasound-guided procedures as part of their daily practice. Primary care is organized in many ways across Europe and as a result, primary care physicians have different qualifications in terms of using and integrating point-of-care ultrasound in patient care. To ensure high quality and standardized practice across Europe, this position paper of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) describes training recommendations and a generic core curriculum for frontline physicians working in primary care. The core curriculum was developed through a Delphi process and includes basic ultrasound examinations corresponding to the EFSUMB competence level 1 for medical ultrasound practice. The training recommendations are intended to build a common foundation while national adjustments must be made to ensure relevance in the clinical setting and patient population. German abstract: In der Primärversorgung tätige Ärzte setzen zunehmend diagnostische Ultraschalluntersuchungen und einfache ultraschallgesteuerte Verfahren als Teil ihrer täglichen Routine ein. Die Primärversorgung ist in Europa sehr unterschiedlich organisiert, sodass die Qualifikationen der Ärzte, die Point-of-Care-Ultraschall in der primären Patientenversorgung einsetzen und integrieren, sehr unterschiedlich sind. Mit dem Ziel, eine hohe Qualität und standardisierte Ausübungspraxis in ganz Europa zu gewährleisten, stellt dieses Positionspapier der European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Ausbildungsempfehlungen und ein PoCUS Basis-Curriculum für in der Primärversorgung tätige Ärzte vor. Das Basis-Curriculum wurde im Rahmen eines Delphi-Verfahrens entwickelt und umfasst grundlegende Ultraschalluntersuchungen, die dem EFSUMB-Kompetenzniveau 1 für die medizinische Ultraschallpraxis entsprechen. Die Ausbildungsempfehlungen sollen eine gemeinsame Grundlage schaffen, wobei durch nationale Anpassungen die Relevanz für das konkrete klinische Umfeld und die betreuten Patientengruppen sichergestellt werden muss.}, }
@article {pmid41386298, year = {2026}, author = {Ealy, A and Serapiglia, AM and Panicker, N}, title = {Sterile innate immune mechanisms in neurodegenerative diseases.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {2}, pages = {111039}, pmid = {41386298}, issn = {1083-351X}, support = {R00 AG066862/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Immunity, Innate ; *Neurodegenerative Diseases/immunology/pathology ; Animals ; Amyotrophic Lateral Sclerosis/immunology/pathology ; Parkinson Disease/immunology/pathology ; Alzheimer Disease/immunology/pathology ; Signal Transduction ; Multiple Sclerosis/immunology/pathology ; }, abstract = {Neurodegenerative diseases are characterized by the dysfunction and death of susceptible neuronal populations. Increasing evidence has demonstrated that sustained neuroinflammation and activation of innate immune complexes underlie neurodegeneration, worsening disease progression and outcomes. Sterile inflammation (which occurs in the absence of infection) can be triggered by neurodegenerative disease-associated misfolded proteins. These studies highlight the need to decipher the complexities of innate immune signaling mechanisms and their contribution to neuropathology. In this review, we focus on major neurodegenerative diseases that have a well-documented neuroinflammatory component: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and frontotemporal dementia. In the context of these diseases, we discuss recent advances in innate-immune mechanisms that have been demonstrated to partake in disease progression and neurodegeneration. These include evolutionarily conserved innate-immune signaling complexes whose uncontrolled activation amplifies neurodegeneration, damaging lipid droplets that accumulate within myeloid cells and prevent their ability to clear toxic protein aggregates, as well as genome-wide studies-implicated genes/proteins. The individual and/or concerted actions of these pathways could be leveraged to rationally target the pathogenesis or progression of neurodegenerative diseases.}, }
@article {pmid41386880, year = {2025}, author = {Eshak, D and Arumugam, M}, title = {Integrative analysis of transcriptomics and drug-target networks identifies SMN1 as a novel biomarker and therapeutic target for amyotrophic lateral sclerosis.}, journal = {Journal, genetic engineering &amp; biotechnology}, volume = {23}, number = {4}, pages = {100615}, pmid = {41386880}, issn = {2090-5920}, abstract = {Amyotrophic lateral sclerosis (ALS) is a prevalent and debilitating neurodegenerative disorder characterized by the selective degeneration of motor neurons. This study aims to unravel the molecular mechanisms underlying ALS through an integrated analysis of drug-target networks and gene expression data. Gene expression datasets related to ALS, including GSE115130 and GSE76220, were retrieved from the GEO database and systematically analyzed. Differential gene expression (DEG) analysis identified key upregulated and downregulated genes, while weighted gene co-expression network analysis (WGCNA) uncovered gene modules associated with ALS pathology. DEG analysis revealed genetic insights into ALS by pinpointing genes potentially involved in disease development and progression. WGCNA provided a systems-level understanding of ALS mechanisms, identifying highly correlated gene clusters and their relationship with clinical ALS characteristics. In the GSE115130 dataset, 6,105 genes were upregulated and 6,069 were downregulated. Conversely, the GSE76220 dataset showed 4,850 upregulated genes and 7,691 downregulated genes. Using the STRING database, a protein-protein interaction (PPI) network was constructed to investigate the functional relationships among ALS-associated genes. The findings highlighted the significant role of the survival motor neuron 1 (SMN1) gene in ALS, particularly in sporadic cases. Additionally, drug-target network mapping identified potential therapeutic targets and candidate drugs, offering valuable insights into the molecular mechanisms of ALS and possible interventions. This integrative approach underscored SMN1 as a novel diagnostic biomarker and potential therapeutic target for ALS, emphasizing its critical role in disease pathogenesis. These findings pave the way for further mechanistic studies and clinical validation, aiming to enhance therapeutic strategies for ALS.}, }
@article {pmid41386904, year = {2025}, author = {eBioMedicine, }, title = {The accelerating pace of amyotrophic lateral sclerosis research.}, journal = {EBioMedicine}, volume = {122}, number = {}, pages = {106079}, doi = {10.1016/j.ebiom.2025.106079}, pmid = {41386904}, issn = {2352-3964}, }
@article {pmid41386992, year = {2026}, author = {Myers, AK and Sakheim, M and Rivell, C and Fengler, C and Festa, LK and Guerra, KM and Jarrahy, L and Shin, R and Case, M and Chapman, C and Basel, L and Springer, S and Kern, N and Gidicsin, J and Cho, G and Kim, S and Tighiouart, M and Golden, JA}, title = {Anxiety-Associated Behaviors Following Ablation of Miro1 from Cortical Excitatory Neurons.}, journal = {eNeuro}, volume = {13}, number = {1}, pages = {}, pmid = {41386992}, issn = {2373-2822}, support = {R01 NS100007/NS/NINDS NIH HHS/United States ; R56 NS100007/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *rho GTP-Binding Proteins/genetics/metabolism/deficiency ; *Anxiety/metabolism/genetics/pathology ; Mice ; *Neurons/metabolism ; Male ; *Mitochondrial Proteins/genetics/metabolism ; *Cerebral Cortex/metabolism/pathology ; Mitochondria/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Behavior, Animal/physiology ; Female ; Disease Models, Animal ; }, abstract = {Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction (Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 (Miro1) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility (Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and studied mice of both sex. We found that mitochondrial mislocalization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to several anxiety-like behaviors.}, }
@article {pmid41387380, year = {2025}, author = {Savasan-Sogut, M and Campos-Melo, D and Strong, MJ}, title = {3'UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70364}, pmid = {41387380}, issn = {1742-4658}, support = {SOP-160442/CAPMC/CIHR/Canada ; }, abstract = {While most human genes express mRNA 3'untranslated region (3'UTR) variants of different lengths, their impact on cell physiology and disease remains largely unknown. Here, we studied 3'UTR length heterogeneity in amyotrophic lateral sclerosis (ALS) and determined that three ALS-linked transcripts exhibit lengthening of their 3'UTRs in patient samples. We investigated phenotypical effects in a neuronal cell line expressing these 3'UTRs and observed that expression of these unique 3'UTRs induces morphological changes at different levels. Among the most expressed 3'UTR variants in ALS, NEFH 3'UTR-Long induces the formation of nuclear RNA clusters, and Superoxide Dismutase 1 3'UTR-Long diminishes filopodia in the plasma membrane. Sequestosome 1 3'UTR-Long did not show major changes in nuclear RNA clusters or filopodia. Our findings provide the first evidence that 3'UTRs can modulate cellular phenotype independent of the coding region, further expanding the impact of alterations in mRNA biogenesis in ALS.}, }
@article {pmid41388206, year = {2025}, author = {Schmitt, P and Schumann, P and Koerbs, A and Lin, HJ and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Großkreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P and Meyer, T}, title = {Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis-results from a multicenter screening program.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {22}, pmid = {41388206}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/physiopathology/diagnosis ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; C9orf72 Protein/genetics ; Phenotype ; Aged ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Adult ; Disease Progression ; Cohort Studies ; DNA-Binding Proteins/genetics ; }, abstract = {OBJECTIVE: In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.<br><br>METHODS: In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to C9orf72 (n&#x2009;=&#x2009;137), SOD1 (n&#x2009;=&#x2009;54), TARDBP (n&#x2009;=&#x2009;27), and FUS (n&#x2009;=&#x2009;19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. Serum NfL (sNfL)&#xa0;was measured and related to ALS progression (ALSPR, monthly change of ALS Functional Rating Scale-Revised). To quantify NfL elevation relative to ALSPR, the logNfL(index), the log-transformed ratio of sNfL to ALSPR was calculated.<br><br>RESULTS: C9orf72-associated ALS showed frequent bulbar onset (n&#x2009;=&#x2009;42.6%), higher ALSPR (0.95, SD 0.84), highest NfL (116.3, SD 72.7&#xa0;pg/mL) and logNfL(index) (5.02, SD 0.88). SOD1-ALS had mostly limb onset (n&#x2009;=&#x2009;96.1%), slower ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4&#xa0;pg/mL) and a comparably high logNfL(index) (4.94, SD 1.03). FUS-ALS exhibited mostly limb onset (82.4%), lower motor neuron dysfunction (70.6%), a wide range of faster (22.2%) to slower ALSPR (55.6%), lower NfL (66.2, SD 32.9) and logNfL(4.65, SD 0.9). TARDBP-ALS displayed the lowest ALSPR (0.53, SD 0.52), the lowest NfL (43.3, SD 31.8 pg/mL) and the lowest logNfL(index) (4.40, SD 0.7).<br><br>CONCLUSION: In C9orf72-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in SOD1-, FUS- and TARDBP-associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.}, }
@article {pmid41389101, year = {2025}, author = {Li, Y and Zhou, Y and Yu, L and Bi, Y and Yi, L and Li, C and Liu, Y}, title = {Myeloid Irf5 Deficiency Enhances the Therapeutic Efficacy of IMD-0354 in a TDP-25-Induced Neurodegeneration Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {290}, pmid = {41389101}, issn = {1559-1182}, support = {H2024206009//the Hebei Natural Science Foundation/ ; 81901290//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Interferon Regulatory Factors/deficiency/metabolism ; *DNA-Binding Proteins/toxicity/metabolism ; Macrophages/metabolism/drug effects ; Mice, Knockout ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; Mitochondria/metabolism/drug effects ; Cell Line ; Amyotrophic Lateral Sclerosis/drug therapy ; Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Nerve Degeneration/drug therapy/pathology/metabolism ; *Myeloid Cells/metabolism/drug effects ; }, abstract = {Neuroinflammation is recognized as a key contributor to the pathogenesis and progression of amyotrophic lateral sclerosis (ALS), with dysregulated innate immune activation implicated in exacerbating neuronal injury. However, the molecular mechanisms by which macrophages contribute to neurodegeneration in motor neurons harboring TAR DNA-binding protein 43 (TDP-43) mutations are not fully understood. M1 macrophages were generated from the bone marrow of Irf5 knockout or wild-type mice and co-cultured with the NSC34 motor neuron-like cell line overexpressing the C-terminal fragment of TDP-43 (TDP-25) using a Transwell system. Mitochondrial alterations, and apoptosis were evaluated through Western blotting, flow cytometry, and transmission electron microscopy. IMD-0354 mitigated mitochondrial dysfunction and apoptosis induced by TDP-25 exposure. This neuroprotective effect was attenuated in the presence of pro-inflammatory macrophages. Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation.}, }
@article {pmid41389317, year = {2025}, author = {Argo, A and Puntarello, M and Malta, G and Tarantino, M and Midiri, M and Pellerito, S and Albano, GD and Zerbo, S}, title = {Verification of the persistence of sperm traces under different chain-of-custody conditions. Care pathway and justice for victims of sexual violence and abuse.}, journal = {Forensic science, medicine, and pathology}, volume = {}, number = {}, pages = {}, pmid = {41389317}, issn = {1556-2891}, abstract = {The primary aim of this study was to verify the persistence of seminal traces under varying chain-of-custody conditions, along with determining how different contamination factors, time intervals between collection, and storage methods influence the detectability of semen in the context of sexual assault cases. This study combined laboratory and field analyses to simulate real-case scenarios. Three forensic detection tools-Sperm Tracker Lab, Sperm Tracker Spray, and RSID™ tests-were evaluated on multiple substrates (skin, hair, nylon, cotton, and car interiors) and under various contamination conditions, including the presence of blood, dust, soil, and bodily fluids. Detection techniques included contact-pressure methods (Sperm Tracker Lab), application on uneven surfaces (Sperm Tracker Spray), fluorescence-based searches with ALS (alternative light sources), and immunochromatographic testing (RSID™ kits) for sperm-specific proteins. Positive findings were confirmed via microscopic examination and DNA analysis. All the samples were labelled and stored following strict chain-of-custody protocols. Sperm Tracker Spray demonstrated consistent effectiveness, successfully detecting minimal volumes (1-2 µL) across a wide range of materials. Conversely, ALS showed reduced sensitivity, especially in the presence of diluted or minimal traces and on textured or dark fabrics. RSID™ kits provided reliable confirmation of the presence of semen, even when environmental or biological contamination was present. Accurate and thorough documentation of the chain of custody proved essential for preserving sample authenticity and reducing the risk of error. The findings underscore the importance of a multidisciplinary forensic approach combining specialized reagents, confirmatory immunochromatographic testing, and rigorous adherence to chain-of-custody procedures. This integrated strategy enhances the reliability of seminal trace detection in investigations of sexual assault. Moreover, verifying trace persistence under diverse conditions contributes significantly to the evidentiary value of forensic samples in judicial contexts.}, }
@article {pmid41389646, year = {2026}, author = {Bhatia, S and Mohanty, V and Balappanavar, AY and Sarkar, C and Malhotra, S and Gupta, R}, title = {Fostering the concept of "inclusion oral health" through experiential learning: A mixed-methods approach to explaining health inequities to dental students.}, journal = {Social science &amp; medicine (1982)}, volume = {390}, number = {}, pages = {118859}, doi = {10.1016/j.socscimed.2025.118859}, pmid = {41389646}, issn = {1873-5347}, mesh = {Humans ; *Students, Dental/psychology/statistics &amp; numerical data ; *Oral Health/education ; *Problem-Based Learning/methods ; India ; Male ; Female ; Education, Dental/methods ; Surveys and Questionnaires ; Adult ; *Health Status Disparities ; }, abstract = {BACKGROUND: "Inclusion oral health" (IOH) is an emerging framework focusing on developing innovative solutions to tackle oral health inequities. We intend to provoke reflection, stimulate discussion, and give students practice in responding to the needs of vulnerable population. Newer experiential teaching models have shown substantial potential for affecting values and behaviors of dental students towards underserved population. Hence, it was our aim to teach third-year dental students about IOH while simultaneously comparing the effectiveness of conventional and experiential teaching methods.<br><br>METHOD: All third-year dental students (n&#xa0;=&#xa0;40) enrolled at a teaching dental hospital in New Delhi, India, were allocated into groups A (standard teaching, n&#xa0;=&#xa0;20) and B (experiential teaching, n&#xa0;=&#xa0;20). Data were collected from January to March 2023. A questionnaire based on the theme was used for pre-post assessment. A didactic lecture on the topic was delivered to both groups. Group B participants were further shown an educational movie and a field visit to a shelter. Reflections were collected from both groups using Rolfe et al.'s reflective model. Statistical and thematic analysis was performed.<br><br>RESULTS: After the intervention, knowledge of group B participants (&#x394;k&#xa0;=&#xa0;28.9) was higher than A (&#x394;k&#xa0;=&#xa0;15.8) (p&#xa0;=&#xa0;0.04). There was a shift in the attitude of students towards community service and social responsibility, especially among the group B participants. Thematic analysis of "Reflections" revealed 6 themes under 3 main domains.<br><br>CONCLUSION: Thematic analysis shed light on the learning continuum for creating socially-sensitive and proactive dental workforce. Contemporary concepts like IOH should be woven into the dental curriculum to introduce students to critical thinking and realistic problem-solving. Experiential teaching was effective in educating the concept through engagement and critical reflection.}, }
@article {pmid41389796, year = {2026}, author = {Alessandrini, F and Wright, M and Kurosaki, T and Perloff, OS and Ngo, M and Kofler, JK and Donnelly, CJ and Maquat, LE and Kiskinis, E}, title = {TDP-43 dysfunction compromises UPF1-dependent mRNA metabolism in ALS.}, journal = {Neuron}, volume = {114}, number = {4}, pages = {640-660.e10}, pmid = {41389796}, issn = {1097-4199}, support = {R01 NS134166/NS/NINDS NIH HHS/United States ; R21 NS131713/NS/NINDS NIH HHS/United States ; R35 GM149268/GM/NIGMS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 GM059614/GM/NIGMS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R21 GM147719/GM/NIGMS NIH HHS/United States ; R01 AG086270/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *RNA, Messenger/metabolism ; *Trans-Activators/metabolism/genetics ; *Motor Neurons/metabolism ; *RNA Helicases/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Phosphorylation ; 3' Untranslated Regions ; Animals ; }, abstract = {Up-frameshift protein 1 (UPF1)-mediated mRNA decay maintains transcriptome integrity and cellular homeostasis. However, its role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by TAR DNA-binding protein 43 (TDP-43) pathology and disrupted mRNA metabolism in motor neurons (MNs), remains unresolved. Here, we integrated RNA sequencing (RNA-seq) after UPF1 knockdown with RNA immunoprecipitation (RIP)-seq of phosphorylated UPF1 to delineate direct UPF1 targets in induced pluripotent stem cell (iPSC)-derived MNs. These transcripts are enriched for autophagy and structurally characterized by GC-rich, long 3' untranslated regions (3' UTRs). UPF1 activity, measured by this transcript signature, is diminished in TDP-43-depleted and ALS patient MNs. Mechanistically, TDP-43 depletion impairs UPF1 phosphorylation; the two proteins interact in an RNA-dependent manner and co-aggregate in pathological inclusions in ALS tissue. Transcriptomic analyses reveal convergent regulation of alternative polyadenylation and 3' UTR length by UPF1 and TDP-43, processes disrupted in ALS models and patient neurons. Our study defines the mRNA surveillance network of UPF1 in MNs and uncovers a link between RNA decay, TDP-43 dysfunction, and ALS neurodegeneration.}, }
@article {pmid41389988, year = {2026}, author = {Gomez-Almeria, M and Martinez-Gonzalez, L and Matos, AT and Rodriguez-Cueto, C and Vaz, AR and Martín-Baquero, R and Pérez de la Lastra, C and Infantes, R and Fernández-Ruiz, J and Palomo, V and Gil, C and Brites, D and Martinez, A and de Lago, E}, title = {Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy.}, journal = {Neuropharmacology}, volume = {285}, number = {}, pages = {110804}, doi = {10.1016/j.neuropharm.2025.110804}, pmid = {41389988}, issn = {1873-7064}, mesh = {*Riluzole/administration &amp; dosage/pharmacology/therapeutic use ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/administration &amp; dosage ; Drug Therapy, Combination ; *Casein Kinase Idelta/antagonists &amp; inhibitors/metabolism ; *TDP-43 Proteinopathies/drug therapy ; *Protein Kinase Inhibitors/pharmacology/administration &amp; dosage/therapeutic use ; Mice, Transgenic ; Male ; Dose-Response Relationship, Drug ; DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3-18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.}, }
@article {pmid41391687, year = {2026}, author = {Donison, N and Hintermayer, MA and Palik, J and Fisher, J and Volkening, K and Strong, MJ}, title = {MAPK family members differentially regulate pThr175 tau-mediated pathogenicity.}, journal = {Neurobiology of disease}, volume = {218}, number = {}, pages = {107223}, doi = {10.1016/j.nbd.2025.107223}, pmid = {41391687}, issn = {1095-953X}, mesh = {Animals ; *tau Proteins/metabolism ; Phosphorylation ; Male ; *Brain Injuries, Traumatic/metabolism/pathology ; Humans ; Rats ; Mice ; Rats, Sprague-Dawley ; *Tauopathies/metabolism/pathology ; Mice, Inbred C57BL ; Threonine/metabolism ; Mitogen-Activated Protein Kinase 8/metabolism ; }, abstract = {The phosphorylation of tau is a critical determinant of both its physiological function and the induction of pathological misfolding and aggregation. We have previously provided evidence that tau phosphorylation at Thr175 results in the exposure of the N-terminal phosphatase-activating domain (PAD) leading to the subsequent phosphorylation of Thr231, and formation of tau oligomers. A number of tauopathies, including chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis with cognitive impairment (ALSci), and experimental traumatic brain injury (TBI) have been proposed to be associated with this cascade of events. However, the cellular mechanism by which Thr175 tau is phosphorylated remains unclear. In this study we identified ERK2, JNK1, and p38 as candidate kinases through molecular and histological analyses in a rodent model of TBI, where increased kinase activity and protein interaction were associated with pThr175 tau. We confirmed that both ERK2 and JNK1 are capable of phosphorylating Thr175 tau in vitro, but only ERK2-mediated phosphorylation of Thr175 tau induced the pathological cascade characterized by PAD exposure and the generation of oligomeric, truncated and neurofibrillary tau. Thr175 phosphorylation was also associated with an altered interaction between tau and the molecular chaperone protein DnaJC7, which regulates tau misfolding. Additionally, we observed that pThr175 and pThr231 tau were increased by oxidative stress, which was associated with the activation of the MAPK signaling pathways. These findings further clarify the mechanisms leading to Thr175 tau phosphorylation and its role in pathological tau formation by identifying ERK1 and JNK2 as important cellular mediators.}, }
@article {pmid41392158, year = {2025}, author = {Le Friec, J and Mourier, H and Couly, S and Cubedo, N and Dubois, K and Meunier, J and Delprat, B and De Zordo-Banliat, A and Ayad, T and Virieux, D and Su, TP and Lasbleiz, C and Maurice, T and Liévens, JC}, title = {Positive modulation of sigma-1 receptor: a new weapon to mitigate disease progression in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {68}, pmid = {41392158}, issn = {2047-9158}, support = {grant 23667//AFM-T&#xe9;l&#xe9;thon/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; *Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; Zebrafish ; Disease Progression ; Mice ; Humans ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Disease Models, Animal ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of motor neurons, leading to muscle weakness and progressive paralysis. Currently, no treatment is available to halt or reverse the progression of the disease. Oxidative stress, mitochondrial dysfunction, accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS. A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death. Targeting sigma-1 receptor (S1R) could meet this objective, as this chaperone protein modulates many cell survival mechanisms. So far, the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2% of patients. In the present study, the impact of two different S1R activators, the reference agonist PRE-084 and the positive modulator OZP002, was compared on two key ALS genes: TDP43 and C9orf72.<br><br>METHODS: The dissociation of S1R from Binding immunoglobulin Protein (BiP) was determined using ELISA. OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations. The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide. Their effects on NRF2 target gene expression were studied by qPCR. The beneficial effect was further examined on the locomotor performances of TDP43[A315T] mice using rotarod and beam walking tests. We also performed analysis on motor neuron loss and glial reactivity.<br><br>RESULTS: OZP002 is a positive modulator of S1R, that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists. S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide. The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction. More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43[A315T] transgenic mice. Astroglial and microglial reactivities were also reduced by both activators.<br><br>CONCLUSIONS: We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology. Additionally, we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.}, }
@article {pmid41392206, year = {2025}, author = {Wang, W and Wen, C}, title = {Determining MCID threshold for Knee Society Score to assess patient satisfaction in knee arthroplasty.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {757}, pmid = {41392206}, issn = {2398-6352}, abstract = {This Matters Arising questions the MCID threshold for the Knee Society Score in Xiaodi Liu et al.’s study, noting that it represents an excessively large proportion of the total score and may not accurately capture the minimal meaningful change perceived by patients. We suggest adopting MCID thresholds defined by Wu et al. or Alejandro et al., derived from patient-reported satisfaction and supported by robust sample sizes.}, }
@article {pmid41392526, year = {2026}, author = {Maitland, S and Birkbeck, M and Schofield, I and Best, L and Scott, J and Blamire, A and Whittaker, RG}, title = {MRI of Neurogenic Human Motor Units Following Poliomyelitis.}, journal = {Muscle &amp; nerve}, volume = {73}, number = {3}, pages = {403-411}, pmid = {41392526}, issn = {1097-4598}, support = {//NIHR Newcastle Biomedical Research Centre/ ; }, mesh = {Humans ; Female ; Male ; *Poliomyelitis/diagnostic imaging/complications/physiopathology/pathology ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Motor Neurons/physiology/pathology ; Electromyography ; Aged ; Retrospective Studies ; *Muscle, Skeletal/diagnostic imaging/physiopathology/innervation ; Adult ; Electric Stimulation ; }, abstract = {INTRODUCTION/AIMS: Surviving motor units in neurogenic diseases demonstrate collateral reinnervation. Scanning electromyography (EMG) reveals normal motor unit corridor length, but with "silent regions," suggesting that reinnervation does not result in increased motor unit size but may increase motor unit complexity. Motor unit magnetic resonance imaging (MUMRI) pairs MR imaging with electrical nerve stimulation to visualize individual motor units. This study aimed to assess the motor unit dimensions and complexity in patients with previous poliomyelitis compared to healthy controls.<br><br>METHODS: Patients with a history of polio were recruited from the British Polio Fellowship, compared to a retrospective cohort of healthy controls. They underwent medical history and examination of lower limb power, fatigue assessment (fatigue severity score, FSS), and a 3&#x2009;T MUMRI scan of the less-affected lower limb. The cross-sectional area, maximum, and minimum Feret diameter of the motor unit territories in tibialis anterior were calculated. Motor unit complexity was computed using the Hausdorff box-counting method.<br><br>RESULTS: Of 12 polio survivors, n&#x2009;=&#x2009;8 (6 female) were suitable for analysis and were compared to 19 controls. The mean motor unit maximum Feret diameter was 10.3&#x2009;&#xb1;&#x2009;3.1&#x2009;mm compared to 8.4&#x2009;&#xb1;&#x2009;5.2&#x2009;mm in controls (p&#x2009;=&#x2009;0.34). The mean shape complexity was 0.59&#x2009;&#xb1;&#x2009;0.12 compared to 0.45&#x2009;&#xb1;&#x2009;0.2 in controls (p&#x2009;=&#x2009;0.03).<br><br>DISCUSSION: Polio survivors demonstrate motor units with normal dimensions but increased shape complexity, indicating nonuniform collateral reinnervation largely limited to existing territories. The size and shape of motor units could help in understanding the physiological processes behind reinnervation, both in polio and other neurogenic diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid41392874, year = {2025}, author = {Jung, HJ and Cheong, EN and So, J and Kang, HW and Choi, Y and Lee, EJ and Kim, H and Lim, YM}, title = {ALS With and Without Upper Motor Neuron Signs: A Comparative Study Supporting the Gold Coast Criteria.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70288}, pmid = {41392874}, issn = {2328-9503}, support = {2023IP0108//Asan Institute for Life Sciences, Asan Medical Center/ ; RS-2023-00211443//Ministry of Science and ICT, South Korea/ ; }, abstract = {OBJECTIVE: The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups.<br><br>METHODS: ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n&#x2009;=&#x2009;51) and ALSwoUMN (n&#x2009;=&#x2009;20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method.<br><br>RESULTS: The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p&#x2009;=&#x2009;0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed.<br><br>INTERPRETATION: Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria.}, }
@article {pmid41393069, year = {2025}, author = {Yan, K and Deng, J and Yong, Y and Bi, F}, title = {Proteomic Identification of ALDOA as a Pathogenic TDP-43 Interaction Partner in ALS.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {15}, number = {}, pages = {123-132}, pmid = {41393069}, issn = {1179-9900}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, and its pathogenesis has not been fully elucidated. TAR DNA-binding protein 43 (TDP-43), as one of the key pathogenic genes in ALS, participates in the disease process through interactions with various proteins. This study aims to investigate the interaction mechanism between TDP-43 and aldolase A (ALDOA) in ALS.<br><br>METHODS: HEK293T cell models transfected with wild-type and mutant TDP-43 (TDP-43[M337V]) plasmids were constructed. The interaction between TDP-43 and ALDOA was analyzed through proteomic screening of specific peptides and co-immunoprecipitation, and the co-localization of the two in cells was detected by immunofluorescence. Changes in ALDOA expression levels after intervention with mutant TDP-43 were detected by Western blot and quantitative real-time PCR.<br><br>RESULTS: Proteomic analysis identified ALDOA as a potential interacting protein of TDP-43. Protein-protein interaction (PPI) analysis, co-immunoprecipitation, and immunofluorescence experiments further confirmed that both wild-type and mutant TDP-43 interact with ALDOA. Western blot and quantitative real-time PCR results showed that, compared with the wild-type TDP-43 group, the ALDOA expression was significantly increased in the TDP-43[M337V] mutant group.<br><br>CONCLUSION: TDP-43 interacts with ALDOA in ALS, and the TDP-43[M337V] mutation significantly promotes ALDOA expression, suggesting that ALDOA may be involved in the pathogenesis of TDP-43-mediated ALS. These findings provide new insights into the pathogenesis of ALS and highlight a potential therapeutic target.}, }
@article {pmid41393525, year = {2025}, author = {Guedes, A and de Camargo, OP and Matos, EP and Carreiro, MC and Rios, FF and Guimarães, AHS and Meyer, KA and de Lima, NFL and Barreto, BG and de Mattos, ESR and Antunes, CR and Barreto, ESR}, title = {EVALUATION OF A DECADE OF ONCOLOGICAL-ORTHOPEDIC PROCEDURES IN BRAZIL (2015-2024) AND THE IMPACT OF COVID-19.}, journal = {Acta ortopedica brasileira}, volume = {33}, number = {spe3}, pages = {e297250}, pmid = {41393525}, issn = {1413-7852}, abstract = {OBJECTIVE: To evaluate the regional distribution of hospital admission authorizations (AIH), total and average hospitalization cost (AHC), average length of stay, number of deaths and mortality rate related to oncological-orthopedic procedures funded by the Unified Health System (SUS) between 2015 and 2024, with an emphasis on the impact of the COVID-19 pandemic.<br><br>METHODS: Ecological study with time series based on data obtained from the SUS Hospital Information System, analyzed by Brazilian regions in the pre-pandemic, pandemic and post-pandemic periods. Regional differences were calculated using ANOVA or Kruskal-Wallis. The impact of the pandemic was analyzed using T-tests and ARIMA with intervention. Statistical analysis was performed in R.<br><br>RESULTS: 9,120 AIHs were recorded, mostly in the Southeast (4,375) and South (2,252) regions. Multiple regional variations were found for all the variables evaluated. Only the AHC was impacted - there was an increase in costs per procedure; The other variables maintained the trend after the beginning of the pandemic.<br><br>CONCLUSIONS: Despite the increase in the AHC, we did not observe significant variation in the number of AIH, ALS, and MR when analyzing the pre-pandemic and pandemic periods, suggesting that there was no direct impact on the performance of the analyzed procedure. Level of Evidence III; Retrospective f comparative study e.}, }
@article {pmid41394620, year = {2025}, author = {Vivek, R and Kume, T and Roschdi, S and Record, MT and Hoskins, AA and Butcher, SE}, title = {TDP-43 controls RNA structure through high affinity lattice interactions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394620}, issn = {2692-8205}, support = {R35 GM118131/GM/NIGMS NIH HHS/United States ; R35 GM136261/GM/NIGMS NIH HHS/United States ; S10 RR013790/RR/NCRR NIH HHS/United States ; }, abstract = {TDP-43 is an RNA binding protein implicated in neurodegenerative disease. TDP-43 binds to GU dinucleotide repeats, which are highly abundant sequences in human RNA. Here we show TDP-43 has one of the highest affinities and specificities measured for an RNA binding protein. Binding prevents formation of the pUG fold, an intramolecular quadruplex, and conversely pUG fold formation prevents TDP-43 binding. A rapid on-rate allows TDP-43 to capture single stranded RNA prior to folding. The protein recognizes the RNA as a 1D lattice, in which overlapping binding sites produce efficient initial binding events that interfere with subsequent interactions. This effect is partially overcome by RNA facilitated protein-protein interactions, which serve to increase the on-rate of a second TDP-43 molecule. In conjunction with all atom models, these data reveal how TDP-43 recognizes RNA repeat sequences and identify an interplay between RNA folding and protein recognition that may be relevant to human disease.}, }
@article {pmid41394638, year = {2025}, author = {Sutter, AB and Buksh, BF and Mojsilovic-Petrovic, J and Dalton, C and Till, NA and Morgan, DC and MacMillan, DWC and Kalb, RG}, title = {The molecular mechanism of uptake and cell-to-cell transmission of arginine-containing dipeptide repeat proteins.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394638}, issn = {2692-8205}, support = {R01 NS122908/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; R35 GM134897/GM/NIGMS NIH HHS/United States ; }, abstract = {Micro-satellite repeat expansion of the 5' GGGGCC 3' sequence in the C9orf72 gene is the most common monogenic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) translated from the mutant allele can be detected in postmortem brains of afflicted individuals. The arginine containing peptides, poly-PR and poly-GR, are particularly noxious to cells. Both have been shown to undergo cell-cell transmission, but the underlying mechanisms are not understood. We found rapid internalization and nucleolar localization of bath-applied hemagglutinin (HA) tagged poly-PR with twenty repeats (HA-PR20) in cell lines and neurons. Small molecule and RNAi approaches implicated a temperature-dependent, fluid phase endocytosis mechanism in HA-PR20 uptake. We sought to identify DPR-related cell surface uptake factors using a high-resolution proximity labeling technique developed in the MacMillan group, termed μMap. DPR-iridium conjugates identified candidate cell-surface proteins which were interrogated in an RNAi screen. Focusing on our strongest candidate, chondroitin sulfate proteoglycan 4 (CSPG4), we showed that cellular uptake of HA-PR20 is blocked by inhibition of glycosaminoglycan chain synthesis (using drugs or RNAi) and knockdown or ablation of CSPG4 (using RNAi or CRISPR editing). Reduction of CSPG4 protected PR20-induced neuronal toxicity. We used a dual reporter system to interrogate in vitro neuron-to-neuron transmission of PR50 and found that PR50 synthesized by one neuron readily spread to neighboring neurons. Transmission was significantly reduced when CSPG4 was knocked down. These results suggest CSPG4 is an important factor in poly-PR internalization and transmission and therefore may be a therapeutic target to slow DPR transmission and disease progression.}, }
@article {pmid41394659, year = {2025}, author = {Tendulkar, S and Wu, T and Strickland, A and Hackett, AR and Sato-Yamada, Y and Mao, X and Sasaki, Y and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394659}, issn = {2692-8205}, support = {R37 NS065053/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; R01 NS119812/NS/NINDS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, abstract = {Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb [+/-] heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. SC-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants- TDP43 [Q331K] and Sod1 [D83G] knock-in alleles-to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.}, }
@article {pmid41394670, year = {2025}, author = {O'Connor, JT and Loo, HQ and Guo, C and Pickles, S and Sundali, S and Jawahar, VM and Dickson, DW and Bloom, AJ and Petrucelli, L and Gitler, AD and Milbrandt, J and DiAntonio, A}, title = {TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394670}, issn = {2692-8205}, support = {R01 NS133348/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; R01 NS065053/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; F32 AG086044/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, abstract = {Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.}, }
@article {pmid41394711, year = {2025}, author = {Mehta, PR and Solomon, T and Pickles, S and Harley, P and Barioglio, M and Schweingruber, C and Marrero-Gagliardi, A and Gao, Y and Mattedi, F and Barattucci, S and Lin, LT and Ryadnov, E and Zanovello, M and Cammack, AJ and Isaacs, AM and Burrone, J and Shaw, CE and Keuss, MJ and Petrucelli, L and Fratta, P and Ruepp, MD}, title = {U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394711}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including UNC13A and STMN2, disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement in vivo, positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.}, }
@article {pmid41394713, year = {2025}, author = {Ross, D and Lewis, O and McLean, O and Bhanot, S and Donahue, S and Baker, R and Dias, R and Eagerton, D and Mohanty, V and Mohanty, BK}, title = {Thermally activated irreversible homogenization of G-quadruplexes in an ALS/FTD-associated gene.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394713}, issn = {2692-8205}, abstract = {A significant proportion of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases exhibit a substantial copy number expansion of the hexanucleotide GGGGCC/GGCCCC sequence in the C9ORF72 gene. The GGGGCC sequence forms a non-canonical DNA structure called a G-quadruplex (G4) which has been associated with the disease states and with nucleic acid condensate formation. G4s can fold into various topologies, which can differentially impact fidelity of DNA synthesis. However, how G4 conformational heterogeneity and its regulation impact hexanucleotide repeat expansion is unclear, and important clues may lie in the thermodynamic properties of different G4 topologies. Here, we use temperature-swept CD spectroscopy to observe configurational homogenization of an initially heterogeneous population of G4s over a small range of temperatures, demonstrating thermally activated behavior. We further show that this reaction is irreversible, since subsequent temperature sweeps do not show CD shifts from non-parallel to parallel G4 topologies. Finally, we provide an analytical theory based on a two-state thermodynamic model which is compatible with experimental evidence, and we discuss alternate mechanisms for the homogenization transition. These findings suggest that kinetic regulation of non-canonical DNA structures may play a role in cellular homeostasis or disease pathogenesis.}, }
@article {pmid41395145, year = {2025}, author = {Yi, X and Zhou, W and Cheng, C and Chen, X}, title = {Remimazolam-remifentanil general anaesthesia without muscle relaxants for percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: A retrospective analysis.}, journal = {Indian journal of anaesthesia}, volume = {69}, number = {12}, pages = {1413-1416}, pmid = {41395145}, issn = {0019-5049}, }
@article {pmid41395267, year = {2025}, author = {Roy, T and Al-Chalabi, A and Iacoangeli, A and Al Khleifat, A}, title = {Biomarkers in ALS trials: from discovery to clinical utility.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1636303}, pmid = {41395267}, issn = {1662-4548}, abstract = {INTRODUCTION: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disorder characterized by motor neuron degeneration, leading to muscle weakness, paralysis, and eventual respiratory failure. Despite advances in understanding its pathology, effective therapies remain limited, underscoring the need for reliable biomarkers to aid early diagnosis, monitor disease progression, and optimize clinical trials. This systematic review explores the role of biomarkers in ALS, focusing on their application in clinical trials to accelerate therapeutic development and enhance patient care.<br><br>METHODS: A comprehensive search of PubMed, EMBASE, MedLine, and Google Scholar identified 93 studies investigating various biomarkers, including neurofilament light chain (NFL), inflammatory markers, genetic markers like SOD1 and C9orf72, and imaging modalities.<br><br>RESULTS: NFL emerged as a robust biomarker, strongly correlating with disease progression and therapeutic response, and was frequently used in trials like RESCUE-ALS and CENTAUR. Genetic biomarkers, such as C9orf72 and SOD1 mutations, provided insights into ALS mechanisms and informed targeted therapeutic approaches. Emerging biomarkers, such as retroviral elements, show potential but require further validation. Included studies span key trials such as Lighthouse-II, MIROCALS, and MND-SMART.<br><br>DISCUSSION: This systematic review evaluates which biomarkers are currently validated for monitoring disease progression and therapeutic response in ALS clinical trials, including protein, genetic, inflammatory, metabolic, and imaging markers. It also highlights the critical role of biomarkers in advancing MND clinical trials by enabling adaptive trial designs, patient stratification, and the use of surrogate endpoints, thereby reducing trial duration and improving efficiency. The review also highlights the translational gap between biomarker discovery and clinical application, emphasizing their potential to optimize trial design and patient stratification. While biomarkers like NFL have transformed trial methodologies, challenges such as disease specificity and inter-patient heterogeneity persist. Future efforts should focus on multimodal biomarker approaches to achieve comprehensive disease assessment and advance personalized therapeutic strategies, ultimately improving outcomes for patients with MND.}, }
@article {pmid41395499, year = {2025}, author = {Li, L and Yang, W and Hong, Y and He, Q and Lu, X and Wang, H and Tao, P and Shu, C and Chen, M and Bao, G and Jiang, L}, title = {Identification of Nanoplastics by Probing the Viscous Nanoenvironment.}, journal = {Small science}, volume = {5}, number = {12}, pages = {e202500430}, pmid = {41395499}, issn = {2688-4046}, abstract = {With the growing prevalence of global microplastic and nanoplastic pollution, the accumulation of nanoplastics in the human body has increased, heightening the risk of noncommunicable diseases including cancer, cardiovascular disease, and amyotrophic lateral sclerosis. However, the development of fluorescent probes for detecting nanoplastics remains challenging due to the lack of reactive sites on nanoplastics for conventional design of responsive probes. In this work, a novel strategy for the sensitive detection of nanoplastics by probing the viscous nanoenvironment surrounding them is presented. This study synthesizes a cationic fluorescent probe, Purification by silica gel column chromatography (CH2Cl2/MeOH) provided (E)-2-(2-(4-(dimethylamino)nanphthalen-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium (named HCY due to its structural similarity to hemicyanine dyes) as a tawny solid (HCY), via a simple one-step reaction. HCY demonstrates high sensitivity to nanoplastics, achieving an 8.5-fold fluorescence enhancement in the presence of carboxylated polystyrene nanoplastics, with a detection limit of 0.153 μg mL[-1]. Moreover, HCY exhibits excellent biocompatibility, enabling the monitoring of nanoplastics level in living cells and visualization of nanoplastics distribution in zebrafish. This work offers a new design strategy for responsive fluorescent probes and provides a promising avenue for detecting environmental pollutants.}, }
@article {pmid41396180, year = {2026}, author = {Xu, X and Zhou, Q and Zhang, X and Li, T and Niu, L and Xu, G and Chen, S and Shao, Y and Le, W}, title = {Untargeted metabolomics based on LC-MS and GC-MS reveal metabolic reprogramming and putative biomarkers in amyotrophic lateral sclerosis.}, journal = {Chinese medical journal}, volume = {139}, number = {4}, pages = {610-619}, pmid = {41396180}, issn = {2542-5641}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Metabolomics/methods ; *Biomarkers/metabolism/blood ; Male ; Female ; Middle Aged ; *Gas Chromatography-Mass Spectrometry/methods ; Chromatography, Liquid/methods ; Adult ; Aged ; ROC Curve ; Metabolic Reprogramming ; Liquid Chromatography-Mass Spectrometry ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unknown etiology. The absence of reliable biochemical and imaging markers often delays diagnosis and limits treatment effectiveness. As metabolic reprogramming is increasingly recognized as a hallmark of ALS, a comprehensive untargeted metabolomics analysis was employed to identify critical metabolic perturbations in ALS and explore novel candidate biomarkers with potential utility in clinical diagnosis.<br><br>METHODS: Plasma from two independent cohorts comprising 399 participants (170 ALS patients, 200 healthy controls, and 29 ALS-unrelated neurological disease controls) was included. Cohort 1 was recruited from Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (April 2020-September 2022), and cohort 2 from Sichuan Academy of Sciences-Sichuan Provincial Hospital, Ruijin Hospital, Shanghai Jiaotong University Affiliated Sixth People's Hospital, and The First Affiliated Hospital of Dalian Medical University (October 2022-February 2023). Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approaches were used to identify metabolic alterations and potential diagnostic biomarkers for ALS. Complementary multivariable and univariable statistical approaches were applied to characterize disease-specific metabolic reprogramming in ALS. In addition, the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of differential metabolites, and binary logistic regression analysis was used to construct a multivariate biomarker model.<br><br>RESULTS: Metabolic changes of ALS were mainly observed in amino acids, fatty acyls , and purines. Inosine and hypoxanthine were found to be the most significantly and critically dysregulated metabolites in ALS. Aminoacyl-transfer ribonucleic acid (tRNA) biosynthesis and amino acid metabolism were regarded as the most significantly perturbed pathways. Across both cohorts, 26 metabolites were consistently changed. Notably, a biomarker panel comprising hypoxanthine, inosine, and trigonelline was constructed using binary logistic regression, achieving excellent diagnostic performance in distinguishing ALS from controls, with an area under the ROC curve of 0.982 in cohort 1 (sensitivity 0.970, specificity 0.940) and 0.934 in cohort 2 (sensitivity 0.942, specificity 0.791).<br><br>CONCLUSION: The disturbed pathways and biomarker candidates identified in this study may provide novel insights into ALS pathogenesis and improve diagnostic strategies.}, }
@article {pmid41396347, year = {2025}, author = {Vandermorris, A and Metzger, DL and Vyver, E and Harrison, M and Wong, S and , }, title = {Correction: Response to Kulatunga Moruzi et al.'s (2025) "The Cass Review and Gender-Related Care for Young People in Canada: A Commentary on the Canadian Paediatric Society Position Statement on Transgender and Gender-Diverse Youth".}, journal = {Archives of sexual behavior}, volume = {54}, number = {10}, pages = {4293}, doi = {10.1007/s10508-025-03391-0}, pmid = {41396347}, issn = {1573-2800}, }
@article {pmid41396532, year = {2025}, author = {Sabey, TB and Shanklin, BC and Colquitt, JA and Baer, MD}, title = {The approach-inhibition theory of power: A meta-analytic test and synthesis.}, journal = {Psychological bulletin}, volume = {151}, number = {10}, pages = {1245-1279}, doi = {10.1037/bul0000500}, pmid = {41396532}, issn = {1939-1455}, mesh = {Humans ; *Inhibition, Psychological ; *Psychological Theory ; *Power, Psychological ; *Cognition ; *Affect/physiology ; }, abstract = {Keltner et al. (2003) presented an integrative theory of the social implications of possessing power. Their theory-the approach-inhibition theory of power-quickly became the dominant lens for empirical investigations of how power influences a person's cognition, affect, and behavior. Despite the many benefits of Keltner et al.'s theory, the past 20 years of research have surfaced several potential issues with the theory, including empirical dissensus, mediational ambiguity, and questions about cognitive versus affective primacy. The purpose of this study is to resolve these issues by conducting the first meta-analytic synthesis of the literature on the outcomes of power. Specifically, we tested Keltner et al.'s propositions that power is positively related to the approach-oriented outcomes of attention to rewards, automatic cognition, positive affect, and disinhibited behavior and negatively related to the inhibition-oriented outcomes of attention to threats, controlled cognition, negative affect, and inhibited behavior. Our meta-analysis included a final set of 1,712 effect sizes from 813 independent samples of 432 manuscripts with 269,534 participants. Our analysis demonstrates that the theory is well-supported; approach associations are larger than inhibition associations; power influences behavior indirectly through attention, cognition, and affect; and those indirect effects are largely conveyed through affect. Based on these findings, we suggest several future directions that scholars can take as the literature on power continues to evolve. (PsycInfo Database Record (c) 2025 APA, all rights reserved).}, }
@article {pmid41396654, year = {2026}, author = {Šakotić, RJ and Crişan, I}, title = {Laying the Groundwork for Clinical Neuropsychology in Romania: Beliefs and Practices of Psychologists Regarding Validity Testing in Clinical Assessment.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {41}, number = {3}, pages = {}, doi = {10.1093/arclin/acaf116}, pmid = {41396654}, issn = {1873-5843}, mesh = {Humans ; Romania ; Male ; Female ; Adult ; Surveys and Questionnaires ; *Neuropsychology/standards/methods ; Reproducibility of Results ; Middle Aged ; *Neuropsychological Tests/standards ; *Attitude of Health Personnel ; Psychologists ; }, abstract = {OBJECTIVE: The present study aimed to explore and document Romanian psychologists' practices and beliefs regarding validity testing in clinical assessment, given the lack of neuropsychology as a practice field in this country.<br><br>METHOD: We developed a questionnaire addressing several key aspects, including demographic and professional information, and beliefs and practices related to validity testing in clinical assessment. The questionnaire was distributed to all practitioners licensed in clinical psychology registered on the official website of the Romanian College of Psychologists (RCP). The final sample consisted of 344 practitioners, 312 of whom had been active in assessments during the previous year.<br><br>RESULTS: Our findings revealed several cultural particularities, including the preference of 49.4% of the sample for employing the Tree Drawing Test (Koch, K. (1954). Der Baumtest - Der Baumzeichenversuch als psychodiagnostisches Hilfsmittel. Hans Huber. Romanian translation by Mocanu, S. (2002). Testul Arborelui - Diagnosticul psihologic cu ajutorul testului arborelui. Profex. Bucuresti) - a projective drawing technique - as a validity test. Only 16.7% of practitioners reported using empirically supported validity tests in clinical evaluations, and several performance validity tests were reported by 2-12.5% of the sample. Additionally, the prevalence of malingering was estimated to be 5%-20% and most respondents associated it with personality disorders.<br><br>CONCLUSIONS: The results indicate a need to bridge the gap between science and practice by adopting evidence-based approaches within the Romanian assessment culture. Our survey offers novel empirical insights into the current state of validity assessment in Romania, thereby contributing foundational knowledge that may support the legitimization and further development of neuropsychology within the national context.}, }
@article {pmid41396667, year = {2025}, author = {Drake, RE and Bond, GR and Becker, DR}, title = {Letter to the Editor regarding Schrader et al.'s (2025) "Work and recovery from substance use disorder in Veterans Affairs".}, journal = {Psychiatric rehabilitation journal}, volume = {}, number = {}, pages = {}, doi = {10.1037/prj0000680}, pmid = {41396667}, issn = {1559-3126}, abstract = {Comments on an article by S. W. Schrader et al. (see record 2026-54463-001). Schrader et al. recently reported on VA programs for veterans in early stages of recovery from substance use disorder (SUD), finding that 78% of 78 veterans elected to receive therapeutic work activity, which has a primary goal of clinical recovery rather than employment, and only 22% selected programs focusing on competitive employment. Three possible interpretations may explain Schrader et al.'s anomalous finding and deserve further research. They are discussed in the current commentary. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid41396714, year = {2025}, author = {Haenssler, AE and Okada, J and Eshghi, M and Clark, A and Iyer, A and Richburg, BD and Cavanaugh, R and Onnela, JP and Burke, KM and Berry, JD and Green, JR and Connaghan, KP}, title = {What can vowel acoustics reveal about the communicative participation of people living with ALS?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2598433}, pmid = {41396714}, issn = {2167-9223}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; R42 DC019877/DC/NIDCD NIH HHS/United States ; R01 DC021446/DC/NIDCD NIH HHS/United States ; R15 DC018944/DC/NIDCD NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; F32 DC020896/DC/NIDCD NIH HHS/United States ; }, abstract = {Objective: Bulbar dysfunction often diminishes the accuracy and speed of the tongue, lip, and jaw movements necessary for speech production. Vowel acoustic features derived from speech recordings can serve as sensitive markers of articulatory accuracy and movement timing. We examined whether degraded speech caused by amyotrophic lateral sclerosis (ALS), assessed through vowel acoustic features, was associated with communicative participation restrictions. As a secondary aim, we assessed the association of two global speech characteristics, rate and intelligibility, with vowel features and communicative participation. Materials &amp; Methods: Thirty-three people with ALS (plwALS) recorded a reading passage and completed surveys using a smartphone application. Speaking rate and acoustic vowel features (duration, vowel articulation index [VAI]) were extracted from the recordings. Three speech-language pathologists rated speech intelligibility. Communicative participation was assessed using the Communicative Participation Item Bank (CPIB) short form. Bivariate correlation, partial correlation, and regression analyses were used to evaluate the associations between vowel features, intelligibility, speaking rate, and CPIB scores. Results: Significant bivariate correlations, ranging from rs = -0.39 to rs = 0.64, were found between speech variables and CPIB scores. A combined regression model including VAI, vowel duration, and sex explained 52% of the variance in CPIB scores. Including speaking rate or intelligibility in the partial correlation analysis attenuated the associations between vowel acoustics and CPIB. Conclusions: Vowel features and global dysarthria characteristics are linked to communicative participation in ALS. Clinical practices designed to target vowel production, speaking rate, and intelligibility may help to maintain daily communication in ALS.}, }
@article {pmid41397217, year = {2025}, author = {Vijayasimha, M}, title = {Toward neonatal analytical stewardship: building on Cadamuro et al.'s minimum-volume framework.}, journal = {Clinical chemistry and laboratory medicine}, volume = {}, number = {}, pages = {}, pmid = {41397217}, issn = {1437-4331}, }
@article {pmid41397557, year = {2026}, author = {Esposto, J and Stock, NL and Huber, RJ and Martic, S}, title = {Differential binding of copper and zinc to a TDP-43 RNA recognition motif decapeptide and disulfide formation at residues C173/5 revealed by ESI-MS/MS.}, journal = {Analytical biochemistry}, volume = {710}, number = {}, pages = {116031}, doi = {10.1016/j.ab.2025.116031}, pmid = {41397557}, issn = {1096-0309}, mesh = {*Copper/metabolism/chemistry ; *Zinc/metabolism/chemistry ; *DNA-Binding Proteins/chemistry/metabolism ; Spectrometry, Mass, Electrospray Ionization/methods ; *Disulfides/chemistry/metabolism ; Tandem Mass Spectrometry ; Humans ; Binding Sites ; *RNA Recognition Motif ; Protein Binding ; }, abstract = {Copper (Cu) and zinc (Zn) metal ions play important roles in the proper functioning and localization of neurological proteins, such as transactive response DNA-binding protein 43 (TDP-43), which is linked to amyotrophic lateral sclerosis (ALS). Previous experimental and computational studies have identified putative Zn-binding regions within the RNA recognition motif 1 (RRM1) of TDP-43. However, Cu-binding interactions have been less explored despite their redox activity in regulating thiol (C173/175) conversion to disulfide within the RRM1 domain, influencing protein structure and function. Herein, the structural characterization and fragmentation pattern analysis of a TDP-43 decapeptide (166-HMIDGRWCDC-175), within RRM1, coordinated to Cu(II) and Zn(II) ions using electrospray ionization tandem mass spectrometry (ESI-MS/MS) was conducted under non-denaturing conditions. Higher-energy collision dissociation (HCD) fragmentation analysis identified that Cu(II) prefers His/Met residues, while Zn(II) was weakly coordinated to various binding sites in the peptide, specifically His, Met, Glu, Cys, Trp and Asp residues. Computational modeling using a metal ion binding server (MIB2) confirmed the binding sites and coordination sphere of metal-peptide complexes. No significant coordination to C173 and C175 was observed with Cu or Zn, as identified by using a double Cys mutant peptide. A complete thiol-to-disulfide conversion was observed in the presence of Cu(II)/(I) only, which was confirmed by the comparison of a preformed intramolecular disulfide peptide. Overall, unique differential coordination environments were observed for each metal ion with the peptide. The study provides new insights into metal ion interactions with TDP-43 RRM1 peptide, leading to a greater understanding of metal homeostasis in TDP-43 protein biochemistry and neurodegeneration.}, }
@article {pmid41397872, year = {2026}, author = {Tam, SB and Waldeck, NJ and Wright, M and Mojsilovic-Petrovic, J and Baker, EM and Kiskinis, E and Bass, J and Kalb, RG}, title = {A role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.}, journal = {Life science alliance}, volume = {9}, number = {3}, pages = {}, pmid = {41397872}, issn = {2575-1077}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; R01 NS122908/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; T32 HL007909/HL/NHLBI NIH HHS/United States ; }, mesh = {*Circadian Clocks/genetics/physiology ; Animals ; Humans ; Mice ; *Cholinergic Neurons/metabolism/physiology ; *RNA/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Transcriptome/genetics ; Neurodegenerative Diseases/genetics/metabolism ; ARNTL Transcription Factors/genetics/metabolism ; Alternative Splicing/genetics ; RNA-Binding Proteins/metabolism/genetics ; Circadian Rhythm/genetics ; Male ; Gene Regulatory Networks ; Gene Expression Regulation ; Spinal Cord/metabolism ; }, abstract = {Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease commonly marked by disrupted RBP function. Here, we reveal that the spinal cord cholinergic neuron rhythmic transcriptome is enriched for genes associated with ALS and other neurodegenerative diseases. We show that there is time-of-day-dependent expression of ALS-linked RBP transcripts and rhythmic alternative splicing of genes involved in microtubule cytoskeleton organization, intracellular trafficking, and synaptic function. Through in silico analysis of RNA sequencing data from sporadic ALS patients, we find that gene expression profiles altered in disease correspond with rhythmic gene networks. Finally, we report that clock disruption through cholinergic neuron-specific deletion of clock activator BMAL1 increases neurodegeneration and drives time-of-day-dependent alternative splicing of RNA processing genes. Our results establish a role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.}, }
@article {pmid41398098, year = {2025}, author = {Pieper, AA and Paul, BD}, title = {Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders.}, journal = {Handbook of experimental pharmacology}, volume = {}, number = {}, pages = {}, pmid = {41398098}, issn = {0171-2004}, support = {R01 AG071512/AG/NIA NIH HHS/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; }, abstract = {Hydrogen sulfide (H2S) is a gaseous signaling molecule, also known as a gasotransmitter, present in nearly all mammalian organs. It plays crucial roles in regulating various physiological processes in both the brain and peripheral systems. The body maintains tight control over H2S levels, as both excessive and deficient levels can disrupt normal physiological functions and lead to disease. H2S has a significant impact on cognitive and motor functions, which are often compromised in neurodegenerative disorders. It modulates signaling and metabolism primarily by post-translationally modifying reactive cysteine residues on proteins through sulfhydration, also known as persulfidation. This chapter reviews the signaling mechanisms regulated by H2S in neurodegenerative diseases that significantly affect motor function, specifically focusing on Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), and Leigh syndrome (LS), as well as other mitochondrial disorders. While PD, HD, and SCA are linked to decreased levels of H2S, elevated levels of H2S are associated with ALS, DS, and LS. We also explore potential therapeutic applications of modulating H2S levels in the brain.}, }
@article {pmid41398118, year = {2025}, author = {Dunlop, RA and Cox, PA and Mehta, P and Stommel, EW and Banack, SA}, title = {miRNA Biomarkers Diagnose Amyotrophic Lateral Sclerosis in Circulating Blood.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {298}, pmid = {41398118}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/genetics ; Humans ; Biomarkers/blood ; Female ; Middle Aged ; Male ; *MicroRNAs/blood/genetics ; Aged ; Adult ; Area Under Curve ; Sensitivity and Specificity ; }, abstract = {A rapid, accurate diagnostic test for amyotrophic lateral sclerosis (ALS) would reduce diagnostic delays and improve patient outcomes. We extracted eight circulating miRNAs from 788 blood plasma samples and analyzed them using qPCR for ALS diagnostic accuracy. The biomarker parameters were established previously using 449 individual blood samples and applied prospectively to an independent cohort for validation of a predictive model. The primary outcome was ALS classification accuracy as measured by diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), and area under the curve (AUC). The secondary outcome was comparative fold-regulation values determined prior to data collection. The diagnostic test had an AUC of 0.98 (95% CI 0.97-0.99), with 97% sensitivity (95% CI 96-98), 93% specificity (95% CI 90-96), 93% PPV (95% CI 91-96), and 97% NPV (95% CI 96-98). The fold-regulation values exceeded or were equal to prior calculated values. Streamlined methods resulted in higher diagnostic accuracy, cut both assay time and cost, reduced technical barriers, and enhances the feasibility for widespread clinical adoption. The high accuracy of this diagnostic biomarker suggests that continued evaluation is warranted.}, }
@article {pmid41398473, year = {2026}, author = {Moffatt, C and Arora, A and Vaeth, KF and Guzman, BB and Bhardwaj, G and Hoelscher, A and Gifford, LB and Russ, HA and Dominguez, D and Taliaferro, JM}, title = {TDP-43 directly inhibits mRNA accumulation in neurites through modulation of mRNA stability.}, journal = {The EMBO journal}, volume = {45}, number = {3}, pages = {692-721}, pmid = {41398473}, issn = {1460-2075}, support = {F31GM155957//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31GM151819//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM133385/GM/NIGMS NIH HHS/United States ; R01 NS122911/NS/NINDS NIH HHS/United States ; R35GM133385//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35 GM142864/GM/NIGMS NIH HHS/United States ; R01NS122911//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; T32GM136444//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31 GM151819/GM/NIGMS NIH HHS/United States ; T32 GM136444/GM/NIGMS NIH HHS/United States ; F31 GM155957/GM/NIGMS NIH HHS/United States ; R35GM142864//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Animals ; *RNA, Messenger/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Mice ; *RNA Stability ; *Neurites/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Motor Neurons/metabolism ; Ganglia, Spinal/metabolism ; }, abstract = {The subcellular localization of many mRNAs to neuronal projections allows neurons to efficiently and rapidly react to spatially restricted external cues. However, for most of these RNAs, the mechanisms that govern their localization are unknown. Here, using subcellular fractionation and single-molecule RNA FISH, we found that loss of TDP-43 results in increased accumulation of hundreds of mRNAs in neurites. Using high-throughput functional assays in cells and high-throughput binding assays in vitro, we subsequently identified specific regions within these mRNAs that mediate their TDP-43-dependent localization and interaction with TDP-43. We found that the same regions also mediated TDP-43-dependent mRNA instability, suggesting a mechanism by which TDP-43 regulates mRNA localization. ALS-associated mutations in TDP-43 resulted in similar mRNA mislocalization phenotypes as did TDP-43 loss in mouse dorsal root ganglia and human iPS-derived motor neurons. These findings establish TDP-43 as a direct negative regulator of mRNA abundance in neurites and suggest that mislocalization of specific transcripts may occur in ALS patients.}, }
@article {pmid41398488, year = {2025}, author = {Seabrooke, T and Modirrousta-Galian, A and Higham, PA}, title = {Re-examining the bad news game: No evidence of improved discrimination of Indian true and fake news headlines.}, journal = {Psychonomic bulletin &amp; review}, volume = {33}, number = {1}, pages = {13}, pmid = {41398488}, issn = {1531-5320}, mesh = {Humans ; *Deception ; India ; Adult ; *Truth Disclosure ; Male ; Female ; Young Adult ; *Discrimination, Psychological ; *Communication ; }, abstract = {Gamified inoculation interventions such as the Bad News game are a widely adopted approach to mitigating the influence of misinformation. While Bad News has been predominately studied with participants from Western, Educated, Industrialized, and Rich Democracies (WEIRD), one recent study (Iyengar et al., Applied Cognitive Psychology, 37:290-303, 2023) assessed its efficacy in an Indian sample. In that study, participants rated the reliability of a series of Indian news headlines in a pre-test, played Bad News, and completed a post-test with a different set of headlines. Participants showed better discrimination of true and fake headlines in the post-test than the pre-test. This finding contrasts with a meta-analysis showing that Bad News primarily produces a conservative response bias rather than improving discrimination (Modirrousta-Galian and Higham, Journal of Experimental Psychology: General, 152:2411-2437, 2023). The current preregistered study used the same design as Iyengar et al., although participants of Indian nationality (N = 150) were recruited via Prolific and the allocation of news headlines to the pre-test and post-test was counterbalanced. When both counterbalancing conditions were included, no significant differences in discrimination or response bias appeared between the pre-test and post-test. When only the counterbalancing condition matching Iyengar et al.'s experiment was examined, no significant effect on discrimination was observed, but a conservative response bias shift was seen in the post-test. This finding suggests that the Bad News game may be less effective for improving discrimination than previously thought - an important consideration given its popularity as an intervention to combat misinformation.}, }
@article {pmid41398684, year = {2025}, author = {Fuad, NA and Pitros, P and Brown, G and Besi, E}, title = {Will L-PRF Be the Future of Endodontic Microsurgery? A Series of Case Reports.}, journal = {Clinical and experimental dental research}, volume = {11}, number = {6}, pages = {e70198}, pmid = {41398684}, issn = {2057-4347}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Humans ; *Microsurgery/methods ; Periapical Tissue/surgery ; Root Canal Therapy/methods ; Treatment Outcome ; Wound Healing ; }, abstract = {OBJECTIVES: This case series aimed to evaluate the healing potential of apical tissues with large periapical radiolucencies (> 10 mm) after apical microsurgery with L-PRF. The secondary objectives were to evaluate L-PRF's benefits and adverse effects as well as to aid in the development of a clinical protocol.<br><br>MATERIALS AND METHODS: This case series was conducted in accordance with the Preferred Reporting Items for Case Reports in Endodontics (PRICE) 2020 guidelines. Thirteen patients with persistent endodontic infections, unresponsive to nonsurgical root canal treatment/retreatment, were treated at the Restorative and Oral Surgery Departments with endodontic microsurgery. L-PRF preparation followed Choukroun et al. (2001) and the L-PRF 2018 guidelines under the supervision of an experienced consultant. Postoperative follow-up included a phone call at 24&#x2009;h to assess pain, swelling, and daily functions. Sutures were removed at 7 days, and a 6-month clinical and radiographic review was conducted. The clinical assessment included patient-reported symptoms and extraoral and intraoral examinations. Periapical radiographs were assessed for periapical healing based on Rud et al.'s (1972) radiographic criteria. Radiographs were reviewed by one clinician under standardized conditions.<br><br>RESULTS: Histopathological analyses identified 76.9% (n&#x2009;=&#x2009;10) radicular cysts and 23.0% (n&#x2009;=&#x2009;3) periapical granulomas from the 13 cases. At the 6-month review, 76.9% (n&#x2009;=&#x2009;10) showed incomplete healing, 15.4% (n&#x2009;=&#x2009;2) demonstrated complete healing, and 7.7% (n&#x2009;=&#x2009;1) had incomplete healing at 4 months. All patients remained asymptomatic with no reported complaints. Radiographic assessments showed a significant reduction in the size of periapical radiolucency in all cases. At 24&#x2009;h, 69.2% (n&#x2009;=&#x2009;9) reported no pain, while mild pain was noted in 15.4% (n&#x2009;=&#x2009;2). Swelling was observed in 69.2% (n&#x2009;=&#x2009;9) and absent in 15.4% (n&#x2009;=&#x2009;2), with missing records for 15.4% (n&#x2009;=&#x2009;2).<br><br>CONCLUSION: L-PRF appears beneficial in endodontic microsurgery. However, larger, low-bias studies with extended follow-up periods are needed for definitive conclusions on its application.}, }
@article {pmid41398973, year = {2025}, author = {Veh, A and Ewald, M and da Cruz Neris Geßner, V and Giridhar, NJ and Hutchings, AJ and Stigloher, C and Binotti, B and Heinze, KG and Lüningschrör, P}, title = {Age-dependent removal of Atg9-containing vesicle accumulations in motoneuron disease models by physical exercise.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {69}, pmid = {41398973}, issn = {2047-9158}, support = {DFG LU 2347/3-1//Deutsche Forschungsgemeinschaft/ ; 218894163//Deutsche Forschungsgemeinschaft/ ; F-N-439//Interdisziplin&#xe4;res Zentrum f&#xfc;r Klinische Forschung, Universit&#xe4;tsklinikum W&#xfc;rzburg/ ; Z-12 to KGH//Interdisziplin&#xe4;res Zentrum f&#xfc;r Klinische Forschung, Universit&#xe4;tsklinikum W&#xfc;rzburg/ ; }, mesh = {Animals ; *Physical Conditioning, Animal/physiology ; Mice ; Disease Models, Animal ; *Synaptic Vesicles/metabolism/pathology ; *Motor Neuron Disease/metabolism/pathology ; Autophagy/physiology ; *Autophagy-Related Proteins/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism/pathology ; Mice, Knockout ; Mice, Transgenic ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Atg9-containing vesicles are enriched in synapses and undergo cycles of exo- and endocytosis similarly to synaptic vesicles, thereby linking presynaptic autophagy to neuronal activity. Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease (MND), which leads to impaired synaptic integrity and function. Here, we asked whether boosting neuronal activity by physical exercise modulates the cellular and motor phenotypes of Plekhg5-deficient mice, an MND model with defective presynaptic autophagy.<br><br>METHODS: To characterize the vesicle accumulations in Plekhg5-deficient mice, we performed immunohistochemical staining, electron microscopy, and super-resolution imaging. Following voluntary running wheel exercise, we quantified the histopathological changes within the spinal cord and at neuromuscular junctions using an unbiased machine-learning approach. Additionally, we analyzed the motor performance of the animals by measuring their grip strength. To assess changes in the autophagic flux upon physical exercise in vivo, we utilized mRFP-GFP-LC3 expressing mice. The presence of Atg9-containing vesicle clusters in SOD1[G93A] was analyzed to examine the relevance of this pathological feature in a second MND model.<br><br>RESULTS: We found marked accumulations of Atg9-containing vesicles at presynaptic sites of Plekhg5-deficient mice, which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5-deficient mice. However, physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal. In line with these findings, short-term voluntary exercise triggered motoneuron autophagy in young but not old mice. Pointing to a broader role of Atg9-containing vesicles in the pathophysiology of MND, we also found Atg9-containing vesicle accumulations in SOD1[G93A] mice, a well-established ALS model. Strikingly, physical exercise in presymptomatic SOD1[G93A] mice resulted in a reduction of the vesicle accumulations.<br><br>CONCLUSIONS: Our data highlight the essential role of Atg9 in presynaptic autophagy and suggest that boosting autophagy by physical exercise provides a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly amyotrophic lateral sclerosis.}, }
@article {pmid41399249, year = {2025}, author = {Dellarole, IL and Aprea, V and Catania, M and Battipaglia, C and Romeo, A and Villa, C and Burato, A and Celauro, L and Bella, ED and Riva, N and Salvi, E and Rossi, G and Fede, GD and Legname, G and De Houwer, JFH and Alberici, A and Borroni, B and Seelaar, H and van Swieten, JC and Moda, F and Caroppo, P}, title = {Detection of TDP-43 seeds in CSF of presymptomatic and symptomatic genetic FTD/ALS.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70989}, pmid = {41399249}, issn = {1552-5279}, support = {PNRR-MCNT2-2023-12377336//Ministero della Salute/ ; 2021-650-104//JPND/ ; }, mesh = {Humans ; *DNA-Binding Proteins/cerebrospinal fluid/genetics ; *Frontotemporal Dementia/genetics/cerebrospinal fluid/diagnosis ; Male ; Female ; Middle Aged ; C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/diagnosis ; Progranulins/genetics ; Mutation/genetics ; Aged ; tau Proteins/genetics/cerebrospinal fluid ; Adult ; Biomarkers/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid/genetics ; }, abstract = {INTRODUCTION: Seed amplification assays (SAAs) have shown promising results in detecting misfolded transactive response (TAR) DNA-binding protein 43 (TDP-43) in cerebrospinal fluid (CSF) of genetic frontotemporal dementia (FTD). To date, the use of SAA has yet to be evaluated in presymptomatic individuals.<br><br>METHODS: Thirty patients carrying GRN or C9orf72 mutations, 2 microtubule-associated protein tau (MAPT) carriers, 14 presymptomatic subjects, and 27 controls underwent CSF collection. We used SAA for detecting misfolded TDP-43 (TDP-43_SAA) and single molecule array (SIMOA) technology for neurofilament light chain (NfL) dosage.<br><br>RESULTS: TDP-43 seeding activity was detected in 67% of TDP-43-linked symptomatic patients, with a specificity of 93%. Almost half of presymptomatic subjects tested positive, mostly GRN carriers. Interestingly, among TDP-43_SAA positive presymptomatic individuals, two GRN carriers underwent phenoconversion.<br><br>DISCUSSION: TDP-43_SAA can also detect misfolded TDP-43 in the CSF of presymptomatic individuals. A possible link exists between positive TDP-43_SAA and conversion to the symptomatic phase.<br><br>HIGHLIGHTS: Seed amplification assay of transactive response (TAR) DNA-binding protein 43 (TDP-43_SAA) can detect misfolded TDP-43 in the cerebrospinal fluid (CSF) of patients with genetic frontotemporal dementia (FTD), linked to GRN and C9orf72 mutations. TDP-43_SAA can detect misfolded TDP-43 also in the CSF of presymptomatic individuals. In both groups, most TDP-43_SAA positive cases were carriers of GRN mutation. Two GRN carriers that resulted TDP-43_SAA positive converted to the symptomatic phase of the disease.}, }
@article {pmid41399314, year = {2026}, author = {Chung, WKV and Chan, KP and Hsu, DY and Ma, YKS and Chan, LYE and Ng, SH and Chow, SLE and Hong, YF and Chan, YHJ and Ma, YK and Lee, S and Lui, WCJ and Cheng, HWB}, title = {A 10-year service evaluation of a multidisciplinary neuro-palliative care model in motor neuron disease: Impact on palliative care service delivery &amp; advance care planning.}, journal = {Palliative medicine}, volume = {40}, number = {2}, pages = {253-264}, doi = {10.1177/02692163251396020}, pmid = {41399314}, issn = {1477-030X}, mesh = {Humans ; *Motor Neuron Disease/therapy/nursing ; *Palliative Care/organization &amp; administration/methods ; Male ; Female ; Retrospective Studies ; Hong Kong ; Middle Aged ; Aged ; *Advance Care Planning/organization &amp; administration ; *Patient Care Team/organization &amp; administration ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Multidisciplinary neuro-palliative care has been increasingly recommended for the management of patients with motor neuron disease. While international guidelines have highlighted the importance of early palliative care referral, the best model of practice has not been well-defined.<br><br>AIM: The objective of this study is to evaluate the outcomes of a structured multidisciplinary neuro-palliative care model developed in regional hospitals in Hong Kong.<br><br>DESIGN: A 10-year retrospective chart review.<br><br>SETTING/PARTICIPANTS: Adult motor neuron disease patients under care of three regional hospitals in Hong Kong. Data of patients under the care of multidisciplinary neuro-palliative care taskforce and those who were not were analyzed.<br><br>RESULTS: There were 140 motor neuron disease patients included in study. Patients in multidisciplinary neuro-palliative care group received more healthcare intervention and palliative care services, including occupational therapist (92.86% vs 78.57%, p = 0.021), dietician (67.35% vs 42.86%, p = 0.007) and speech therapist (96.94% vs 76.19%, p = 0.000) services, community support by non-governmental organizations (74.49% vs 19.05%, p = 0.000) and formal bereavement support (78.26% vs 17.07%, p = 0.000). Significantly more patients in multidisciplinary neuro-palliative care group had completed Advance Medical Directives (46.94% vs 4.76%, p = 0.000). Patients under multidisciplinary care had longer survival compared to those who were not (HR 0.539, 95% CI 0.372-0.782, p = 0.001). This remains significant after adjusting for factors affecting survival in multivariate analysis.<br><br>CONCLUSIONS: Multidisciplinary neuro-palliative care demonstrated benefits in motor neuron disease patients in terms of better care coordination and service delivery, higher rate of Advance Medical Directive completion, with possible better survival observed. Future prospective studies are warranted to assess the impact on patient-centered outcomes.}, }
@article {pmid41399419, year = {2025}, author = {Chen, HW}, title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e99153}, pmid = {41399419}, issn = {2168-8184}, abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.}, }
@article {pmid41399686, year = {2026}, author = {Riyapan, S and Chokvanich, W and Chakorn, T and Somboonkul, B and Chantanakomes, J and Phinyo, N and Konwitthayasin, P and Buangam, K and Saengsung, P}, title = {Implementation of high-performance CPR by basic life support (BLS) personnel: a pilot study in Thailand.}, journal = {Resuscitation plus}, volume = {27}, number = {}, pages = {101164}, pmid = {41399686}, issn = {2666-5204}, abstract = {BACKGROUND: High-performance cardiopulmonary resuscitation (HP-CPR) is a structured, pit-crew-style resuscitation model that has been shown to improve performance in advanced life support (ALS) systems. However, its applicability in volunteer-based basic life support (BLS) settings remains uncertain. This study aimed to describe the implementation of HP-CPR training for BLS personnel in Bangkok, Thailand, and to evaluate its impact on BLS performance using video-based process indicators, as well as to report patient- and system-level characteristics before and after the intervention.<br><br>METHODS: We conducted a single-centre, before-and-after study of adults with non-traumatic out-of-hospital cardiac arrest (OHCA) managed by the Siriraj EMS Centre between July 2022 and January 2025. HP-CPR training for BLS personnel was delivered over a fivemonth period. The primary outcome was BLS performance, assessed through predefined process indicators using video review. Secondary outcomes included system-level characteristics and clinical outcomes.<br><br>RESULTS: Of 423 patients screened, 214 met the inclusion criteria (110 pre-intervention; 104 post-intervention). Video recordings were available for 39 cases. Post-training, significant improvements were observed in two performance indicators: "counting during CPR" (0.0&#xa0;% vs. 66.7&#xa0;%, p&#xa0;<&#xa0;0.01) and the "hover technique" (0.0&#xa0;% vs. 62.5&#xa0;%, p&#xa0;<&#xa0;0.01). Other indicators, including uninterrupted CPR, assisted ventilation, AED use, and data handover, improved but did not reach statistical significance. Secondary outcomes-including AED use, CPR initiation by BLS, prehospital return of spontaneous circulation (ROSC), and survival outcomes-showed no significant differences between phases.<br><br>CONCLUSION: Following HP-CPR training, improvements were observed in selected BLS process indicators. However, further research is needed with larger sample sizes to assess the long-term impact of HP-CPR training in volunteer-based EMS systems.}, }
@article {pmid41399798, year = {2025}, author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S}, title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.}, journal = {Chinese herbal medicines}, volume = {17}, number = {4}, pages = {643-672}, pmid = {41399798}, issn = {2589-3610}, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.}, }
@article {pmid41400569, year = {2025}, author = {Vacchiano, V and Cherici, A and Criante, MS and Mengoli, E and Fonti, C and Bonan, L and de Pasqua, S and Donadio, V and Giannoccaro, MP and Rizzo, G and Quarta, CC and Marzocchi, E and Taggi, F and Liguori, R and , }, title = {Cognitive and behavioral impairment may influence shared care planning and treatment decisions in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2597937}, pmid = {41400569}, issn = {2167-9223}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, often accompanied by cognitive and/or behavioral impairments. Shared Care Planning (SCP) involves a collaborative decision-making process, playing a key role in aligning medical treatments with patient values. This study aimed to investigate potential associations between neuropsychological impairment and treatment decisions in ALS patients. Methods: We included 118 ALS patients who had completed at least the cognitive section of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). As part of routine clinical practice, patients were invited to participate in Shared Care Planning (SCP) discussions regarding key medical interventions, namely noninvasive ventilation (NIV), artificial nutrition via PEG/RIG, and tracheostomy. Results: SCP discussions were initiated with 78% of patients. NIV was accepted by 96% of patients, PEG/RIG by 63.9% and tracheostomy by 17.8%. Patients who accepted PEG/RIG were more frequently female (p = 0.047) and had significantly lower adjusted scores on the total ECAS (p = 0.027), ALS-specific domains (p = 0.020), verbal fluency (p = 0.012), and semantic fluency (p = 0.042), compared to those who refused PEG/RIG. Acceptance of tracheostomy was more common among younger patients (p < 0.001) and those with cognitive or behavioral impairments (p = 0.014). Binary logistic regression analysis, using tracheostomy acceptance as the dependent variable and age, sex, and Strong's diagnostic categories as independent variables, revealed a significant association with age (p = 0.002) and with certain Strong's categories, particularly ALS with combined cognitive and behavioral impairment (ALS-CBI) (p = 0.031). Conclusions: Cognitive and behavioral impairment appeared to increase the likelihood of consenting to invasive treatments in ALS patients.}, }
@article {pmid41400574, year = {2025}, author = {Huang, S and Li, A and Ling, Y and Yang, X and Wang, J and Yuan, J and Qin, D and Yao, X}, title = {Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1224}, pmid = {41400574}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1[G93A], TDP43[A315T], and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1[G93A] transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1[G93A] transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.}, }
@article {pmid41401197, year = {2026}, author = {Yang, L and Liu, T and Li, HG and Wang, G and Deng, S}, title = {Functional divergence of ALMTs mediates organic acid transport and callose synthesis for aluminum tolerance in rose myrtle.}, journal = {Plant physiology}, volume = {200}, number = {1}, pages = {}, doi = {10.1093/plphys/kiaf655}, pmid = {41401197}, issn = {1532-2548}, support = {32500264//National Science Foundation of China/ ; 2020-KJCX011//Guangdong Forestry Science and Technology Innovation/ ; 2023B1212060046//Guangdong Science and Technology Plan Project/ ; }, mesh = {*Aluminum/toxicity ; *Glucans/biosynthesis/metabolism ; *Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; *Organic Anion Transporters/metabolism/genetics ; Biological Transport ; Arabidopsis/genetics/metabolism ; Malates/metabolism ; Adaptation, Physiological ; Plant Roots/drug effects/metabolism ; Plants, Genetically Modified ; }, abstract = {Ionic aluminum (Al) forms in acidic soils and inhibits plant growth, even at low concentrations. Rose myrtle (Rhodomyrtus tomentosa), a shrub native to tropical and subtropical regions, thrives in acidic-Al soils. Here, we found that mild concentrations of Al promote rose myrtle growth. Transcriptomic disturbances induced by low or high Al stress were predominantly nonoverlapping in the species. Mild Al stress (0.1 mM Al3+) enhanced rose myrtle root elongation through the upregulation of xyloglucan metabolism, nutrient uptake and utilization, and auxin transport. In contrast, high Al stress (1 mM Al3+) activated detoxification pathways, including the secretion of organic acid and glutathione metabolism. Members of the aluminum-activated malate transporter (ALMT) family, particularly the conserved RtALMT11 and variable RtALMT18, play a pivotal role in Al tolerance. Heterologous expression of RtALMT11 and RtALMT18 complemented the Al-sensitive phenotype of almt1-KO Arabidopsis (Arabidopsis thaliana). High Al3+ induced the expression of RtALMT11, mediating the synthesis of callose, which may serve as a physical barrier to mitigate Al penetration and facilitate vacuolar Al sequestration. RtALMT18 pre-emptively regulated internal defense in the stele independently of aluminum load, while also functioning as a proton/malate transporter. Beyond enhancing Al tolerance, RtALMT18 promoted the growth of transgenic Arabidopsis and poplar (Populus alba × Populus glandulosa, "84K"). The functional divergence within the ALMT family reveals distinct roles in promoting the growth of rose myrtle under low Al conditions and during the high-Al detoxification process. These findings uncover Al's dual role as both a growth promoter and stress inducer, offering insights for developing Al-tolerant crops and rehabilitating acidic soils.}, }
@article {pmid41401652, year = {2026}, author = {Braverman, A and Frenkel, A and Schwarzfuchs, D and Jaffe, E and Bitan, Y}, title = {Verbal and visual information exchange in EMS-to-ED patient handovers: An observational and attitudinal study.}, journal = {International emergency nursing}, volume = {84}, number = {}, pages = {101735}, doi = {10.1016/j.ienj.2025.101735}, pmid = {41401652}, issn = {1878-013X}, mesh = {Humans ; *Patient Handoff/standards/statistics &amp; numerical data ; Male ; Female ; Israel ; Adult ; Emergency Service, Hospital/organization &amp; administration/statistics &amp; numerical data ; *Emergency Medical Services/methods/standards/statistics &amp; numerical data ; Middle Aged ; Surveys and Questionnaires ; *Attitude of Health Personnel ; Communication ; }, abstract = {BACKGROUND: Although effective information exchange during emergency medical services (EMS)-to-emergency department (ED) patient handovers is critical for care continuity and patient safety, handover communication patterns and information gaps remain poorly characterized.<br><br>OBJECTIVE: To characterize verbal and visual information exchange patterns in EMS-to-ED handovers while comparing EMS and ED staff perceptions of handover quality.<br><br>METHODS: This was a dual-methods study conducted at a tertiary medical center in Israel (June-November 2024) in which 83 EMS-to-ED handovers [35 advanced life support (ALS), 48 basic life support (BLS)] were directly observed. We documented information elements, duration, and communication patterns via a structured checklist. In addition, an electronic survey (Qualtrics) of 103 participants (62 EMS, 41 ED staff) was used to assess perceptions with 6-point Likert scales. Statistical analyses utilized Mann-Whitney U tests, effect sizes (Cohen's d), and 95&#xa0;% confidence intervals (CIs).<br><br>RESULTS: The handovers were dominated by verbal communication (97.6&#xa0;%, 95&#xa0;% CI: 91.6-99.3&#xa0;%) of brief duration [ALS: Median&#xa0;=&#xa0;40&#xa0;s, interquartile range (IQR) 35-45; BLS: Median&#xa0;=&#xa0;25&#xa0;s, IQR 25-35]. Significant information gaps included: pre-hospital treatment details, which were absent in 36.1&#xa0;% of the handovers (95&#xa0;% CI: 26.6-46.9&#xa0;%), allergy details in 55.4&#xa0;%, and demographic details in 61.4&#xa0;%. The ALS teams provided more complete information than did BLS teams (treatment: 94&#xa0;% vs. 46&#xa0;%, p&#xa0;<&#xa0;0.001; allergies: 60&#xa0;% vs. 33&#xa0;%, p&#xa0;=&#xa0;0.02). EMS documentation was available in only 7.2&#xa0;% of handovers (95&#xa0;% CI: 3.4-14.9&#xa0;%). Patient background documents were valued more by ED staff than by EMS personnel (Median&#xa0;=&#xa0;4.84 vs. 3.44, p&#xa0;<&#xa0;0.001, d&#xa0;=&#xa0;0.98), and they reported higher confidence in using received information (Median&#xa0;=&#xa0;4.12 vs. 3.15, p&#xa0;<&#xa0;0.001, d&#xa0;=&#xa0;0.78).<br><br>CONCLUSIONS: Because EMS-to-ED handovers rely almost exclusively on brief verbal communication, they are vulnerable to information loss. Critical safety-relevant information (allergies, medications) is frequently omitted, with BLS teams showing greater gaps than ALS teams. Structured handover protocols may improve information completeness and continuity of care by incorporating digital tools to complement verbal communication.}, }
@article {pmid41402228, year = {2026}, author = {Vovard, B and Faure-de Baets, J and Codron, P and Allain, P and Cassereau, J}, title = {Assessment of social cognition impairments in patients with amyotrophic lateral sclerosis: How can it be improved? A systematic review.}, journal = {Revue neurologique}, volume = {182}, number = {1-2}, pages = {10-25}, doi = {10.1016/j.neurol.2025.11.003}, pmid = {41402228}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; *Social Cognition ; Theory of Mind/physiology ; Neuropsychological Tests/standards ; Empathy/physiology ; *Cognitive Dysfunction/diagnosis/psychology/etiology ; Emotions/physiology ; }, abstract = {OBJECTIVES: The aim of this review was to evaluate the current evidence on which part of social cognition is impaired in amyotrophic lateral sclerosis (ALS) patients among emotion recognition, affective empathy and Theory of Mind (ToM) and to suggest improvements in social cognition testing protocols.<br><br>METHODS: A systematic review was conducted according to PRISMA guidelines. We included controlled cross-sectional or longitudinal studies published in English before September 1, 2024, that assessed social cognition in non-demented ALS patients. Searches were performed in Medline, Embase, Web of Science, and PsycINFO using specific MeSH terms. Studies using social cognition tests as a primary or secondary outcome were included.<br><br>RESULTS: Thirty-four studies were analyzed. Impairments in emotion recognition -&#xa0;especially for negative emotions&#xa0;- were frequently reported, even in cognitively preserved ALS patients. Results for cognitive ToM were mixed and may be confounded by executive dysfunction or test limitations. In contrast, affective ToM deficits were more consistently identified. However, no included study directly assessed affective empathy. Tests used in the reviewed studies were often overly specific and lacked ecological validity, which may explain inconsistent results across domains and weak correlations with imaging or executive function.<br><br>CONCLUSION: Social cognition is increasingly recognized as a key non-motor domain affected in ALS. However, current assessment tools may lack the sensitivity and ecological validity needed to capture real-life deficits. The implementation of dynamic, multimodal assessments such as real-life social interaction tests or tests like the Movie Assessment for Social Cognition (MASC) could improve detection and guide clinical interventions but remain to be validated for ALS patients.}, }
@article {pmid41403093, year = {2026}, author = {Ghaderi, S and Mohammadi, S and Kalra, S}, title = {Hippocampal Subfield Integrity and Age-Driven Neural Correlates of Appetite Loss in Amyotrophic Lateral Sclerosis.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {63}, number = {4}, pages = {1067-1078}, doi = {10.1002/jmri.70206}, pmid = {41403093}, issn = {1522-2586}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications ; Female ; Middle Aged ; Cross-Sectional Studies ; *Magnetic Resonance Imaging ; *Hippocampus/diagnostic imaging/physiopathology/pathology ; Aged ; Appetite ; Age Factors ; }, abstract = {BACKGROUND: Appetite loss is a non-motor symptom in amyotrophic lateral sclerosis (ALS) linked to poorer prognosis. While the hippocampus regulates "meal memory", a key cognitive modulator of eating behavior, its structural role in ALS-related appetite loss is unknown.<br><br>PURPOSE: To determine if hippocampal subfield integrity influences appetite dysregulation in ALS and to evaluate the strength of neuroanatomical versus demographic factors.<br><br>STUDY TYPE: Cross-sectional secondary analysis.<br><br>POPULATION: Thirty-two patients with ALS (mean age: 58.97&#x2009;&#xb1;&#x2009;8.91&#x2009;years; 24 males) and 22 non-neurodegenerative controls (NNDc) (mean age: 53.86&#x2009;&#xb1;&#x2009;9.98&#x2009;years; 16 males).<br><br>FIELD STRENGTH/SEQUENCE: 3T; 3D T1-weighted magnetization-prepared rapid gradient-echo (MP2RAGE) and 3D T2-weighted turbo spin-echo (T2-SPACE) sequences.<br><br>ASSESSMENT: Appetite was measured using the Council on Nutrition Appetite Questionnaire (CNAQ). Hippocampal subfield volumes (CA1, CA2/3, CA4/DG, stratum radiatum/lacunosum/moleculare [SRLM], subiculum) and asymmetry indices were segmented from T1w and T2w images using the HIPS automated pipeline.<br><br>STATISTICAL TESTS: Analysis of Covariance (ANCOVA) (adjusting for age, sex, body mass index (BMI), total intracranial volume (TIV), and subfield volumes/asymmetry) and hierarchical multiple regression analyses were used. Significance was set at p&#x2009;<&#x2009;0.05.<br><br>RESULTS: Patients with ALS (adjusted mean: 29.51&#x2009;&#xb1;&#x2009;0.53) had significantly lower adjusted CNAQ scores compared to controls (adjusted mean: 31.98&#x2009;&#xb1;&#x2009;0.66; mean difference: -2.47, partial &#x3b7; [2]&#x2009;=&#x2009;0.195). In the ANCOVA model, left SRLM volume was the only significant neuroanatomical covariate (F [1, 30]&#x2009;=&#x2009;6.45, partial &#x3b7; [2]&#x2009;=&#x2009;0.177). However, hierarchical regression revealed that age was the only consistent independent predictor of CNAQ scores (B&#x2009;=&#x2009;-0.158), explaining the largest variance (&#x394;R [2]&#x2009;=&#x2009;0.165). Hippocampal volumes and asymmetry did not remain significant predictors after adjusting for age (left SRLM: p&#x2009;=&#x2009;0.853; SRLM asymmetry: p&#x2009;=&#x2009;0.868).<br><br>DATA CONCLUSION: Appetite loss is a non-motor symptom in ALS. While associated with lower left SRLM volume at the group level, appetite decline is more robustly and independently associated with advancing age.<br><br>EVIDENCE LEVEL: 3.<br><br>TECHNICAL EFFICACY: 3.}, }
@article {pmid41403635, year = {2025}, author = {Li, CY and Xie, WX and You, HP and Hu, HR and Chen, ZY}, title = {A multi-stage genomic approach to uncover druggable gene targets and neural pathways in postpartum depression.}, journal = {Archives of medical science : AMS}, volume = {21}, number = {5}, pages = {2047-2057}, pmid = {41403635}, issn = {1734-1922}, abstract = {INTRODUCTION: Postpartum depression (PPD) is a severe emotional disorder affecting women worldwide, with significant impacts on maternal and infant health. Its genetic contributors and biological mechanisms are poorly understood. Identifying druggable genes and clarifying their causal roles may offer insights for developing more effective treatments.<br><br>MATERIAL AND METHODS: We identified drug-related genes and screened gene expression quantitative trait loci (eQTL) from the eQTLGen consortium and genotype tissue expression (GTEx) v8 dataset, focusing on 13 brain tissues, along with Qi et al.'s meta-study on the cerebral cortex. Mendelian randomization (MR) analyses were used to investigate causal relationships between gene expression and PPD risk. Replication analyses in an independent PPD cohort validated initial findings, and meta-analysis combined MR results. Summary-data-based MR (SMR) and heterogeneity in dependent instruments (HEIDI) tests were also performed, followed by colocalization analyses to assess shared causal variants. Mediation analyses were conducted to explore how genetic effects may influence brain connectivity patterns.<br><br>RESULTS: From 5,883 druggable genes, 37 showed potential causal links to PPD. Replication analyses confirmed 9 of these genes, with 4 remaining significant in meta-analysis. SMR and HEIDI analyses focused on CLCN7, which showed robust evidence for causal involvement in PPD. Colocalization analyses suggested shared causal variants, and mediation analyses revealed that CLCN7's genetic risk is partially mediated by left- to right-hemisphere visual network white-matter structural connectivity.<br><br>CONCLUSIONS: Our analysis identified CLCN7 as a potential causal factor in PPD, with its effect mediated through brain connectivity. These findings offer targets for future studies and therapeutic strategies for PPD.}, }
@article {pmid41404604, year = {2025}, author = {Bilal Jilani, S and Ashok, N and Bomble, YJ and Guss, AM and Olson, DG}, title = {Engineering Clostridium thermocellum for production of 2,3-butanediol from cellulose.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41404604}, issn = {2692-8205}, support = {P20 GM113132/GM/NIGMS NIH HHS/United States ; }, abstract = {Clostridium thermocellum is a promising host for consolidated bioprocessing due to its ability to directly ferment cellulose into fuels and chemicals. However, natural product formation in this organism is limited. Here, we report engineering C. thermocellum for the production of 2,3-butanediol (23BD), a valuable industrial chemical. We functionally expressed a thermophilic 23BD pathway in this organism resulting in a 23BD titer of 19.7 mM from cellulose, representing a metabolic yield of 24%. We used a cell-free systems biology approach to identify limiting steps in the 23BD pathway, revealing that exogenous 23BD dehydrogenase (BDH) activity was essential for production, while native acetolactate synthase (ALS) and acetolactate decarboxylase (ALDC) activities were present but limiting in the parent strain. This approach also revealed redox balance limitations. We demonstrated that this improved understanding of redox balance limitations could be used to increase 23BD titer in vivo, showing that adding acetate could be used to increase 23BD yield. This work establishes a foundation for developing C. thermocellum into a robust platform for 23BD production directly from cellulose and highlights the utility of cell-free systems for guiding metabolic engineering in non-model organisms.}, }
@article {pmid41404692, year = {2025}, author = {Żur-Wyrozumska, K}, title = {A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.}, journal = {Folia medica Cracoviensia}, volume = {65}, number = {3}, pages = {173-183}, doi = {10.24425/fmc.2025.156692}, pmid = {41404692}, issn = {0015-5616}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Sequestosome-1 Protein/genetics ; Middle Aged ; Female ; NF-E2-Related Factor 2/genetics/metabolism ; Autophagy/genetics ; NF-kappa B/genetics ; Mutation ; Signal Transduction ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.<br><br>MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-&#x3ba;B/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.<br><br>CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-&#x3ba;B inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.<br><br>DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-&#x3ba;B activation. The interplay between NF-&#x3ba;B and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.<br><br>CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.}, }
@article {pmid41405451, year = {2025}, author = {Liampas, I and Kimiskidis, VK and Zouvelou, V and Veltsista, D and Moscholouri, A and Triantafyllou, E and Daponte, A and Xirou, S and Sterpi, AE and Salakou, S and Poulidou, V and Arnaoutoglou, M and Tsouris, Z and Ralli, S and Dardiotis, E and Papagiannopoulos, S and Zampetakis, A and Zaganas, &#x399; and Mitsias, P and Giannakis, A and Konitsiotis, S and Kefalas, F and Alexiou, E and Stoiloudis, P and Parissis, D and Kiamelidis, S and Terzoudi, A and Tsivgoulis, G and Rentzos, M and Chroni, E}, title = {Greek Registry for Amyotrophic Lateral Sclerosis (ALS-GR): An Observational Cohort of Individuals With ALS Across 11 Specialized Centers in Greece.}, journal = {European journal of neurology}, volume = {32}, number = {12}, pages = {e70403}, pmid = {41405451}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/drug therapy/therapy ; Greece/epidemiology ; *Registries ; Male ; Middle Aged ; Female ; Aged ; Cohort Studies ; Disease Progression ; Adult ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Epidemiological studies on amyotrophic lateral sclerosis (ALS) in Greece are scarce and outdated.<br><br>METHODS: We performed an observational cohort study in 11 specialized centres across Greece. Adult individuals with ALS diagnosed based on the Gold Coast criteria were recruited. Data were collected on socio-demographics, somatometrics, comorbidities, early life exposures, disease-related parameters, riluzole intake, motor and non-motor symptoms, as well as functional progression. Follow-up evaluations were scheduled on approximately 6-9-12-18-24&#x2009;months. Our aim was to identify shortcomings in the monitoring of patients with ALS in specialized centers, delineate the course of the disease, and capture factors related to the earlier occurrence of ALS and potential diagnostic delays.<br><br>RESULTS: A total of 229 ALS patients were included in the present registry. The average age of diagnosis was 63.7&#x2009;years, with an average 12.8-month interval between symptom onset and diagnosis. The presence of bulbar symptoms at onset was associated with shorter diagnostic delays. Systematic physical exercise was strongly linked to the earlier onset of symptoms. Disease progression was slower during the prediagnostic stage, more precipitous over the first year following diagnosis, and milder thereafter (~1-point monthly decline in ALSFRS-R on average, post-diagnosis). The majority of associated motor and non-motor symptoms accumulated over time. The overwhelming majority of patients were prescribed the liquid form of riluzole, which exhibited an excellent tolerability profile. Greek islands are probably the most underprivileged in terms of specialized monitoring of ALS cases.<br><br>CONCLUSIONS: The present observational cohort study mapped key aspects and shortcomings of ALS management in Greece.}, }
@article {pmid41406304, year = {2025}, author = {Geva, M and Goldberg, YP and Leitner, ML and Cruz-Herranz, A and Hand, R and Chen, K and Gershoni Emek, N and Tan, AM and Paganoni, S and Berry, JD and Macklin, EA and Shefner, JM and Cudkowicz, ME and Hayden, MR}, title = {Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2025.2597935}, pmid = {41406304}, issn = {2167-9223}, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.}, }
@article {pmid41406788, year = {2026}, author = {Vijayakumar, S and Schwaighofer, A and de Juan, A and Rocha de Oliveira, R and Mach-Aigner, A and Lendl, B and Ramer, G}, title = {Fusion of incomplete QCL-IR and ECD datasets using MCR-ALS to extend the viable concentration range for studying protein denaturation.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {349}, number = {}, pages = {127340}, doi = {10.1016/j.saa.2025.127340}, pmid = {41406788}, issn = {1873-3557}, mesh = {*Protein Denaturation ; *Circular Dichroism/methods ; Spectrophotometry, Infrared/methods ; *Lasers, Semiconductor ; *Proteins/chemistry ; }, abstract = {While several techniques exist to study the secondary structure of proteins, mid-IR and electronic circular dichroism spectroscopy are complementary techniques that stand out for liquid measurements due to their non-destructive nature, broad applicability and ease of use. CD spectroscopy however is only used to measure low protein concentrations and suffers from signal interferences from common buffers. With advances in laser-technology, the achievable pathlengths used in IR-spectroscopy have increased with the use of external cavity quantum cascade lasers (EC-QCL) as light sources. This has not only enabled protein denaturation to be studied without aggregates clogging the measurement cell, as was the case with shorter pathlengths, but also expanded the concentration range that can be measured with the technique. Yet, the concentration range where both IR and CD measurements can be made has only a small overlap. In this study, the IR and CD spectra obtained during the thermal denaturation of α-chymotrpysin (α-CT) in the overlapping concentration range of the two spectroscopy techniques, between 10mgmL[-1] to 40mgmL[-1], are used to extract more information about the denaturation process of the protein and its concentration dependence. To this end, the protein denaturation spectra from both methods between 20°C to 80°C are fused and analyzed using multivariate curve resolution-alternating least squares (MCR-ALS), a bilinear unmixing technique that provides thermal profiles and pure fingerprints of the protein conformations involved in the denaturation process. However, in these measurements, a large and information-dense part of the CD spectra found at the lowest UV wavelengths cannot be used due to the saturated signal linked to high protein concentration levels. A modified version of MCR-ALS is hence introduced to overcome this issue, which allows all available information to be used without sacrificing the quality of the fit. The prowess of the adapted MCR-ALS technique as a tool for data fusion was demonstrated by not only providing a better fit than the individual models (CD and IR spectra analyzed separately), but also by aiding in squeezing out information about a third protein conformation that forms during the denaturation of α-CT.}, }
@article {pmid41407165, year = {2026}, author = {Ghosh, N and Ghosh, J and Ghosh, S and Sinha, K and Sil, PC}, title = {Nutraceutical interventions for neuroprotection: a comprehensive review.}, journal = {Biochemical pharmacology}, volume = {245}, number = {}, pages = {117637}, doi = {10.1016/j.bcp.2025.117637}, pmid = {41407165}, issn = {1873-2968}, mesh = {Humans ; *Dietary Supplements ; Animals ; *Neuroprotective Agents/administration &amp; dosage ; *Gastrointestinal Microbiome/drug effects/physiology ; *Neuroprotection/drug effects/physiology ; *Neurodegenerative Diseases/metabolism/prevention &amp; control ; Probiotics/administration &amp; dosage ; }, abstract = {Nutraceuticals, bioactive compounds derived from food sources, are emerging as promising agents for neuroprotection, particularly through their modulation of gut health. Unlike conventional single-molecule therapeutics that often target isolated pathways, nutraceuticals offer a multi-targeted approach by influencing the gut-brain axis, a bidirectional communication network linking the gut microbiota and the central nervous system. Key nutraceuticals such as probiotics, prebiotics, polyphenols, omega-3 fatty acids, and vitamins have been shown to beneficially alter microbiota composition, reduce intestinal inflammation, and strengthen gut barrier integrity. These changes can significantly influence brain function by modulating neurotransmitter activity and systemic immune responses. This review compares the holistic action of nutraceuticals with the more focused effects of single-molecules, particularly in the context of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's Disease and Motor Neuron Diseases like amyotrophic lateral sclerosis. It discusses how nutraceuticals may mitigate key pathological features of these conditions-including neuroinflammation, oxidative stress, and mitochondrial dysfunction, through gut-mediated pathways. Despite their potential, challenges remain regarding the standardization of formulations, bioavailability, dosage optimization, and long-term safety. Further clinical research is needed to validate the efficacy of nutraceuticals as complementary or alternative strategies to traditional neuroprotective agents.}, }
@article {pmid41408263, year = {2025}, author = {Doughty, J and Booth, J and Smith, M and Saini, K and Paisi, M and Rodriguez, A and Levine, A and Bedos, C and Muirhead, V and Martins de Barros, C and Freeborn, C}, title = {Unmasking oral health stigma: a qualitative scoping review.}, journal = {BMC oral health}, volume = {26}, number = {1}, pages = {345}, pmid = {41408263}, issn = {1472-6831}, mesh = {Humans ; *Social Stigma ; *Oral Health ; Qualitative Research ; Self Concept ; Stereotyping ; }, abstract = {INTRODUCTION: Health-related stigma can limit access to care, impair adherence to treatment, and negatively impact mental health and quality-of-life. Oral health stigma, defined as stigma arising from oral conditions that diverge from sociocultural norms, operates through labelling, stereotyping, othering, and exclusion. Oral health stigma can lead to shame, diminished self-confidence, and avoidance of dental care, creating a self-perpetuating cycle of poor oral health and reinforcing internalised and anticipated stigma. While previous research has explored the social implications of oral appearance, little is known about the broader concept of oral health stigma or strategies to mitigate it.<br><br>METHODS: This scoping review adopted Levac et al.'s six-stage framework. The review utilised data from qualitative studies to explore lived experiences of oral health stigma and consider ways to mitigate it. Patient and public involvement (PPI) informed the development of the research question, search strategy, and interpretation of findings.<br><br>RESULTS: Seventy-two qualitative studies were included, comprising 2,455 participants. Themes included stigma associated with physical appearance and attractiveness, judgement, labelling, and stereotyping. Consequences included low self-esteem, social exclusion, impacts to care seeking behaviours, and efforts to conceal oral appearance. Participants highlighted the transformative value of dental care and described coping strategies to build resilience. Other proposed solutions included fostering social connection and implementing trauma-informed, non-judgemental dental care.<br><br>CONCLUSION: Oral health stigma has significant social and psychological consequences and impacts on care-seeking behaviours. Addressing it requires targeted interventions at multiple levels, including individual, community, professionals and wider system / policy.}, }
@article {pmid41408351, year = {2025}, author = {Ibragimov, U and Giordano, NA and Amaresh, S and Getz, T and Matuszewski, T and Steck, AR and Li, Y and Blum, EH and Tuttle, J and Pipalia, H and Cooper, HLF and Carpenter, JE}, title = {Implementation outcomes and strategies of a peer recovery coach program: findings from a qualitative assessment in the U.S. South, 2024-2025.}, journal = {Addiction science &amp; clinical practice}, volume = {20}, number = {1}, pages = {95}, pmid = {41408351}, issn = {1940-0640}, support = {R01 CE003509/CE/NCIPC CDC HHS/United States ; R01CE003509/ACL/ACL HHS/United States ; R01CE003509/CC/CDC HHS/United States ; }, mesh = {Humans ; *Peer Group ; *Substance-Related Disorders/rehabilitation/therapy ; Qualitative Research ; *Emergency Service, Hospital ; Male ; Female ; Georgia ; Adult ; Program Evaluation ; Middle Aged ; *Mentoring ; Interviews as Topic ; }, abstract = {INTRODUCTION: Successful implementation of peer recovery coach (PRC) programs may help improve linkage to services and clinical outcomes for emergency department (ED) patients with substance use disorder (SUD). However, literature on implementation outcomes and strategies of PRC programs is limited. We conducted a qualitative assessment of implementation outcomes and strategies for an ED-based PRC program in Atlanta, Georgia.<br><br>METHODS: We conducted qualitative interviews with 27 program participants (ED patients with SUD served by PRC program) and 29 service providers and partners (peer recovery coaches, ED physicians and staff, SUD treatment and other service providers) in October 2023 - March 2025. We transcribed audio-recordings and analyzed data using rapid qualitative analysis approach mapping emerging themes to Proctor's model of implementation outcomes and Leeman et al.'s implementation strategies framework.<br><br>RESULTS: We identified two major themes related to implementation outcomes: (1) PRC program acceptability (patients' positive interactions with PRCs) and (2) appropriateness (sub-themes include: successful linkage to community services; PRC program as an important resource for patients; added value of PRC team; no negative impact on ED workflow). Themes related to implementation strategies include (1) streamlined communication between PRC and ED teams (direct communication via electronic medical records system, single contact phone number, informing ED service providers of clinical and program outcomes), (2) addressing barriers to community-based services (preparing patient's medical documentation, insurance, transportation to community services); (3) supportive supervision of PRCs (addressing daily and long-term issues through regular meetings; limiting caseload; and providing orientation, on-job training and mental health support) and (4) addressing telehealth implementation challenges (ensuring access to electronic medical records system).<br><br>CONCLUSION: This study outlines key implementation outcomes and strategies for PRC programs, offering practical guidance for successful ED-based PRC program implementation.}, }
@article {pmid41409685, year = {2025}, author = {Ran, X and Wuu, J and Qin, ZS and Cooper-Knock, J and Granit, V and Grignon, AL and Li, Y and Lin, E and Fernandez, MC and Colato, D and Carberry, N and Lill, CM and Piazza, P and Malaspina, A and Benatar, M}, title = {Predicting Phenoconversion to Clinically Manifest ALS: Results of a Large-Scale Proteomic Study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41409685}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease, and when. In this longitudinal Olink Explore high-throughput proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. We identified 81 proteins whose concentrations changed prior to phenoconversion; characterized the longitudinal trajectory of these proteins; and identified a core panel of 19 proteins that, collectively, predicted phenoconversion over the 0.5- to 5-year time horizons (areas under curve 0.80-0.89) and yielded estimates of time-to-phenoconversion with a mean absolute error of 1.6 years. These findings were replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (e.g. NEFL, EDA2R, CA3) and that a multi-protein panel outperformed NEFL alone in estimating time-to-phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of novel susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.}, }
@article {pmid41411011, year = {2025}, author = {Lawley, KS and Kang, TW and Rech, RR and Karmakar, M and Carroll, R and Perez Gomez, AA and Amstalden, K and Jones-Hall, Y and Threadgill, DW and Welsh, CJ and Young, CR and Brinkmeyer-Langford, C}, title = {The association between virus-induced spinal cord pathology and the genetic background of the host.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, pmid = {41411011}, issn = {1554-6578}, support = {P30 ES029067/ES/NIEHS NIH HHS/United States ; //National Institute for Neurological Disorders and Stroke (NINDS)/ ; 2P30 ES029067//National Institute for Environmental Health Sciences (NIEHS)/ ; DGE 1746932//National Science Foundation Graduate Research/ ; R01 NS103934/NS/NINDS NIH HHS/United States ; }, abstract = {Theiler's murine encephalomyelitis virus (TMEV) infection in mice has been used to study diverse neurological diseases, including multiple sclerosis and epilepsy. In this investigation, 5 strains of collaborative cross (CC) mice were infected with TMEV and examined clinically and histologically at days 4, 14, and 90 post-infection (dpi). All CC strains tested exhibited lumbar spinal cord and/or ventral peripheral nerve lesions by 14 dpi; CC027, CC023, and CC078 strains exhibited lesions at 4 dpi. At 90 dpi, lesions were remnants of the inflammatory responses associated with earlier infection; there was skeletal muscle atrophy in the CC023 strain. Increased microglial/macrophage reactivity was observed in all strains at 4 and 14 dpi, but not at 90 dpi. TMEV mRNA expression was greatest in the CC023 and CC078 strains at the acute timepoints; TMEV was completely cleared in all mice at 90 dpi. The neuropathological and clinical profiles in CC023 mice, mainly at 14 dpi, share some clinical and histologic features with those in amyotrophic lateral sclerosis patients. This work demonstrates how viral infection might interact with the genetic background of a susceptible individual to contribute to the onset, clinical presentation and persistence of lesions despite viral clearance.}, }
@article {pmid41411702, year = {2026}, author = {Lebkuecher, AL and Coslett, HB and Buxbaum, LJ}, title = {The cognitive neuropsychology of action semantics: A review.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {194}, number = {}, pages = {159-190}, doi = {10.1016/j.cortex.2025.11.008}, pmid = {41411702}, issn = {1973-8102}, mesh = {Humans ; *Semantics ; *Cognition/physiology ; *Brain/physiology/physiopathology ; Neuropsychology ; }, abstract = {The conceptual knowledge that mediates our ability to use familiar objects, understand viewed actions, and engage in communication about actions is often termed "action semantics". The underlying format, cognitive organization, and neural substrates of these representations are matters of active scientific investigation. This review synthesizes the large and diverse literature on action semantics in individuals with neurological disorders characterized by prominent motor deficits (e.g., Parkinson's disease and Amyotrophic lateral sclerosis), as well as those for whom motor deficits are often less prominent (e.g., Alzheimer's disease, Frontotemporal Dementia, stroke). Research in these two groups of disorders is strikingly "siloed" and offers many contradictory findings with respect to whether action semantic representations are abstract (i.e., "disembodied") or grounded in sensory and motor features that reflect the way knowledge was acquired. Findings across these populations also disagree as to whether action semantic representations are organized somatotopically or with a semantic feature-based architecture, and mediated by anterior motor-related or relatively posterior sensory-related brain regions. Many of these disparate findings can be reconciled with consideration of a multidimensional, multimodal representational architecture mediated by a distributed left-lateralized network of brain regions. We provide suggestions for specific methodological approaches for research with neurological populations that may further our understanding of the format, organization, and neural substrates of action semantics.}, }
@article {pmid41412960, year = {2026}, author = {Goutman, SA and Stouffer, DG and Jang, DG and Park, J and Murdock, BJ and Auchus, RJ}, title = {Sex Hormones Associate With Amyotrophic Lateral Sclerosis Risk and Survival.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {3}, pages = {612-617}, pmid = {41412960}, issn = {2328-9503}, support = {R01TS000339/ACL/ACL HHS/United States ; AL200064//U.S. Department of Defense/ ; //Eric and Linda Novak/ ; //James and Margaret Hiller/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //Stanford Morris ALS Research Fund/ ; K23ES027221/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; //University of Michigan/ ; R01TS000339/ACL/ACL HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality ; Female ; Male ; Middle Aged ; Aged ; *Gonadal Steroid Hormones/blood ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) risk differs by sex and age, implicating sex hormones as potential modifiers. This study examined plasma levels of biologically active sex hormones and their association with ALS odds and survival in cases (females n = 131, males n = 189) and controls (females n = 138, males n = 150) from the University of Michigan Pranger ALS Clinic. Higher 11-ketotestosterone levels were associated with increased ALS odds. In females, higher estrone, androstenedione, and 11-hydroxyandrostenedione were associated with increased ALS odds, while elevated estrone and estradiol predicted shorter survival. These findings highlight the potential significance of sex hormones in ALS.}, }
@article {pmid41414999, year = {2025}, author = {Kamadi, EN and Shah, J and Hooker, J and Jenkins, TM and Sokhi, DS}, title = {Clinical phenotypes of motor neurone disease in a Kenyan hospital-based population.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1662690}, pmid = {41414999}, issn = {1664-2295}, abstract = {BACKGROUND: Motor neurone disease (MND) presentation is globally heterogenous and data on the clinical phenotype in Sub-Saharan Africa (SSA) is scarce. We sought to address this by describing the profile of MND patients in a Kenyan hospital-based population.<br><br>METHODS: The medical charts of all adult MND patients assessed in the facility between January 2010 and December 2023 were retrospectively reviewed. The biographical data and clinical features of these patients were captured from their electronic and manual health records and statistical analysis performed.<br><br>RESULTS: In total, 160 patients had their data analyzed. The male to female ratio was 1.76:1. The median age at presentation was 55.0 (IQR: 45.0-68.0) years with a median diagnosis delay of 4.0 (IQR: 2.0-8.5) months. The site of first symptom onset was the lower limbs in 34.4% and the bulbar region in 33.1% [95% CI (26.4-42.5%)]. Notably, 59% of the patients were not tested for HIV and amongst those tested, 13.9% were HIV positive on ART. Majority (56.2%) of the patients were on Riluzole.<br><br>CONCLUSION: This Kenyan case series of MND patients demonstrated a higher rate of bulbar onset disease [33.1, 95% CI (26.4-42.5%), p&#x202f;=&#x202f;0.018] in comparison to what has been demonstrated in other African studies. A finding that supports geographic variation in MND presentation and that emphasizes the need for region specific genetic studies.}, }
@article {pmid41415845, year = {2025}, author = {Harsa, HS and González Domenech, CM and Prvulović, M and Agirbasli, Z and Bagherzadehsurbagh, E and Simeunović, V and Naziri, E and Adesemoye, E and Yigit Cinar, A and Mukherjee, A and Laranjo, M and Vidović, B and Alves, E and Vukojević, A and Özmen Toğay, S and Düven, G and Saar, H and Salminen, S and Matalas, A and Paveljšek, D and Schneider, E and Liwinski, T and Chassard, C and Vergères, G and Bär, C and Praćer, S}, title = {The effects of Lactobacillus and/or Bifidobacterium in fermented foods on cognitive health: a systematic review.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1682419}, pmid = {41415845}, issn = {2296-861X}, abstract = {BACKGROUND: Psychobiotics are microorganisms that modulate brain function via the gut-brain axis and are increasingly studied for their cognitive benefits. Lactobacillus and Bifidobacterium species, widely present in fermented foods, are considered safe and may influence cognition by modulating neuroinflammation, neurotransmitters, and gut barrier integrity. This systematic review examined the effects of foods fermented with these species on cognitive performance in healthy adults and individuals with mild cognitive impairment.<br><br>METHODS: We conducted the systematic review following EFSA guidelines, Cochrane methodology, and a PROSPERO protocol, using CADIMA for study selection and data extraction. PubMed, Scopus, and Cochrane Library were searched (1 January 1970-31 August 2023) for human intervention and observational studies assessing cognitive outcomes after ingestion of foods fermented with Lactobacillus or Bifidobacterium. Eligible populations included healthy adults and individuals with mild cognitive impairment; studies involving disease were excluded. Screening, data extraction, and bias assessment followed Muka et al.'s 24-step guide using ROBINS and Cochrane/CADIMA frameworks. Evidence was synthesized narratively, while a non-systematic component examined food characteristics, potential mechanisms, and factors affecting bioavailability of bioactive constituents.<br><br>RESULTS: We included 21 studies (8 interventional, 13 observational). The majority of studies reported benefits, particularly in episodic memory, executive functions, and global cognition, but evidence was limited by inadequate controls, small sample sizes, short interventions, inconsistent domain assessment, and incomplete food characterization. Observational studies had larger populations and longer follow-ups but were limited by exposure assessment and depth of cognitive testing.<br><br>CONCLUSION: Consumption of foods fermented with Lactobacillus and/or Bifidobacterium species may offer promising cognitive benefits. However, following EFSA's guidance on the substantiation of health claims, the current evidence is "neither convincing nor sufficient" to establish a causal relationship. Well-designed studies with thorough product characterization are needed to substantiate effects and support potential health claims.<br><br>This study was registered at the Open Science Framework (10.17605/OSF.IO/Z6GRW).}, }
@article {pmid41416937, year = {2025}, author = {Jensen, TR and Jacobs, I and Kverková, K and Lalić, L and Polonyiová, A and Stehlík, P and Reber, SA and Osvath, M}, title = {T. rex cognition was T. rex-like-A critical outlook on diverging views of the neurocognitive evolution in dinosaurs.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {}, number = {}, pages = {}, doi = {10.1002/ar.70074}, pmid = {41416937}, issn = {1932-8494}, abstract = {A recent debate has emerged between Caspar et al. (2024) and Herculano-Houzel (2023) on inferring extinct dinosaur cognition by estimating brain neuron counts. While thought-provoking, the discussion largely overlooks the function of cognition, as well as partly neglects the difficulties involved in estimating neuron numbers, which according to us leads to oversimplified conclusions. We use this exchange as a springboard to further explore how extinct cognition might be studied and the potential pitfalls involved. One of the main emphases is on introducing basic concepts and contemporary views of cognition and its evolution. In relation to this, we highlight the shift in thermobiology during the Mesozoic-from ectothermy to endothermy-and its major impact on cognition and brain evolution. We also examine the challenges of estimating neuron counts in extinct dinosaurs based on current knowledge and take issue with several aspects of the approaches used by both Caspar et al. and Herculano-Houzel. At the same time, we challenge Caspar et al.'s claim that telencephalic neuron numbers, if estimable, would be largely uninformative about extinct dinosaur cognition, while also disagreeing with Herculano-Houzel's somewhat reductive view. We further emphasize the value of comparative cognitive studies in extant animals, alongside neural correlates, to infer the cognitive evolution of non-avian dinosaurs. We briefly outline how cognition is studied in living species and the extent to which such research can inform evolutionary inference. Our focus here is on non-avian theropods, as they are central to the current debate and belong to the lineage that led to modern birds.}, }
@article {pmid41417044, year = {2026}, author = {Rott, N and Reinsch, L and Dirks, B and Böttiger, BW}, title = {[The new European Resuscitation Council (ERC) guidelines 2025-Overview of the most important changes; the first 3-5 min are decisive].}, journal = {Die Anaesthesiologie}, volume = {75}, number = {1}, pages = {44-50}, pmid = {41417044}, issn = {2731-6866}, mesh = {Adult ; Humans ; Advanced Cardiac Life Support/standards ; *Cardiopulmonary Resuscitation/standards/methods ; Epinephrine/administration &amp; dosage ; Europe ; Heart Arrest/therapy ; *Practice Guidelines as Topic ; *Resuscitation/standards/methods ; Time Factors ; }, abstract = {In October 2025 the new resuscitation guidelines of the European Resuscitation Council (ERC) were published. In the chapter on advanced life support (ALS) for adults the update emphasizes topics such as efficient ventilation with adequate chest compressions, early defibrillation, identification and treatment of reversible causes as rapidly as possible and the administration of epinephrine in cases of non-defibrillatable cardiac arrest. The aim of the guidelines is to sustainably improve survival rates after cardiac arrest through structured and evidence-based care systems.}, }
@article {pmid41417080, year = {2025}, author = {Zafar, U and Abdullah, M and Butt, TN and Uddin, MMZ and Masood, MH and Chu, LC and Zaheer, A}, title = {A bibliometric analysis of the 100 most cited radiology papers on pancreatic diseases (1990-Present).}, journal = {Abdominal radiology (New York)}, volume = {}, number = {}, pages = {}, pmid = {41417080}, issn = {2366-0058}, abstract = {PURPOSE: To map the intellectual evolution of pancreatic radiology through a comprehensive bibliometric analysis of the 100 most-cited articles, identifying influential contributors and publications, geographical and institutional patterns, and delineating the thematic and technological trends shaping research from 1990 to the present.<br><br>METHODS: A systematic search of the Scopus database, conducted on May 11, 2025, identified the top 1,000 most-cited pancreatic radiology records between 1990 and 2025. Two reviewers independently screened articles for a primary focus on pancreatic imaging within core radiology journals. The final 100 articles were analyzed using the Bibliometrix R package to evaluate publication trends, contributor influence, and collaborative networks. The conceptual structure and thematic evolution of the field were mapped using VOSviewer (version 1.6.20).<br><br>RESULTS: The median citation count was 223 (IQR: 190.2-264.5). A significant temporal bias was evident: the most-cited article was Balthazar et al.'s 1990 study on CT in pancreatitis (1,424 citations), while a 2015 deep learning paper achieved the highest citation velocity (58.5 citations/year). Analysis of research topics revealed a strong oncologic focus, with pancreatic neoplasms accounting for 51% of all articles. CT was the predominant imaging modality (55%), followed by MRI (24%). The research ecosystem was concentrated, with the United States contributing 46 articles and Radiology publishing 44 of the top 100 papers. Leading institutions included Johns Hopkins University and the Mayo Clinic. Co-authorship network analysis identified Megibow AJ as the researcher with the highest network centrality, highlighting the importance of collaborative hubs.<br><br>CONCLUSION: This bibliometric analysis charts the field's evolution from foundational CT/MRI applications to the current AI frontier. Our findings serve as a guide to the characteristics of high-impact research, highlighting a consistent focus on oncology, driven by key authors and US institutions. While historical benchmarks focused on morphological assessment, citation metrics confirm computational methods as the principal driver of future innovation.}, }
@article {pmid41417753, year = {2025}, author = {Lam, P and Zygmunt, DA and Bennett, M and Ashbrook, A and Hefty, J and Martin, PT}, title = {Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251405918}, doi = {10.1177/22143602251405918}, pmid = {41417753}, issn = {2214-3602}, abstract = {The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne[lox/lox] gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER[T2]/Rosa-CreER[T2]Gne[lox/lox] mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER[T2/+]Gne[lox/lox] mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne[lox/lox] mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.}, }
@article {pmid41419037, year = {2026}, author = {Henriksson, S and Bäckström, M and Westberg, H and Hagberg, J}, title = {PCDD/Fs in food products produced near a contaminated former sawmill - concentrations, congener profiles and risk assessment.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {390}, number = {}, pages = {127529}, doi = {10.1016/j.envpol.2025.127529}, pmid = {41419037}, issn = {1873-6424}, mesh = {Polychlorinated Dibenzodioxins/analysis ; *Food Contamination/analysis/statistics &amp; numerical data ; Risk Assessment ; Sweden ; Animals ; *Benzofurans/analysis ; Dibenzofurans, Polychlorinated ; Cattle ; Sheep ; Humans ; Environmental Monitoring ; *Environmental Pollutants/analysis ; Dietary Exposure/statistics &amp; numerical data ; Milk/chemistry ; Soil Pollutants/analysis ; }, abstract = {Hillringsberg, a former sawmill site in Sweden, is severely contaminated with polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). This study collected site-specific data to assess the human health risks associated with locally produced food. To evaluate potential exposure, samples of salmon, perch, cow's milk, cattle, and sheep were collected near the site and analyzed for PCDD/Fs. The findings reveal that the most frequently detected congeners in the food samples corresponded with the most abundant congeners in the soil, underscoring the impact of contaminated sites on PCDD/F concentrations in locally produced food. Particularly concerning is the level of PCDD/Fs in sheep meat, which was found to be 11 times higher than the Tolerable Weekly Intake (TWI) for adults and 26 times higher for children. Comparing food samples from the sawmill site to those from the National Swedish Control Programme revealed that all food samples from Hillringsberg exhibited some level of contamination, even though the concentrations of PCDD/Fs remained below the European Maximum Limits (MLs) and Action Limits (ALs). The concentrations and patterns of contaminants in nearly all samples, particularly those from sheep, cattle and perch, were influenced by local contamination from the historical use of pentachlorophenol (PCP) at the old sawmill site. PCA showed that sheep and soil samples from the storage area exhibited strong covariance. Perch and sediment samples from the sawmill pond were also grouped together. These findings highlight the necessity of evaluating food production activities near contaminated sites during the initial stages of site-specific risk assessments. Ensuring food safety in these areas is crucial, and if necessary, relocating grazing lands, fish farms, and similar operations can help mitigate health risks associated with contaminated food.}, }
@article {pmid41419286, year = {2025}, author = {Phillips, G and Sharma, D and O'Reilly, G and Romero, L and Cameron, P}, title = {Developing emergency care systems in low-income and middle-income countries: a scoping review to examine the role of leadership and governance.}, journal = {BMJ open}, volume = {15}, number = {12}, pages = {e102624}, pmid = {41419286}, issn = {2044-6055}, mesh = {Humans ; *Developing Countries ; *Leadership ; *Emergency Medical Services/organization &amp; administration ; }, abstract = {BACKGROUND: More knowledge and resources are required to strengthen 'leadership and governance' (L+G) as a central building block to further develop emergency care (EC) systems in low-income and middle-income countries (LMICs).<br><br>OBJECTIVES: This scoping review aimed to examine and map the impact of individual, collective or institutional L+G on the development of EC systems (prehospital and facility-based) in LMICs.<br><br>ELIGIBILITY CRITERIA: English language publications from January 2005 to April 2024 that linked any L+G action with the development and capacity of everyday EC in LMICs, specifically excluding disaster responses.<br><br>SOURCES OF EVIDENCE: Medline (Ovid), Embase (Ovid), CINAHL, Web of Science (Clarivate), Central (Cochrane Central Register of Controlled Trials), Global Health (Ovid) and select grey literature.<br><br>CHARTING METHODS: Data from all eligible papers were jointly extracted using a piloted tool developed from the literature and WHO's EC Systems Framework. L+G descriptors included level (from clinical to national) and components (informed by Siddiqi et al's LMIC health system 'good governance' framework and a synthesis of EC policy documents). Impact of L+G on EC systems and key lessons were extracted from each publication.<br><br>RESULTS: From an initial 9713 items, 129 papers were included for final analysis and divided by EC component: prehospital (n=35), facility-based (n=53) and 'whole of EC system' (n=41). Qualitative and descriptive papers were most common, and 72 out of a possible 131 LMICs were represented. Findings were heterogeneous across all building blocks of EC systems and for different components of leadership and/or governance. Cross-cutting L+G themes were identified that demonstrated consistent impact across all EC systems development: government recognition, vision and human rights framing; coalition-building for effective partnerships and trained, empowered EC clinicians demonstrating emotionally intelligent, transformational leadership.<br><br>CONCLUSIONS: Applying new models such as Theories of Change and Social Network Analysis concepts may assist to illuminate how effective L+G is attained, what are the essential components and how these influence EC systems for better patient-centred outcomes. Further understanding the role of L+G for EC systems has utility for future EC clinician leadership training and policy-maker awareness, to strengthen resilience of overall health systems against likely future shocks.}, }
@article {pmid41419800, year = {2025}, author = {Sun, Y and Zhong, Q and Chu, X and Wan, D and Peng, Y}, title = {Total intravenous anesthesia without neuromuscular blockers for ureteral lithotripsy in an ALS patient with orthopnea: a case report.}, journal = {BMC anesthesiology}, volume = {26}, number = {1}, pages = {52}, pmid = {41419800}, issn = {1471-2253}, abstract = {Patients with amyotrophic lateral sclerosis (ALS) rarely need urological surgery. This case report describes the successful use of total intravenous anesthesia (TIVA) with propofol and remifentanil combined with laryngeal mask airway (LMA) ventilation in a 55-year-old ALS patient with severe orthopnea who underwent ureteral lithotripsy. Given the progressive respiratory muscle weakness and inability to tolerate supine positioning, a tailored anesthetic approach is imperative. By avoiding neuromuscular blockers and minimizing opioid doses, we aimed to reduce postoperative respiratory depression. The procedure was completed uneventfully, with stable hemodynamics and rapid postoperative recovery. This case underscores the importance of individualized anesthetic strategies in neuromuscular disorders to optimize safety and outcomes.}, }
@article {pmid41419928, year = {2025}, author = {An, J and Hendricks, N and Wheeler, J and Hincks, J and Benitez, JAR and Snyder, JM and Kraemer, BC and Liachko, NF and Elkon, KB}, title = {Neuronal TDP-43 pathology drives astrocytic interferon response in a mouse model of ALS.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {29}, pmid = {41419928}, issn = {1742-2094}, support = {R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; RF1AG055474/NH/NIH HHS/United States ; I01 BX004044/BX/BLRD VA/United States ; R01AG066729/NH/NIH HHS/United States ; I01BX004044//The United States Department of Veterans Affairs/ ; RF1 AG055474/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; IK6BX006467//The United States Department of Veterans Affairs/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Astrocytes/metabolism/pathology ; Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; *Neurons/pathology/metabolism ; Humans ; *Interferon Type I/metabolism ; Mice, Inbred C57BL ; }, abstract = {Neuroinflammation is implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Amongst potential innate immune mediators of disease, Type I interferon (IFN-I) could play an important role due to its ability to inhibit protein synthesis and affect neuronal synapses and metabolism. These effects could be cell intrinsic or non-cell autonomous mediated by glia or immune cells. We examined IFN-I in rNLS8 mice that have been engineered to express doxycycline suppressible human Transactive response DNA binding protein 43 kDa (hTDP-43) with a defective nuclear localization signal (hTDP-43ΔNLS) regulated by the neurofilament heavy chain (NEFH) promoter. Following induction of hTDP-43ΔNLS in rNLS8 mice, we observed upregulation of IFN-I stimulated genes (ISG) and, specifically, activation of the DNA sensor, cyclic GMP-AMP synthase (cGAS), as determined by mass spectrometry identification of the cyclic dinucleotide, cGAMP, in whole brain. To determine the cellular source of IFN-I, we performed single nucleus RNA sequencing of whole brain. We observed that ISG were most highly upregulated in astrocytes suggesting that astrocytes themselves were largely responsible for IFN-I production and / or response in rNLS8 mice. This observation was confirmed by immunohistochemical and immunofluorescence staining of IFN-I stimulated proteins in astrocytes in the cerebrum, especially in the hippocampus. These results point to a pivotal role of astrocytes in responding to cell damage at a relatively early phase of disease which prior studies have shown is partially reversible.}, }
@article {pmid41420107, year = {2026}, author = {Campos-Ribeiro, MA and Donnarumma, E and Nolte, H and Cobine, P and Vimont, E and Milenkovic, D and Hernandez-Camacho, JD and Langa-Vives, F and Kornobis, E and Pénard, E and Yde, S and Langer, T and Paquis-Flucklinger, V and Wai, T}, title = {Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.}, journal = {EMBO molecular medicine}, volume = {18}, number = {2}, pages = {542-574}, pmid = {41420107}, issn = {1757-4684}, support = {ANR-21-CE14 0052-02//Agence Nationale de la Recherche (ANR)/ ; ANR-23-CE13-0043-01//Agence Nationale de la Recherche (ANR)/ ; ANR-10-INSB-04-01//Agence Nationale de la Recherche (ANR)/ ; ANR-10-LABX-62-IBEID//Agence Nationale de la Recherche (ANR)/ ; INNOV 164-2022//Institut Pasteur (Pasteur Institute)/ ; }, mesh = {Animals ; Oxidation-Reduction ; *Mitochondrial Proteins/genetics/metabolism ; Mice ; *Signal Transduction ; *Mitochondria/metabolism ; *Cytochromes c/metabolism ; Humans ; Disease Models, Animal ; Mutation ; Gene Knock-In Techniques ; Mitochondrial Diseases/genetics/pathology ; }, abstract = {Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10[S59L] variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1[E324Q/E324Q] knock-in mice, we show that blunting mtISR in Chchd10[S55L/+] mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10[S55L/+] mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.}, }
@article {pmid41420832, year = {2026}, author = {Wang, X and Wei, M and Qiao, Y}, title = {Modulation of Liquid-to-Solid Phase Transition in Coacervates for Neurodegenerative Disease Treatments.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {27}, number = {2}, pages = {e202500795}, doi = {10.1002/cbic.202500795}, pmid = {41420832}, issn = {1439-7633}, support = {2023YFC2507000//National Key R&amp;D Program of China/ ; 22272183//National Natural Science Foundation of China/ ; T2425001//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Phase Transition ; Animals ; }, abstract = {Coacervates formed through liquid-liquid phase separation represent a fundamental model for protocell and serve as a membraneless organelle in living cells, modulating various biological processes. During aging or under stress, protein misfolding and oligomerization trigger aberrant liquid-to-solid phase transition (LSPT), a process driven by multivalent interactions. These phase transitions disrupt cellular equilibrium, leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The regulatory strategies is summarize to enhance molecular interactions in coacervate LSPT into three categories, including physical stimulation, molecular modulation, and sequence regulation. This review aims to establish a conceptual framework for modulating coacervate LSPT and further explores potential clinical treatments for neurodegenerative diseases.}, }
@article {pmid41420983, year = {2026}, author = {Garcia-Delgado, AB and Bega, S and Campos-Cuerva, R and Martín-Banderas, L and Paradas, C and Fernandez-Muñoz, B}, title = {Generation of the human iPSC line ESi148-A from a patient with sporadic amyotrophic lateral sclerosis.}, journal = {Stem cell research}, volume = {90}, number = {}, pages = {103889}, doi = {10.1016/j.scr.2025.103889}, pmid = {41420983}, issn = {1876-7753}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Line ; Leukocytes, Mononuclear/metabolism/cytology ; Male ; }, abstract = {Nearly 90% of patients with amyotrophic lateral sclerosis (ALS) do not carry mutations in genes previously associated with the disease and are classified as sporadic cases with no identified genetic cause. In this study, peripheral blood mononuclear cells from a patient with sporadic ALS were reprogrammed to generate the human induced pluripotent stem cell (iPSC) line ESi148-A. The line was thoroughly characterized for pluripotency and genomic stability. These cells provide a valuable resource for generating 3D biomodels, such as cortical or spinal cord organoids, to investigate disease mechanisms and develop novel therapeutic approaches for sporadic ALS.}, }
@article {pmid41422050, year = {2025}, author = {Valletta, M and Briel, N and Yuksekel, I and Barboure, M and Coward, A and De Houwer, JFH and Fawad, A and González-Mayoral, A and Iaccarino, G and Martínez-Dubarbie, F and Moukaled, S and Andreasson, U and Gobom, J and Brinkmalm, A and Tijms, B and Zetterberg, H and Blennow, K and Suárez-Calvet, M and Schöll, M and Paterson, RW and Montoliu-Gaya, L and Sogorb-Esteve, A}, title = {Fluid biomarkers for neurodegenerative diseases: a comprehensive update.}, journal = {Alzheimer's research &amp; therapy}, volume = {18}, number = {1}, pages = {12}, pmid = {41422050}, issn = {1758-9193}, abstract = {UNLABELLED: Fluid biomarkers are revolutionizing the diagnosis and management of neurodegenerative diseases by enabling earlier diagnosis and disease monitoring. In particular, blood-based biomarkers have emerged as a minimally invasive and scalable alternative to cerebrospinal fluid analysis. Recent advances in blood-based tau biomarkers have shown high diagnostic accuracy for Alzheimer’s disease (AD). Other neurodegenerative diseases—such as synucleinopathies, frontotemporal lobar degeneration, limbic-predominant age-related TDP-43 encephalopathy (LATE), and amyotrophic lateral sclerosis—pose substantial challenges due to their heterogeneous clinical presentations and the current absence of robust biomarkers for hallmark pathologies. Nonetheless, promising candidate markers are emerging for improved disease characterization and staging. Technological innovations, including single-molecule arrays (Simoa), advanced mass spectrometry workflows and nucleic acid linked immune-sandwich assay (NULISA) have markedly enhanced the sensitivity and precision of biomarker quantification from low-concentration biological matrices. More recently, the development of fully automated platforms shows great promise for routine measurement of blood-based biomarkers in clinical settings. Despite this progress key challenges remain, including the need for improved assay reproducibility, standardization, and the optimization of clinical workflows. In this review, we provide a comprehensive update on recent progress in fluid biomarker research across AD and major neurodegenerative diseases, highlight technological advances in detection methods, and discuss current challenges and opportunities for clinical translation.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01919-z.}, }
@article {pmid41422089, year = {2025}, author = {Jun, YW and Lee, S and Almeida, S and Freude, KK and Ichida, JK and Gao, FB}, title = {The Ku80-p53-SIRT1 axis in DNA damage response contributes to sporadic and familial ALS and FTD.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1007}, pmid = {41422089}, issn = {2041-1723}, support = {NA/ALZ/Alzheimer's Association/United States ; R01NS101986//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; NRF-2019R1A6A3A03034014//National Research Foundation of Korea (NRF)/ ; R37NS057553//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Sirtuin 1/metabolism/genetics ; *Tumor Suppressor Protein p53/metabolism/genetics ; Animals ; *DNA Damage ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; *Ku Autoantigen/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Neurons/metabolism/pathology ; Mutation ; Acetylation ; Disease Models, Animal ; Male ; Phosphorylation ; Female ; Drosophila ; }, abstract = {Although TDP-43 pathology is found in most sporadic and familial ALS and FTD cases, other shared pathogenic mechanisms remain largely unknown. Here we show that SIRT1 levels are decreased and acetylated p53 levels are increased in iPSC-derived neurons from sALS patients and with the FTD3-causing CHMP2B mutation. Ectopic expression of SIRT1 in these patient neurons rescues neurodegeneration and reduces acetylated p53 levels. DNA damage is elevated in both sALS and FTD3 neurons, leading to increased phosphorylation of p53 at Serine 15 and elevated levels of Ku80. Knockdown of either p53 or Ku80 rescues neurodegeneration and increases SIRT1 levels in these neurons. Moreover, ectopic expression of SIRT1 or genetic knockdown of either p53 or Ku80 suppresses retinal neurodegeneration caused by FTD3-associated mutant CHMP2B protein in an in vivo Drosophila model. These findings identify a dysregulated SIRT1-p53 feedback loop as a common pathogenic mechanism and promising therapeutic target in both sporadic and familial ALS/FTD.}, }
@article {pmid41423553, year = {2025}, author = {Tang, C and Foucher, J and Öijerstedt, L and Ombelet, F and Ingre, C and Van Damme, P and Van Laere, K and De Vocht, J and Koole, M}, title = {Support vector machine classification of [18]F-FDG PET scans across subtypes of amyotrophic lateral sclerosis.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {41423553}, issn = {1619-7089}, support = {12AQF24N//FWO/ ; fundamental clinical investigatorship//KU Leuven/ ; Een Hart voor ALS//KU Leuven/ ; Laeversfonds voor ALS Onderzoek//KU Leuven/ ; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders//E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders/ ; ALS Liga Belgi&#xeb;//ALS Liga Belgi&#xeb;/ ; }, abstract = {PURPOSE: While [18]F-FDG PET imaging has demonstrated diagnostic value in people with Amyotrophic Lateral Sclerosis (PwALS) and group-level differences were identified between different disease subtypes (e.g., genetic and clinical variants), refining and validating a machine-learning-based subject-level diagnostic algorithm may improve the general applicability and reliability of [18]F-FDG PET as a diagnostic tool in ALS. In this study, we employed support vector machines (SVM) to further explore the diagnostic potential of [18]F-FDG PET in ALS, alongside its ability to classify between different genetic subtypes or clinical phenotypes.<br><br>METHODS: [18]F-FDG PET data of 36 healthy volunteers (HV), 25 people with ALS-mimicking diseases (Mimics), and 167 PwALS, grouped by genetic status (e.g., sporadic (sALS) or carrying a C9orf72 hexanucleotide repeat expansion (ALS[C9orf72RE]) and onset (bulbar or spinal) type, acquired with Biograph 'TruePoint' PET/CT scanner, were included in the study (Dataset 1). A second dataset of 183 PwALS and 31 Mimics acquired with Biograph 'HiRez' scanner was included as an independent cross-validation set (Dataset 2). PET images were spatially normalised to MNI space to fit linear SVMs with cross-validation. Only age-matched groups were considered to eliminate age-related effects.<br><br>RESULTS: For Dataset 1, the linear SVM resulted in an average accuracy of 0.86 for the classification of ALS vs. HV, 0.53 for ALS vs. Mimics, 0.83 for ALS[C9orf72RE] vs. sALS, and 0.58 for bulbar vs. spinal onset. These findings were corroborated with Dataset2, with an accuracy of up to 0.76 for ALS[C9orf72RE] vs. sALS, and 0.59 for bulbar vs. spinal.<br><br>CONCLUSION: [18]F-FDG brain PET imaging, combined with SVM and age-matching, can distinguish between ALS[C9orf72RE] and sALS with good accuracy, but lacks sufficient discriminative power to differentiate between ALS and Mimics and between different sites of onset.}, }
@article {pmid41423699, year = {2025}, author = {Luan, W and San Gil, R and Madrid San Martin, L and Cao, MC and Vassallu, F and Venturato, J and West, PK and Brown-Wright, H and Bademosi, AT and Chye, YJ and Wu, HY and Harutyunyan, A and Robinson, KJ and Chang, MS and Blizzard, CA and Scotter, EL and Igaz, LM and Walker, AK}, title = {Synaptic changes contribute to persistent extra-motor behaviour deficits in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {26}, pmid = {41423699}, issn = {2051-5960}, support = {IG2422//Motor Neurone Disease Australia/ ; Discovery grant//FightMND/ ; Bill Guest Mid-Career Research Fellowship//FightMND/ ; }, abstract = {UNLABELLED: Extra-motor symptoms are increasingly recognised in amyotrophic lateral sclerosis (ALS), encompassing cognitive, social, and behavioural deficits. TAR DNA binding protein 43 (TDP-43) pathology is the central disease marker of almost all cases of ALS and approximately half of frontotemporal dementia (FTD). However, the mechanisms linking TDP-43 pathology with extra-motor symptoms in TDP-43-associated neurodegenerative diseases remain unresolved. In this study, we used the rNLS8 mouse model, which expresses human TDP-43 with an ablated nuclear localisation sequence (hTDP-43[∆NLS]) in a doxycycline-regulatable manner causing progressive motor decline reminiscent of ALS, to delineate molecular changes associated with disease-relevant phenotypes. We found that in addition to previously reported dramatic motor decline, rNLS8 mice also develop extra-motor phenotypes consistent with FTD, including disinhibition-like and anxiety-like behaviours, and social interaction impairments. These changes began in the earliest disease stages and remained readily detectable even when rNLS8 mice became severely motor impaired. Notably, extra-motor deficits persisted in rNLS8 mice that had recovered motor function upon hTDP-43[∆NLS] transgene suppression. This correlates with widespread mis-splicing of RNA in rNLS8 cortex at disease onset with n = 814 genes showing differential exon usage, a molecular phenotype of TDP-43 loss of function. Mis-splicing persists in the rNLS8 cortex in recovery and may represent lasting impacts of cytoplasmic TDP-43 expression. Further, proteomics analysis of the cortex of rNLS8 mice revealed depletion of synaptic proteins, particularly those involved in glutamatergic signalling pathways, which also persisted following hTDP-43[∆NLS] transgene suppression. Similar changes to the glutamatergic pathway were detected in transcriptomic and proteomic datasets from human ALS and FTD post-mortem cortex. Our findings suggest that targeting glutamatergic synaptic components may be an avenue to correct extra-motor deficits associated with TDP-43 pathology.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-025-02150-5.}, }
@article {pmid41426430, year = {2025}, author = {van Vugt, JJFA and Zwamborn, RAJ and Dolzhenko, E and Eberle, MA and Weisburd, B and Bekema, E and Kooyman, M and Wang, BN and ,  and Kamsteeg, EJ and Losekoot, M and Baas, F and Novy, C and Høyer, H and van Eijk, RPA and van Es, MA and van Rheenen, W and Al-Chalabi, A and van den Berg, LH and Veldink, JH}, title = {The role of disease-associated short tandem repeats in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf482}, pmid = {41426430}, issn = {2632-1297}, abstract = {Short tandem repeats (STRs) are recognized contributors to various neurodegenerative disorders, with evidence supporting genetic pleiotropy among these STRs. Multiple STRs have been associated with amyotrophic lateral sclerosis (ALS), although the strength of evidence supporting each association varies. To establish the role of disease-associated repeat expansions as pleiotropic risk factors in ALS susceptibility and progression, we genotyped a panel of 39 STRs, known to cause neurological diseases, within Project MinE in 6519 patients and 2412 controls, utilizing 100 and 150 bp short-read sequencing technology. Pathogenic allele frequencies were compared to those in a control cohort comprising 4930 Genome Aggregation Database (gnomAD) genomes. Repeat sizes and motif changes were detected using ExpansionHunter and ExpansionHunter Denovo. We developed a model to predict genotyping failures in STRs and established a best-practice protocol for assessing the accuracy of STR genotyping in short-read sequencing data. Following our genotyping assessment, 11 out of the 39 STRs exhibited insufficient genotyping accuracy, warranting caution in studying these STRs using these tools in combination with short-read sequencing. Furthermore, the observed differences in STR genotyping accuracy across studies applying different sequencing technologies and genotyping tools in control cohorts highlight the importance of a carefully designed experimental setup when interpreting potential disease-associated STR findings. Pathogenic C9orf72 and premutated ATXN2 expansions were confirmed to be significantly associated with ALS susceptibility. Additionally, pathogenic C9orf72 expansions were significantly associated with reduced mean ALS survival by 11.5 months and an earlier mean age at onset by 2.4 years. Premutation expansions in ATXN1 showed a nominally significant association with ALS susceptibility, while pathogenic expansions in NIPA1 displayed a nominally significant association with ALS survival. Previously reported ALS-associated pleiotropy in HTT and STMN2 could not be confirmed. Motif changes were identified in BEAN1, RFC1, ATXN8, C9orf72, DAB1, FXN and SAMD12; however, none of the motif changes were linked to ALS. Re-evaluation of clinical data from patients with ALS and a repeat expansion typically associated with another disease revealed that 7% of these patients' diagnoses had to be reclassified to the disease associated with the repeat expansion (e.g. Kennedy's disease or spinocerebellar ataxia). This underscores the value of broad STR screening in neurodegenerative cases. Pathogenic and premutation STRs were also found in controls in unexpected high frequencies, suggesting reduced penetrance or underdiagnosis, and highlighting the need for caution when interpreting genetic associations with disease without a proper control cohort.}, }
@article {pmid41426554, year = {2025}, author = {Liang, L and Zhang, Y and Zhang, X and Guo, X and Yan, Y}, title = {Historical evolution, research hotspots and emerging trends of pediatric hand, foot, and mouth disease: a bibliometric worldview since the 21st century.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1722750}, pmid = {41426554}, issn = {2296-858X}, abstract = {BACKGROUND: Hand, foot, and mouth disease (HFMD) poses a significant challenge to global public health. Primarily caused by enterovirus and coxsackievirus infections, the disease has a particularly pronounced impact in the Asia-Pacific region. However, systematic analysis and discussion regarding the developmental trajectory, core research entities, current status, key research directions, and future prospects of pediatric HFMD research remain lacking.<br><br>METHODS: This study collected and analyzed papers and reviews on pediatric HFMD published between January 1, 2000, and February 1, 2025, from the Web of Science Core Collection and PubMed. Key research indicators were analyzed through bibliometric visualization, using tools including Excel, CiteSpace, VOSviewer, and BibliomeTools (an R-based tool in R-Studio).<br><br>RESULTS: Since the start of the 21 st century, academic publications in pediatric HFMD have steadily increased, with a cumulative total of 2,034 papers published by February 1, 2025. Global research distribution exhibits uneven patterns, with China emerging as core contributors. Specifically, Lin, Tzou-Yien from China, has published the largest number of papers, while Chang, Luan-Yin is the co-cited author with the highest citation rate. Solomon T et al.'s "Virology," Epidemiology, Pathogenesis, and Control of Enterovirus 71" being the most cited study in the field. Research on pediatric HFMD is closely integrated with disciplines such as virology and epidemiology, forming core research themes around "HFMD," "enterovirus 71," and "enteroviruses." Recent research has focused on the pathogenesis, epidemiology, novel therapeutic discoveries and vaccine development for pediatric HFMD. Looking ahead, it is essential to delve deeper into the molecular mechanisms underlying the interaction between the human HFMD virus and its host, and to develop multivalent vaccines targeting multiple serotypes.<br><br>CONCLUSION: This study employs bibliometric methods to visualize research in the field of pediatric hand, foot, and mouth disease, revealing trends and frontiers in this area. It will provide valuable reference for scholars seeking key research questions and potential collaborators.}, }
@article {pmid41427267, year = {2025}, author = {Finney, CA and An, L and Winchester, LM and Vogel, J and Wilkins, HM and Burns, JM and Swerdlow, RH and Slawson, C and Rothstein, JD and ,  and Lutz, MW and Saloner, R and Shvetcov, A}, title = {Mapping the circulating proteome across neurodegeneration: A harmonized, consortium-scale framework for uncovering molecular pathophysiology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41427267}, issn = {2692-8205}, support = {RF1 AG064227/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; K23 AG090757/AG/NIA NIH HHS/United States ; R21 TR003589/TR/NCATS NIH HHS/United States ; }, abstract = {Large-scale plasma proteomics offers unprecedented opportunities to investigate the systemic biology of neurodegeneration, yet technical heterogeneity, site-specific artifacts, and clinical confounding remain major barriers to reproducible discovery. Leveraging data from 13,733 individuals with Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), amyotrophic lateral sclerosis (ALS), and non-impaired controls in the Global Neurodegeneration Proteomics Consortium (GNPC), we present a scalable and generalizable analytical framework for harmonizing and interpreting consortium-scale proteomic datasets. Using a high-dimensional perturbation framework, we systematically benchmark five commonly used batch correction methods across a range of realistic confounding structures, including site-disease imbalance, nonlinear effects, and heteroskedasticity. Empirical Bayes modelling via limma consistently emerged as the most robust method, optimally balancing removal of site-related technical variance with retention of disease-relevant biological signal. On this harmonized foundation, we resolve neurodegenerative disease plasma signatures, including a shared immune-metabolic axis in AD and PD, neuromuscular disruption in ALS, and proteostatic imbalance in PD. Tissue and cell-type enrichment highlight widespread immune-endocrine involvement in AD and hematopoietic activation in PD. Demographically matched analyses nominate distinct, candidate biomarkers across diseases, including lipid, redox, and complement factors in AD, lysosomal and cytoskeletal proteins in PD, and muscle-derived markers in ALS. This study establishes a scalable analytical framework for integrating real-world proteomic data and provides a disease-resolved catalogue of circulating signatures to inform biomarker development and targeted intervention across neurodegenerative diseases.}, }
@article {pmid41427945, year = {2026}, author = {Gruda, D and Hanges, P and McCleskey, JA}, title = {Decomposing Spatial Effects of State-Level Health Outcomes: A Methodological Demonstration and Re-Analysis.}, journal = {International journal of psychology : Journal international de psychologie}, volume = {61}, number = {1}, pages = {e70152}, doi = {10.1002/ijop.70152}, pmid = {41427945}, issn = {1464-066X}, mesh = {Humans ; *Narcissism ; Hypertension/mortality/epidemiology ; United States/epidemiology ; Machiavellianism ; Neoplasms/epidemiology ; Depression/epidemiology ; Antisocial Personality Disorder/epidemiology ; Male ; Female ; }, abstract = {While spatial autoregressive (SAR) models are increasingly used in population-level psychological studies, researchers often overlook the crucial step of parsing effects into direct, indirect and total impacts, a standard practice in spatial econometrics. In this paper, we demonstrate the necessity of this practice by re-analyzing Gruda et al.'s (2024) U.S. Dark-Triad and health dataset with heteroskedasticity-robust SAR models and full impact decomposition, revealing significant changes. The previously observed direct protective effect of state-level narcissism on hypertension mortality disappeared when accounting for interstate spillovers. Conversely, the association with lower cancer prevalence and depression strengthened. Several health-behaviour findings reversed direction, indicating naïve regressions conflated within- and between-state effects. Machiavellianism and psychopathy coefficients also shifted. These results demonstrate that spatial spillovers can dilute, negate or reverse local effects, cautioning against policy inferences based solely on direct estimates.}, }
@article {pmid41428120, year = {2025}, author = {Freri, F and Spinelli, EG and Canu, E and Basaia, S and Castelnovo, V and Müller, HP and Kassubek, J and Ludolph, AC and Krishnamurthy, SS and Roselli, F and Filippi, M and Agosta, F}, title = {Uncovering hypothalamic network disruption in ALS.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {37}, pmid = {41428120}, issn = {1432-1459}, support = {EU Joint Programme - Neurodegenerative Disease Research (JPND) - HiCALS project//European Commission/ ; Next Generation EU/National Recovery//European Union/ ; Resilience Plan//European Union/ ; Investment PE8-Project Age-It. Project code: PE00000015; CUP master: D43C22003100007//European Union/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Female ; Male ; Middle Aged ; *Hypothalamus/diagnostic imaging/physiopathology/pathology ; Magnetic Resonance Imaging ; Aged ; Adult ; *White Matter/diagnostic imaging/pathology ; *Nerve Net/diagnostic imaging/physiopathology ; Disease Progression ; *Connectome ; }, abstract = {BACKGROUND: Structural MRI studies have shown hypothalamic atrophy and altered white matter (WM) connectivity in amyotrophic lateral sclerosis (ALS), as a possible substrate of hypermetabolism in this condition. However, hypothalamic functional connectivity and its association with clinical features in ALS remain unclear. This study explored hypothalamic resting-state functional connectivity (RS-FC) in ALS patients compared to controls and its relationship with disease severity defined by the ALS Functional Rating Scale (ALSFRS-r), body mass index (BMI), disease duration, progression rate, survival, hypothalamic volume, and WM integrity.<br><br>METHODS: Seventy-one ALS patients and 39 healthy controls underwent structural and RS functional MRI. The bilateral hypothalamus was segmented, and a seed-based RS-FC analysis was performed. Group differences in hypothalamic RS-FC and their correlations with ALSFRS-r scores, BMI, disease duration, progression rate, survival, hypothalamic volume, and WM integrity were assessed. Tract-based spatial statistics was performed to estimate the correlation between WM damage in ALS and hypothalamic RS-FC.<br><br>RESULTS: ALS patients showed increased hypothalamic RS-FC with caudate nuclei compared to controls. Additionally, greater disease severity correlated with increased hypothalamic RS-FC with the caudate nuclei and orbitofrontal cortex. Hypothalamic RS-FC mean values also associated with FA in the genu of corpus callosum and forceps minor and disease progression rate. No significant correlations were observed with other clinical features.<br><br>CONCLUSIONS: These findings support hypothalamic alterations in ALS. Early detection of hypothalamic changes could be useful in prognostic stratification and evaluating intervention effects.}, }
@article {pmid41428212, year = {2026}, author = {Grønbæk-Thygesen, M and Kampmeyer, C and Eschger, P and Tatham, MH and Arts, M and Hofmann, K and Lindorff-Larsen, K and Boomsma, W and Hartmann-Petersen, R}, title = {The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization.}, journal = {Biochemistry}, volume = {65}, number = {1}, pages = {52-63}, doi = {10.1021/acs.biochem.5c00619}, pmid = {41428212}, issn = {1520-4995}, mesh = {Humans ; *Ubiquitination ; Autophagy-Related Proteins ; Adaptor Proteins, Signal Transducing/metabolism ; *Cell Cycle Proteins/metabolism/genetics/chemistry ; Proteasome Endopeptidase Complex/metabolism ; Lysine/metabolism ; Proteolysis ; Protein Domains ; *Ubiquitins/metabolism ; HEK293 Cells ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Ubiquitin/metabolism ; }, abstract = {UBQLN2 is a member of the UBL-UBA domain protein family that functions as extrinsic substrate receptors for the 26S proteasome. UBQLN2 has been shown to undergo phase separation in vitro. In cells, UBQLN2 forms condensates that may be of importance for tuning protein degradation via the ubiquitin-proteasome system and potentially of relevance for UBQLN2-linked amyotrophic lateral sclerosis (ALS). Here we show that UBQLN2 is ubiquitylated on lysine residues in the N-terminal UBL domain. The C-terminal region of UBQLN2 is lysine-depleted, and we show that introducing lysine residues in this region leads to its E6AP-dependent degradation. The UBL domain critically stabilizes UBQLN2 and protects it from proteasomal degradation. Fusion of ubiquitin to the UBQLN2 N-terminus stabilizes UBQLN2 and increases its propensity for locating in puncta, indicating that ubiquitylation of the UBQLN2 UBL domain regulates abundance and localization.}, }
@article {pmid41428348, year = {2026}, author = {Elman, L and Wymer, J and Lomen-Hoerth, C}, title = {Tofersen, SOD1, and the Treatability of Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {83}, number = {2}, pages = {103-104}, doi = {10.1001/jamaneurol.2025.4927}, pmid = {41428348}, issn = {2168-6157}, }
@article {pmid41428513, year = {2025}, author = {Román-Caballero, R}, title = {Reassessing the cognitive benefits of physical activity: A meta-analytic reanalysis of Mavilidi et al. (2025).}, journal = {Psychological bulletin}, volume = {151}, number = {11}, pages = {1382-1388}, doi = {10.1037/bul0000490}, pmid = {41428513}, issn = {1939-1455}, support = {//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Humans ; *Cognition/physiology ; *Exercise/psychology/physiology ; Meta-Analysis as Topic ; Publication Bias ; }, abstract = {Recent reviews and meta-analyses suggest the cognitive benefits of physical exercise observed in primary studies may be inflated due to multiple sources of bias, including selection bias, placebo effects, regression to the mean, and publication bias. When these biases are accounted for, the evidence for the purported enhancements has been shown to be inconclusive. The recent meta-analysis by Mavilidi et al. (2025) makes a relevant contribution by pointing out the potential role of moderating variables and therefore the possibility that, under certain conditions, the effect may be more substantive. Yet, a critical evaluation of Mavilidi et al.'s methods reveals several issues in the statistical analyses and interpretation of publication bias analyses. These appear to have led Mavilidi et al. to conclude the presence of an overall cognitive benefit of physical activities. The present commentary provides a reanalysis of the data, applying appropriate methodological corrections. After an adequate analytical strategy, the final effect was reduced and yielded inconclusive evidence of an overall cognitive benefit. Particularly, publication bias methods highlight that the overall effect of chronic physical activity on cognition is likely smaller and therefore inconclusive. Yet, as in the original meta-analysis, the cognitive benefits were significantly larger for chronic interventions with an evidence-based delivery, programs with a clear cognitive component, or high cognitive demands compared to other physical exercise interventions. These results support the possibility that motor-cognitive training/sports games and holistic movement practices/martial arts may be effective activities to improve cognitive functioning. (PsycInfo Database Record (c) 2025 APA, all rights reserved).}, }
@article {pmid41428860, year = {2025}, author = {Curtis, SE and Tatlock, S and O'Hara, L and Seçinti, E and Mehdiyoun, NF and Ayala-Nunes, L and Flynn, J and Fernelius, K and Hodson, N and Delbecque, L}, title = {Patient experience and clinical outcome assessment validity in amyotrophic lateral sclerosis: a targeted literature review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/21678421.2025.2604233}, pmid = {41428860}, issn = {2167-9223}, abstract = {OBJECTIVE: To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials.<br><br>METHODS: A targeted literature review was conducted to explore patient experience (stage 1) and COAs used in ALS research (stage 2). Abstracts were screened against predefined eligibility criteria; full-text articles were reviewed for eligible abstracts and relevant data were extracted. Face and content validity of the identified COAs were assessed.<br><br>RESULTS: Stage 1 searches identified 3,527 abstracts, of which 12 full-text articles, two summary reports, and one conference poster were included in this review. Twenty-five symptoms and 35 health-related quality of life (HRQoL) impacts were identified. Frequently reported symptoms included breathing and speech difficulties and muscle/limb weakness, each associated with a diverse range of impacts, including those related to emotional wellbeing, physical function, social and leisure activities, and activities of daily living. Stage 2 searches identified 119 COAs, of which 28 were reviewed. Many had acceptable face (13/28) and content validity (15/28), but 13 had not involved patients during development; only 10 were clearly worded and seven were lengthy, increasing patient burden risk.<br><br>CONCLUSIONS: This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.}, }
@article {pmid41428861, year = {2025}, author = {Soliman, R and Swelam, MS and Fahmy, N and Rashed, HR}, title = {Translation and validation of the Arabic version of the amyotrophic lateral sclerosis assessment questionnaire (ALSAQ40-AR).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2603311}, pmid = {41428861}, issn = {2167-9223}, abstract = {AIM: To validate Arabic version of the ALSAQ-40, (ALSAQ40-AR) and assess the QOL in a cohort of Egyptian patients with ALS.<br><br>METHODS: This is a prospective study. One hundred consecutive ALS patients were included from the Neuromuscular Unit, Ain Shams University Hospital, in the period from February 2022 to June 2024. Functional and cognitive assessments were done using the Arabic version of ALSFRS-R and ECAS-EG questionnaires, respectively. Disease stage was identified via Kings Clinical Staging. QOL was evaluated using the Arabic WHOQOL-BREF and an Arabic version of ALSAQ-40.<br><br>RESULTS: ALSAQ40-AR showed high internal consistency using Cronbach's alpha of >0.9, Inter-rater reliability was tested, values for all variables were compared, and no statistically significant differences were found (ICC = .997). Both WHOQOL-BREF and ALSAQ40-AR domains demonstrated significant correlation with each other and with ALSFRS-R (p-value < 0.0001), denoting construct validity. Moreover, ALSAQ40-AR domains correlated significantly with time since disease onset, and showed significant increase across disease stages (p-value < 0.0001). Ceiling and floor effects were analyzed in both QOL scales, but only WHOQOL-BREF showed ceiling and floor effects.<br><br>CONCLUSION: ALSAQ40-AR and the WHOQOL-BREF were reliable and valid tools to evaluate QOL in patients with ALS; we suggest that the validated ALSAQ40-AR is more suited for ALS patients because it is a disease specific questionnaire that showed higher internal consistency with no floor or ceiling effects. QOL in ALS was correlated with time since disease onset, disease stage, functional, and cognitive disabilities.}, }
@article {pmid41428942, year = {2025}, author = {Sannes, A and Rognli, EW and Hanssen-Bauer, K and Torp, NC and Storfossen, SK and Høstaker, MN and Aalberg, M}, title = {Barriers to and Facilitators of Implementation of Internet-Delivered Therapist-Guided Therapy in Child and Adolescent Mental Health Services: Systematic Review and Bayesian Meta-Analysis.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e83543}, pmid = {41428942}, issn = {1438-8871}, mesh = {Adolescent ; Child ; Humans ; *Adolescent Health Services ; Bayes Theorem ; *Child Health Services ; *Internet ; *Mental Health Services ; *Psychotherapy/methods ; }, abstract = {BACKGROUND: Internet-delivered therapist-guided therapy (e-therapy) represents a promising approach for enhancing accessibility, treatment fidelity, and scalability within child and adolescent mental health services (CAMHS).<br><br>OBJECTIVE: This systematic review aimed to (1) identify and synthesize determinants of implementation, specifically barriers to and facilitators of e-therapy in CAMHS structured according to the Consolidated Framework of Implementation Research (CFIR); and (2) provide pooled benchmark estimates of key implementation outcomes for fidelity, cost-effectiveness, and acceptability.<br><br>METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review was performed across PsycINFO, MEDLINE, Web of Science, CINAHL, Embase, Cochrane, and ProQuest Dissertations &amp; Thesis on June 6, 2025-to identify peer-reviewed studies assessing implementation outcomes or determinants of e-therapy in the context of outpatient CAMHS (ages 8-18 years). Barriers and facilitators were synthesized qualitatively with thematic analysis applying CFIR. A parallel quantitative synthesis of Proctor et al's taxonomy of implementation outcomes was performed using Bayesian multilevel random-effects meta-analyses to estimate pooled effect sizes and 95% credible intervals (CIs). By combining quantitative benchmarks of implementation success with qualitative insights into contextual determinants, the review provides an integrated understanding of what drives effective e-therapy implementation in CAMHS. Study quality was assessed using the CASP (Critical Appraisal Skills Programme) checklist, Cochrane Risk of Bias tool, and Risk Of Bias In Non-randomized Studies-of Interventions tool. Small study effects were evaluated using funnel plots, sensitivity analyses, and the Egger test.<br><br>RESULTS: From 50,026 screened reports, 50 studies published between 2007 and 2025 were included: 18 randomized controlled trials, 17 cohort, and 15 qualitative or mixed methods studies. Most studies originated from Western Europe (n=34), Northern America (n=11), and Oceania (n=5), targeting anxiety (n=24) and depression (n=9), through cognitive behavioral therapy-based programs (n=47), with parallel parent content (n=31). Therapist guidance was primarily asynchronous (n=43). Among the 39 studies reporting determinants, common barriers and facilitators were identified across intervention, organization, therapist, and patient domains, structured via CFIR. Pooled implementation outcomes showed modest dropout rates (~20%, CI 14%-27%), high module completion (~68%, CI 60%-75%), low therapist time (24 min per wk per patient, 95% CI 19-28), and high patient satisfaction (24/32 on Client Satisfaction Questionnaire-8, 95% CI 22-27; and 76% satisfaction rate, 95% CI 62%-87%), suggesting e-therapy is resource efficient and acceptable if implemented successfully.<br><br>CONCLUSIONS: This review provided the first integrated synthesis of pooled benchmarks for implementation outcomes of e-therapy in CAMHS and modifiable determinants to inform future service planning and scale-up. These findings highlighted service-level enablers, such as leadership anchoring, targeted use, technical stability, structured patient flow, and therapist training, that organizations could prioritize to strengthen sustainable e-therapy implementation in CAMHS.}, }
@article {pmid41428955, year = {2025}, author = {Jih, KY and Tsai, YS and Fang, SY and Hsu, FC and Sytwu, HP and Liao, YC and Tsai, PC and Lee, YC}, title = {SOD1 mutations in Taiwanese ALS patients: Clinical characteristics, frequency, and a p.T138R founder effect.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2604236}, pmid = {41428955}, issn = {2167-9223}, abstract = {OBJECTIVE: Mutations in SOD1 are a well-established genetic cause of amyotrophic lateral sclerosis (ALS), exerting toxic gain-of-function effects that promote protein misfolding and aggregation in motor neurons and glial cells. The emergence of SOD1-targeted antisense oligonucleotide therapy underscores the clinical importance of precise genetic diagnosis. This study aimed to determine the frequency, clinical characteristics, and potential founder effect of SOD1 mutations in a large Taiwanese ALS cohort, and to evaluate their aggregation propensity in vitro.<br><br>METHODS: All coding exons of SOD1 were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Haplotype analysis using single nucleotide polymorphism markers flanking SOD1 was conducted to assess a potential founder effect. Protein cross-linking assays were performed to assess the aggregation propensity of 11 SOD1 variants.<br><br>RESULTS: Seventeen pathogenic SOD1 variants were identified in 26 probands and 12 affected relatives. Mean age at onset was 48.9&#x2009;&#xb1;&#x2009;14.9&#x2009;years, and 8% had bulbar-onset ALS. The most frequent variant was p.T138R (8 probands), followed by p.G11A (3 probands). The other 15 variants each occurred in a single family. A shared ancestral haplotype was observed among p.T138R carriers. Cross-linking experiments demonstrated oligomer formation in all tested mutant SOD1 proteins compared to the wild-type protein, supporting their pathogenicity.<br><br>CONCLUSIONS: SOD1 mutations account for approximately 4% of ALS cases in Taiwan, are associated with earlier onset and predominantly spinal-onset ALS, and include a p.T138R founder variant. These findings highlight the importance of genetic screening in ALS, particularly in guiding eligibility for emerging targeted therapies.}, }
@article {pmid41429156, year = {2025}, author = {Gomes, MDM and Freitas, MRG}, title = {Jean-Martin Charcot at 200: revolutionizing neurology through a multidisciplinary lens.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {11}, pages = {1-5}, pmid = {41429156}, issn = {1678-4227}, mesh = {History, 19th Century ; *Neurology/history ; Humans ; }, abstract = {As we near the bicentenary of his birth, Jean-Martin Charcot (1825-1893) is remembered not only as the founder of modern neurology but also as a uomo universale. His multidisciplinary approach transcended 19[th]-century medicine, establishing neurology as a distinct discipline while integrating art, psychology, and philosophy into his study of the nervous system. His work laid foundations for neurodegenerative diseases (amyotrophic lateral sclerosis [ALS], Parkinson's disease, multiple sclerosis [MS]), functional neurological disorders (FNDs), and psychoanalysis, foreshadowing neuroplasticity and the mind-body connection. His innovative teaching at Salpêtrière-merging anatomy with artistic documentation-revolutionized medical education, inspiring figures from Freud to modern neuroscientists. Two centuries later, Charcot's legacy endures not just in eponyms but in his unifying vision of brain, mind, and art - a timeless model for interdisciplinary medicine. The present paper explores his impact on neurodegenerative research, functional disorders, medical pedagogy, and the humanities.}, }
@article {pmid41429969, year = {2025}, author = {Caimi, E and Vaccari, S and Vinci, V}, title = {Comment to "Artificial Intelligence (AI)-Assisted Patient Education and Concerns Following Facelift Surgery: A Study on ChatGPT-4 and Gemini".}, journal = {Aesthetic plastic surgery}, volume = {}, number = {}, pages = {}, pmid = {41429969}, issn = {1432-5241}, abstract = {INTRODUCTION: Artificial intelligence (AI) is increasingly integrated into patient education and postoperative care. Almousa et al. recently evaluated ChatGPT-4 and Gemini for postoperative facelift counseling, reporting high accuracy and clarity. While their study represents an important step toward AI-assisted communication in aesthetic surgery, several methodological issues may limit the validity and clinical applicability of their findings.<br><br>METHODS: We critically appraised Almousa et al.'s study design, data collection, and analytic methods. Specific attention was given to question selection, evaluation metrics, reproducibility, and statistical robustness, comparing them with established standards for AI evaluation and inter-rater reliability.<br><br>RESULTS: The study used ChatGPT-4 itself to generate the five "most common" postoperative questions, introducing circularity and potential selection bias. Responses were assessed on a dichotomous (Yes/No) scale by five surgeons, without reporting inter-rater reliability or use of scaled metrics. It was unclear whether prompts were entered sequentially or independently, raising reproducibility concerns. The limited sample size (five questions per model) provided only 25 binary data points per system, precluding meaningful statistical inference. Furthermore, AI responses lacked individualized safety guidance and escalation advice, limiting clinical safety in real-world postoperative settings.<br><br>CONCLUSION: Although the study highlights the promise of LLMs in aesthetic surgery, future studies should employ patient-derived question sets, graded and reproducible evaluation scales, transparent prompt protocols, and inclusion of complication-related queries to accurately determine the safety and educational value of AI-generated postoperative information.<br><br>LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.}, }
@article {pmid41430073, year = {2025}, author = {Fava, VM and Perico, J and Orlova, M and Dallmann-Sauer, M and Xu, YZ and Thuc, NV and Thai, VH and Belone, AF and Latini, ACP and Schurr, E}, title = {Bridging pleiotropic mechanisms in leprosy type-1 reactions and neurodegenerative diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {45036}, pmid = {41430073}, issn = {2045-2322}, support = {FP 22/9//Leprosy Research Initiative/ ; }, mesh = {Humans ; *Leprosy/genetics/complications/pathology ; *Parkinson Disease/genetics ; *Neurodegenerative Diseases/genetics ; Male ; Genetic Predisposition to Disease ; Female ; Protein Kinases/genetics ; Middle Aged ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Ubiquitin-Protein Ligases/genetics ; *Genetic Pleiotropy ; PTEN-Induced Putative Kinase ; }, abstract = {Leprosy is an infectious disease of the skin and peripheral nervous system. Sudden episodes of hyperinflammation, known as Type 1 Reactions (T1R), are a main contributor to permanent nerve damage in leprosy. The genetic component associated with the neuro-inflammatory phenotype of T1R displays pleiotropic effects with Parkinson's disease (PD). In this study, we explored the genetic overlap between PD and T1R and expanded the evaluation of pleiotropic effects between T1R and other neurodegenerative disorders. We replicated the association of PD-linked rare variants in PRKN with T1R in Vietnamese leprosy patients. Analysis of 24 PD associated-genes revealed compound effects between rare protein-altering variants and T1R in the interacting genes PRKN/PINK1 (P = 2.7[-05]; OR = 4.0) and a combination of rare/low frequency variants in the LRRK2/GAK pair (P = 6.7[-05]; OR = 0.54). These findings validated a genetic overlap between T1R and PD with two distinct axes, one of shared risk via PRKN/PINK1 and a second of antagonistic pleiotropic via LRRK2/GAK. When testing an additional 94 genes associated with neurodegenerative diseases we identified variants in the amyotrophic lateral sclerosis disease-linked gene TBK1 associated with T1R (P = 0.004; OR = 12.9). Our results highlight shared biological processes between leprosy and neurodegenerative diseases, which may indicate candidate drugs for repurposing to improve T1R management.}, }
@article {pmid41430470, year = {2026}, author = {Piol, D and Khalil, B and Robberechts, T and Killian, T and Georgopoulou, M and Partel, G and Wouters, D and Hecker, N and Tziortzouda, P and Verresen, Y and Corthout, N and Kint, S and Vandereyken, K and Van Damme, P and Voet, T and Davie, K and Poovathingal, S and Van Den Bosch, L and Aerts, S and Sifrim, A and Da Cruz, S}, title = {Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.}, journal = {Nature neuroscience}, volume = {29}, number = {1}, pages = {53-66}, pmid = {41430470}, issn = {1546-1726}, support = {962700//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 1060285//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; Eukaryotic Translation Initiation Factor 5A ; *Axons/metabolism ; *Peptide Initiation Factors/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Motor Neurons/metabolism ; *Protein Biosynthesis/physiology ; Drosophila ; Mutation/genetics ; Mice, Transgenic ; }, abstract = {Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.}, }
@article {pmid41431371, year = {2025}, author = {Dobbertin, T and Schirmer, L}, title = {Spatially Resolved Profiling of Compartmentalized Muscle and Brain Inflammation.}, journal = {European journal of immunology}, volume = {55}, number = {12}, pages = {e70119}, pmid = {41431371}, issn = {1521-4141}, support = {P1180016//Gemeinn&#xfc;tzige Hertie-Stiftung/ ; GRK2727(InCheck)//Deutsche Forschungsgemeinschaft/ ; FOR2690(SCHI1330/7-2)//Deutsche Forschungsgemeinschaft/ ; SPP2395(SCHI1330/10-1)//Deutsche Forschungsgemeinschaft/ ; FOR5705(SCHI1330/13-1)//Deutsche Forschungsgemeinschaft/ ; SCHI1330/2-1//Deutsche Forschungsgemeinschaft/ ; SCHI1330/4-1//Deutsche Forschungsgemeinschaft/ ; SCHI1330/11-1//Deutsche Forschungsgemeinschaft/ ; 950584//H2020 European Research Council/ ; }, mesh = {Humans ; Animals ; *Muscle, Skeletal/immunology/pathology/metabolism ; Proteomics/methods ; *Brain/immunology/pathology ; Inflammation/immunology ; *Neuroinflammatory Diseases/immunology ; *Encephalitis/immunology ; Transcriptome ; }, abstract = {Spatial omics technologies enable high-resolution mapping of transcriptomic, proteomic, and metabolic profiles within intact tissues, revealing how immune, stromal, and parenchymal cells interact in situ during inflammation. Chronic inflammation in skeletal muscle and the central nervous system is spatially organized within defined niches that shape disease progression and therapeutic response. In skeletal muscle, spatial analyses have uncovered fiber-type-specific vulnerability, regenerative trajectories, and immune-stromal crosstalk in disorders such as Duchenne muscular dystrophy and inclusion body myositis. In the central nervous system, these approaches have revealed compartmentalized neuroinflammation in multiple sclerosis, innate immune activation in amyotrophic lateral sclerosis, and immune evasion in glioma. Integration with single-cell gene expression enables inference of cell-cell communication networks and identification of spatial gradients of immune activation and tissue remodeling. Despite major advances, clinical translation remains limited by small cohorts, methodological variability, and insufficient functional validation. As spatial profiling becomes more accessible, standardized, and scalable, it promises to stratify inflammatory disease states, identify tissue-resident immune programs, and guide mechanism-based therapies. Hence, spatial omics provide an unprecedented opportunity to resolve the cellular architecture of inflammation, revealing not only where immune activity occurs, but how it is orchestrated within complex tissue microenvironments.}, }
@article {pmid41431415, year = {2026}, author = {Cho, W and Lee, SY and Yoo, SH and Cho, B and Kim, KH and Hwang, IY}, title = {Home Healthcare Needs and Characteristics of Patients with Serious Illnesses Who Use Hospital-Affiliated Home-Based Medical Care in Korea.}, journal = {Yonsei medical journal}, volume = {67}, number = {1}, pages = {62-70}, pmid = {41431415}, issn = {1976-2437}, support = {RS-2021-KH120239//Patient-Centered Clinical Research Coordinating Center/Korea ; }, mesh = {Humans ; Male ; Female ; Republic of Korea ; Aged ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; Emergency Service, Hospital/statistics &amp; numerical data ; *Home Care Services/statistics &amp; numerical data ; *Health Services Needs and Demand ; *Home Care Services, Hospital-Based/statistics &amp; numerical data ; Neoplasms/therapy ; }, abstract = {PURPOSE: The number of homebound adults with serious illnesses is increasing. This study aimed to examine the healthcare needs and characteristics of patients who use a hospital-affiliated physician-led home-based medical care (HBMC) program and identify factors associated with emergency department (ED) visits in Korea.<br><br>MATERIALS AND METHODS: This retrospective observational study included patients who used a HBMC program at a tertiary hospital between 2020 and 2023. Patient characteristics and home healthcare needs were analyzed by disease category: cancer, advanced neurologic disease, and others. Multivariable logistic regression analysis was used to identify factors associated with ED visits within 30 days of a physician's home visit.<br><br>RESULTS: A total of 600 patients were registered and received home visits; 58.5% had cancer and 29.7% had advanced neurologic diseases, e.g., amyotrophic lateral sclerosis. The median age was 72 years [interquartile range (IQR), 62.8-81.0], and 87.0% were dependent in daily activities. The median number of medications per patient was 6 (IQR, 3-10); 66.3% took &#x2265;5 medications and 25.7% took &#x2265;10 (excessive polypharmacy). Physicians provided not only physical examinations (100%) and symptom assessment (90.8%), but also home environment evaluation (86.7%), medical device management (62.0%), advanced care planning (40.7%), and acute health issue management (32.5%). Within 30 days, 19.2% of patients visited the ED. Excessive polypharmacy and cancer diagnosis were associated with increased ED visits.<br><br>CONCLUSION: Most patients who used the hospital-affiliated HBMC program had cancer, advanced neurologic disease, and polypharmacy. Targeted HBMC programs are needed for patients with serious illnesses living at home.}, }
@article {pmid41432316, year = {2026}, author = {Genge, A and Rothstein, J and De Silva, S and Zinman, L and Chum, M and Chiò, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Hirai, M and Sasson, N and Takahashi, F and Cecić, M and Wamil, A and Apple, S}, title = {Phase 3b Extension Study MT-1186-A04 to Evaluate the Continued Efficacy and Safety of Edaravone Oral Suspension for Up to an Additional 48 Weeks in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {73}, number = {4}, pages = {534-543}, pmid = {41432316}, issn = {1097-4598}, support = {//Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration &amp; dosage/therapeutic use ; Male ; Middle Aged ; Double-Blind Method ; Female ; Aged ; Treatment Outcome ; Administration, Oral ; *Free Radical Scavengers/administration &amp; dosage/therapeutic use/adverse effects ; Adult ; Suspensions ; *Antipyrine/analogs &amp; derivatives/administration &amp; dosage/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is currently approved in the US for treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed that IV edaravone slows physical functional decline. Study MT-1186-A04 continued to examine the efficacy and safety of investigational once daily and approved on/off dosing of edaravone oral suspension in patients with ALS.<br><br>METHODS: Study MT-1186-A04 (NCT05151471) was a phase 3b, multicenter, randomized, double-blind, parallel group extension study for up to an additional 48&#x2009;weeks following 48-week Study MT-1186-A02 that randomized patients to investigational once daily or approved 105-mg on/off dosing of edaravone oral suspension. Patients who met Study MT-1186-A04 eligibility criteria, including Study MT-1186-A02 completion, continued in the same treatment regimen as Study MT-1186-A02. The primary efficacy endpoint for MT-1186-A04 was time from randomization in Study MT-1186-A02 to a &#x2265;&#x2009;12-point decrease in ALS Functional Rating Scale-Revised (ALSFRS-R) or death, whichever happened first.<br><br>RESULTS: Over 96&#x2009;weeks, including Study MT-1186-A02, daily dosing did not show a statistically significant difference vs. approved on/off dosing for the primary endpoint (p&#x2009;=&#x2009;0.78). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.<br><br>DISCUSSION: Similar to Study MT-1186-A02, once daily edaravone oral suspension in extension Study MT-1186-A04 did not show superiority in terms of the primary efficacy endpoint, but had equivalent efficacy, safety, and tolerability, compared with the approved On/Off regimen. The results reinforce the appropriateness of the approved dosing regimen.}, }
@article {pmid41432752, year = {2025}, author = {Więcławski, W and Paszulewicz, J}, title = {ERP evidence of attentional selection outside of effective oculomotor range.}, journal = {Experimental brain research}, volume = {244}, number = {1}, pages = {16}, pmid = {41432752}, issn = {1432-1106}, support = {2016/21/N/HS6/02771//Narodowe Centrum Nauki/ ; }, abstract = {UNLABELLED: The close link between visual attention and the oculomotor system is well documented. Within the selection-for-action framework, two perspectives exist. According to Visual Attention Model (VAM) attention is seen as a prerequisite for successful movement execution, though it is considered a distinct cognitive and neural process. By contrast, the premotor theory of attention (PMTA) argues that the beneficial effects of attention are fully accounted for by the system’s preparation for saccadic eye movements. From this standpoint, a central prediction emerges: attentional advantages should be confined to regions within the oculomotor range, since saccadic planning is not feasible outside those limits. A common way to examine this prediction is to present cues and targets in a hemifield beyond the oculomotor range, typically achieved by occluding one eye while abducting the other. Using this method, Smith et al. showed that in a visual search task, exogenous orienting is reduced in the temporal hemifield when the eye is abducted. They concluded that exogenous attentional orienting is constrained by the range of potential saccadic movements. In our study, we sought to replicate Smith et al.’s findings while extending the paradigm with EEG recordings—an approach not yet applied in this context. PMTA predicts that, under eye abduction, stimuli appearing in the temporal hemifield would yield diminished N2pc amplitudes. An ANOVA revealed no reduction of N2pc amplitude in the temporal hemifield. Taken together, our results support the growing body of evidence suggesting that visual attention is not strictly bound to the oculomotor range.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00221-025-07219-0.}, }
@article {pmid41436842, year = {2025}, author = {Mao, H and Matsubara, T and Tanaka, N and Peled, N and Farzaneh, H and Melania Lon, D and Suzuki, N and Richardson, RM and Cole, AJ and Fang, X and Stufflebeam, SM}, title = {Transcriptomic decoding of regional cortical vulnerability to drug-resistant epilepsy using 7T MRI.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {121}, pmid = {41436842}, issn = {2399-3642}, support = {P41 EB015896/EB/NIBIB NIH HHS/United States ; P41 EB030006/EB/NIBIB NIH HHS/United States ; S10 OD023637/OD/NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Female ; Male ; *Drug Resistant Epilepsy/genetics/diagnostic imaging/physiopathology ; Adult ; *Transcriptome ; *Cerebral Cortex/diagnostic imaging/physiopathology/metabolism ; Young Adult ; Case-Control Studies ; Adolescent ; Gene Expression Profiling ; Middle Aged ; }, abstract = {The mechanism by which genetic risk leads to cortical vulnerability in drug-resistant epilepsy (DRE) remains unclear. This study used 7T structural and resting-state functional MRI to investigate cortical neural activity alterations in 105 DRE patients and 105 healthy controls (HCs), and to explore related genetic mechanisms. Vertex-wise analyses of mean amplitude of low-frequency fluctuation (mALFF) and regional homogeneity (ReHo) revealed that DRE patients primarily exhibited decreased mALFF and increased ReHo in the Cingulo-Opercular Network. Using the Allen Human Brain Atlas, we conducted spatial transcriptomic analysis via partial least squares (PLS) and gene enrichment analysis to identify gene categories associated with these functional changes. The results showed that cortical alterations were related to epilepsy-general genes (e.g., TMEM74, KCNN2, RBFOX1) and brain-relevant genes. Genes positively correlated with mALFF alterations enriched in mitochondrial inner membrane, matrix, and carboxylic acid metabolism; negatively in chromatin remodeling, binding, and postsynapse. Genes positively correlated with ReHo alterations enriched in nucleic acid-related catalytic activity, ribonucleoprotein granule, and centrosome; negatively in amyotrophic lateral sclerosis, mitochondrial membrane, and pyrophosphatase activity. These findings link spatial brain activity abnormalities in DRE to specific genetic signatures and biological pathways, suggesting new mechanistic insights and potential therapeutic targets for this difficult-to-treat condition.}, }
@article {pmid41437053, year = {2025}, author = {Su, WM and Duan, QQ and He, SY and Liu, RY and Wen, XJ and Zhang, N and Chen, T and Cao, B and Chen, YP}, title = {Loss of Y chromosome and its implications in male amyotrophic lateral sclerosis: insights from the UK Biobank.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {48}, pmid = {41437053}, issn = {1741-7015}, support = {no. 82371422 and no. 81971188//the National Natural Science Fund of China/ ; no. 2022YFC2703101//the National Key Research and Development Program of China/ ; no. 2023HXFH032//the 1&#xb7;3&#xb7;5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/mortality ; Male ; United Kingdom/epidemiology ; Middle Aged ; *Chromosomes, Human, Y/genetics ; Biological Specimen Banks ; Aged ; Adult ; Prognosis ; UK Biobank ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows a male predominance, yet the underlying mechanism remains unclear. Although the loss of Y chromosome (LOY) in peripheral blood - a male-specific genetic alteration - has been implicated in certain neurodegenerative disorders (NDDs), its association with ALS in men remains unexplored and has not been explored.<br><br>METHODS: We focused on men in the UK Biobank to investigate whether LOY influences the risk and prognosis of ALS. Initially, the LOY level for each male participant was determined using sequencing data. Subsequently, Cox proportional hazards (Cox PH) model analysis was used to assess LOY-associated risk of ALS; thirdly, piecewise linear regression, Kaplan-Meier, and Cox PH analysis assessed LOY's associations with ALS age at onset (AAO) and survival. Fourthly, multiple analytical methods were implemented to explore the relationship between LOY and ALS indicators, including plasma GFAP (glial fibrillary acidic protein) and NfL (neurofilament light chain). Finally, sensitivity analysis was carried out.<br><br>RESULTS: Our final cohort consisted of 158,953 male participants, with a mean follow-up of 11.7&#xa0;years. Among them, 297 individuals developed ALS. After adjusted multiple confounding factors, including C9orf72 hexanucleotide repeat expansion (HRE), male participants with LOY exhibited an elevated risk of developing ALS (HR [95% CI]: 1.619 [1.059-2.475], p&#x2009;=&#x2009;0.026). LOY carrier may be more likely to be associated with a later AAO and shorter survival; however, this association did not reach statistical significance in multivariate models. Additionally, our findings revealed that LOY was significantly associated with elevated plasma NfL levels (p&#x2009;=&#x2009;0.004). Moreover, the median Log2 R ratios of Y chromosome (mLRRY value) exhibited a modest inverse correlation with plasma GFAP levels (Pearson's r&#x2009;= -&#x2009;0.059). Nevertheless, LOY did not exert an influence on the longitudinal trends of NfL and GFAP and was not clearly associated with C9orf72 HRE status.<br><br>CONCLUSIONS: Our results indicate that LOY makes a potential contribution to the risk of ALS and the elevation of plasma NfL levels. While LOY's impact on ALS AAO and survival requires further validation, these findings identify it as a promising sex&#x2011;specific therapeutic target and support its potential for stratifying male ALS patients toward personalized treatments.}, }
@article {pmid41437896, year = {2025}, author = {Lona-Durazo, F and Byrne, RP and Pilon, MO and Greicius, MD and Dubé, MP and Belloy, ME and McLaughlin, RL and Gagliano Taliun, SA}, title = {Sex-aware causal inference assessment of the immune system in complex neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf474}, pmid = {41437896}, issn = {1460-2156}, abstract = {Sex differences, in terms of prevalence, symptoms and disease progression, are established in the etiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence, through genetic and functional analyses, affirming the role of the immune system in such diseases, but a thorough assessment of sex differences linking the immune system and neurodegenerative diseases is understudied. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10,895 cases, 57,062 controls; males = 15,547 cases, 50,145 controls), Parkinson's disease (females = 7,947 cases, 90,662 controls; males = 13,020 cases, 89,660 controls) and Alzheimer's disease (females = 18,822 cases, 281,415 controls; males = 17,293 cases, 213,339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (FDR cutoff < 0.01) from a large sex-combined plasma protein dataset (N = 33,477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (N = 971) as exposures. We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson's disease, and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer's disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson's disease and of GRN, SERPINF2 and TREM2 on Alzheimer's disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson's disease and of CD33 on Alzheimer's disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases. Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer's disease and Parkinson's disease, some of which may be considered as potential candidates for drug development.}, }
@article {pmid41437944, year = {2026}, author = {Tannemann, N and Tsarenko, O and Herbstreit, F and Gestmann, M and Brenner, T and Szalai, C}, title = {Enhancing theoretical BLS knowledge with virtual reality: a randomized controlled trial in medical students.}, journal = {Resuscitation plus}, volume = {27}, number = {}, pages = {101169}, pmid = {41437944}, issn = {2666-5204}, abstract = {BACKGROUND: High-quality cardiopulmonary resuscitation (CPR) training, including both technical and non-technical skills, is essential for medical students. Virtual reality (VR) offers immersive learning environments that may enhance traditional teaching methods. This study investigates the impact of a single VR session prior to an Advanced Life Support (ALS) course on knowledge and performance of basic life support skills among medical students.<br><br>METHODS: In this single blind randomized controlled trial, 126 fourth-year medical students with prior Basic Life Support (BLS) training were assigned to either an intervention group (n&#xa0;=&#xa0;66) with an additional 3-part immersive VR session covering BLS theory and practice or a control group (n&#xa0;=&#xa0;60) receiving standard preparation. All participants underwent a seminar based on advanced life support principles as dictated by the European Resuscitation Council (ERC) and International Liaison Committee on Resuscitation (ILCOR) guidelines. Theoretical knowledge was assessed via multiple-choice questionnaires at three time points (baseline, post-course, 12&#xa0;weeks later). Practical skills were evaluated through an Objective Structured Clinical Examination (OSCE). Data were analyzed using Wilcoxon tests, repeated-measures ANOVA, and linear mixed models. Student evaluations were used to gauge subjective satisfaction with the scenario during teaching.<br><br>RESULTS: No significant differences were observed between groups at baseline. The intervention group demonstrated significantly greater gains in knowledge at both post-course (p&#xa0;<&#xa0;0.01) and follow-up (p&#xa0;=&#xa0;0.04). However, no significant differences were found in OSCE performance. The VR group's improvement over time was significantly higher, suggesting a positive effect of VR on knowledge retention. Students were satisfied with the addition of a VR scenario in the teaching format.<br><br>CONCLUSION: A single VR session prior to ALS training enhanced theoretical knowledge but did not significantly affect practical performance. Students were open to integration of the technology into training, so that VR may serve as a valuable adjunct in CPR education. Further research is needed to evaluate its long-term impact and the optimal integration method into curricula.}, }
@article {pmid41438236, year = {2025}, author = {Li, T and Gao, Y and Zhou, J and Chen, Y and Zhang, S and Gong, X and Liu, Y}, title = {Advancements in the application of brain-computer interfaces based on different paradigms in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1658315}, pmid = {41438236}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological condition that leads to the gradual loss of movement and communicative abilities, significantly diminishing the quality of life for affected individuals. Recent advancements in neuroscience and engineering have propelled the swift evolution of brain-computer interfaces (BCIs), which are now extensively utilised in medical rehabilitation, military applications, assistive technologies, and various other domains. As a communication medium facilitating direct interaction between the brain and the external world independent of the peripheral nervous system, BCI provides ALS patients with an innovative method for communication and control, offering unparalleled prospects for improving their quality of life. Recent collaborative endeavours among several specialists have markedly enhanced the precision and velocity of diverse BCI paradigms, signifying a breakthrough in BCI applications for ALS. Nonetheless, obstacles and constraints remain. This study methodically extracted pertinent literature from the Web of Science and PubMed databases in accordance with PRISMA guidelines. Following stringent inclusion and exclusion criteria, 23 studies were identified. This data allows us to summarise the application results and current limitations of several BCI paradigms in motor control and communication, while delineating prospects in multimodal fusion and adaptive calibration. This review presents evidence-based references for the effective translation and application of BCI technology in ALS rehabilitation.}, }
@article {pmid41438688, year = {2026}, author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H}, title = {In vitro 3D models of neuron-astrocyte interactions.}, journal = {Biochemistry and biophysics reports}, volume = {45}, number = {}, pages = {102400}, pmid = {41438688}, issn = {2405-5808}, abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.}, }
@article {pmid41439884, year = {2025}, author = {Di Gregorio, R}, title = {A Novel Single-Loop Mechanism for Neck Rehabilitation.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {41439884}, issn = {2313-7673}, support = {FAR 2023//University of Ferrara/ ; }, abstract = {Trauma, amyotrophic lateral sclerosis (ALS), and head and neck cancer (HNC), which cause neck pain, are only some of the possible issues requiring suitable therapy for alleviating or even healing the neck dysfunctions they cause. Static and dynamic neck braces are commonly employed in therapies for neck recovery and in the necessary measurements to quantify neck impairment or to set up a suitable therapy. Serial and parallel mechanisms, among others, have been proposed for neck braces. Here, a novel single-loop spherical mechanism is proposed for a possible neck brace. Its kinematics and mobility analyses are presented with reference to their specific applications in a neck brace. Then, dimensional synthesis with a set of neck brace's kinematic requirements is addressed to compute the geometric constants that guarantee an orientation workspace similar to that of the human neck. The presented analyses and syntheses show that the new proposal is effective and can alleviate some concerns about already-proposed mechanisms for neck braces.}, }
@article {pmid41440030, year = {2025}, author = {Su, J and Alaiz Noya, J and Lingappa, AF and Solas, D and Tong, J and Daughrity, L and Castanedes-Casey, M and Kurti, A and Dickson, DW and Lingappa, VR and Petrucelli, L and Zhang, Y}, title = {Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD.}, journal = {Cells}, volume = {14}, number = {24}, pages = {}, pmid = {41440030}, issn = {2073-4409}, support = {ADSF-24-1284327-C//Alzheimer's Disease Strategic Fund grant/ ; NA//Robert Packard Center for ALS Research at Johns Hopkins/ ; NA//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; NA//BrightFocus Foundation/ ; NA//Target ALS Foundation/ ; U19 AG063911/AG/NIA NIH HHS/United States ; NA//Cure Alzheimer's Fund/ ; NA//Kissick Family Foundation/ ; U54NS123743, R35 NS137447, P01NS084974, R01NS132330 and R01NS117461//National Institutes of Health/National Institute of Neurological Disorders and Stroke/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; NA//Association for Frontotemporal Degeneration Biomarkers Initiative/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; 5P30AG0062677, ALLFTD U19AG063911, R01AG089380 and R01AG085307//National Institutes of Health/National Institute on Aging/ ; R01 AG085307/AG/NIA NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; Disease Models, Animal ; *Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism ; Mice ; Humans ; Male ; Mice, Transgenic ; Drug Evaluation, Preclinical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.}, }
@article {pmid41440090, year = {2025}, author = {Martucci, G and Bonilauri, SC and Canalini, A and Baraldi, M and Costantini, L and Mora, F and Vacondio, P}, title = {Integrating Neurology, Palliative Care and Emergency Services in ALS: A Community-Integrated Neuropalliative Pathway in Modena, Italy.}, journal = {Brain sciences}, volume = {15}, number = {12}, pages = {}, pmid = {41440090}, issn = {2076-3425}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes severe motor, respiratory and communication impairment and imposes a high psychosocial burden on patients and families. Recent evidence shows that integrated neuropalliative care-early collaboration between neurology and palliative services with community support-improves quality of life and reduces avoidable hospitalisations. Yet there are few descriptions of how such integration is operationalised.<br><br>OBJECTIVE: This study examines a Community-Integrated Neuropalliative Pathway (CINP) implemented in the province of Modena (Emilia-Romagna, Italy), analysing how neurology, palliative care and emergency services collaborate to provide continuous, person-centred care for people with ALS.<br><br>METHODS: A single, holistic case study was conducted following Yin's analytical approach. Data sources included ten semi-structured interviews with neurologists, palliative physicians, nurses, home-care professionals and emergency clinicians; ethnographic observations in the ALS outpatient clinic; relevant organisational documents (the regional Clinical Pathway on ALS); and aggregated quantitative data from the palliative care registry (January 2023-December 2024). Thematic analysis with investigator triangulation was used to explore care integration, advance care planning and emergency coordination. Quantitative data were summarised descriptively.<br><br>RESULTS: Three interrelated themes were identified: (1) Progressive and flexible integration between neurology and palliative care. Neurologists remained longitudinal reference points while palliative teams were activated in response to evolving needs and became more relevant with the progression of the disease. Regular multidisciplinary meetings and shared discharge planning facilitated coordination. (2) The shared culture of advance care planning. Professionals framed advance care planning (ACP) as a relational, iterative process anchored in therapeutic relationships. Shared care plans, once completed, triggered an electronic Emergency Warning ("warning 118") procedure that notified the emergency service of patient preferences. (3) The integration of palliative and emergency services. The warning system enabled emergency clinicians to respect care plans and avoid aggressive interventions during crises. Quantitative data on 47 ALS patients followed by territorial palliative services showed that 16 had an active Emergency Warning flag; among these, most died at home or in a hospice rather than in hospital.<br><br>CONCLUSIONS: The Modena CINP exemplifies how a public health system can operationalise early neuropalliative integration and connect hospital, community and emergency services. The qualitative findings illustrate the cultural and organisational shifts required for continuous care, while the quantitative data show that the system is correctly used and that patients with the Emergency Warning activation died mostly at home or in a hospice. Lessons from this analytical case study can inform the development of similar pathways in other regions, although further research is needed to assess outcomes in larger populations and such models need to be adapted to local contexts.}, }
@article {pmid41441345, year = {2025}, author = {Endo, K and Kubota, K and Karino, K and Sato, R and Miura, S and Ueda, Y and Iwashita, Y}, title = {Setting the Next Vital Sign Observation Interval as a Learning Objective in Simulation-Based Nursing Education: A Prospective Exploratory Observational Study.}, journal = {Nursing reports (Pavia, Italy)}, volume = {15}, number = {12}, pages = {}, pmid = {41441345}, issn = {2039-4403}, abstract = {Background/Objectives: Abnormal vital signs often precede in-hospital clinical deterioration, but little is known about how nurses decide when to recheck vital signs. We examined how nurse characteristics relate to the next vital sign observation interval after detecting abnormal values and how this decision could be used as a learning objective in simulation-based education. Methods: In this prospective exploratory observational study at a university hospital in Japan, twenty-seven nurses used a full-body patient simulator across three scenarios: normal, low-urgency, and moderate-risk (moderately abnormal vital signs according to National Early Warning Score 2 [NEWS2] risk bands). After each assessment, participants specified in hours the interval they considered appropriate for the next vital sign observation. Nurse characteristics included years of clinical experience, advanced life support (ALS) training, and prior experiences recognizing or responding to deterioration. Mann-Whitney U tests and multiple regression were used to explore univariate and adjusted associations. Results: In the low-urgency scenario, ALS training was associated with shorter intervals (median 1 h vs. 3 h; p = 0.04). In the moderate-risk scenario, univariate analyses showed shorter intervals among nurses with greater experience and among those with ALS training (both p < 0.01). In adjusted models for the moderate-risk scenario, years of experience and prior experiences of recognizing and responding to deterioration were independently associated with shorter intervals (all p < 0.05), whereas ALS training was not. Conclusions: The decision to shorten observation intervals appears to reflect experiential aspects of clinical judgment. Integrating "setting the next observation interval" as an explicit learning objective in simulation may help strengthen nurses' clinical judgment for early recognition of deterioration. As an exploratory, single-center study with a small sample and fixed scenario order, these findings should be interpreted cautiously and used to guide larger confirmatory studies and curricular design. This study was not registered.}, }
@article {pmid41442833, year = {2026}, author = {Zhong, Q and Wang, X and Xu, Y and Wang, R and Zhou, M and Liu, X}, title = {Response to "Constructive appraisal of Zhong et al.'s study on Mycobacterium tuberculosis dormant antigens and PB2-DIMQ vaccine: Opportunities for translational strengthening".}, journal = {Tuberculosis (Edinburgh, Scotland)}, volume = {156}, number = {}, pages = {102723}, doi = {10.1016/j.tube.2025.102723}, pmid = {41442833}, issn = {1873-281X}, }
@article {pmid41444821, year = {2025}, author = {Safkhani, M and Ghorbani Fard, M}, title = {Two secure authentication protocols for mitigating vulnerabilities in IoD.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3132}, pmid = {41444821}, issn = {2045-2322}, support = {1404/385773//Shahid Rajaee Teacher Training University/ ; }, abstract = {The Internet of Drones (IoD) is a network layer control system that manages the communication of Unmanned Aerial Vehicles (UAVs). Drones have emerged as a novel approach to addressing everyday human challenges and are now used in a variety of domains, such as personal activities (e.g., photography and videography), urban applications (e.g., traffic monitoring and structural inspection), commercial operations (e.g., power line and tower inspection), agriculture, and military operations. Given the rapid growth of UAVs and their expanding applications, interconnecting drones to form an IoD is a desirable trend for enhancing flight safety and quality. However, challenges related to security, privacy, and inter-drone communication remain significant obstacles. Numerous authentication protocols have been developed to address these concerns. Recently, Zhang et al. proposed a PUF-based authentication scheme that uses unique identifiers and hash functions to secure authentication in the IoD environment. However, in this paper, we demonstrate that Zhang et al.'s scheme is vulnerable to several attacks, including secret value disclosure, integrity violation, key extraction, traceability, and anonymity violation. The presented attacks are shown to have a success probability of one. We also introduce two enhanced protocols that, through both informal and formal security proofs using the Scyther tool, demonstrate that they do not suffer from the vulnerabilities found in the earlier protocol. The communication costs of the proposed protocols (a) and (b) have increased by [Formula: see text] and [Formula: see text], respectively, compared to the previous protocol. The computational costs for the proposed protocols (a) and (b) have also increased by [Formula: see text] and [Formula: see text], respectively, while the storage costs in both proposed protocols remain unchanged compared to the previous protocol. It is true that the costs in the proposed protocols have risen; however, the previous design was vulnerable to various attacks, whereas the proposed protocols have demonstrated better security and have successfully achieved all their security objectives.}, }
@article {pmid41446138, year = {2025}, author = {Ozguney, B and Puterbaugh, RZ and Viswanathan, R and Shenoy, J and Mohanty, P and Mittal, J and Fawzi, NL}, title = {Site-specific methionine oxidation alters structure and phase separation of TDP-43 C-terminal domain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446138}, issn = {2692-8205}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA binding protein 43 (TDP-43), a key protein linked to ALS pathology, undergoes phase separation and forms functional assemblies via condensation within cells. The conserved region (CR) within its C-terminal domain (CTD) mediates self-assembly through helix-helix interactions, while the flanking intrinsically disordered regions (IDRs) contribute to phase separation through transient interactions involving aromatic and hydrophobic residues. The CTD contains ten methionine residues distributed equally between these regions, making it particularly susceptible to oxidative modifications. While methionine oxidation is known to impair phase separation, neither the precise mechanism nor the specific contribution of methionines in the CR compared to the IDRs has been determined. Here, we combine NMR spectroscopy and all-atom molecular dynamics (MD) simulations to reveal if and how methionine oxidation in each region differentially affects CTD structure and phase separation. We demonstrate that all methionine residues are vulnerable to oxidation, leading to distinct regional effects: oxidation of CR methionines disrupts helical structure and directly impairs intermolecular helical association, while oxidation of IDR methionines disrupts long-range contacts. Hence, oxidation of methionines in both regions contributes to impaired phase separation, albeit through different mechanisms. These findings establish methionines as critical redox-sensitive modulators of TDP-43 phase behavior and provide molecular insights into how oxidative stress may contribute to TDP-43 dysregulation in neurodegenerative diseases.}, }
@article {pmid41449086, year = {2025}, author = {Jankowiak, T and Cholewiński, M and Kryściak, K and Krok, E and Grycz, K and Bączyk, M}, title = {Increase in Ia Afferent Synaptic Excitation of SOD1 G93A Mouse Motoneurons by 2-Week Anodal Trans-Spinal Direct Current Stimulation Does Not Ameliorate the Cellular Burden of the Disease.}, journal = {The European journal of neuroscience}, volume = {62}, number = {12}, pages = {e70375}, pmid = {41449086}, issn = {1460-9568}, support = {2017/26/D/NZ7/00728//National Science Center/ ; 2019/35/B/NZ4/02058//National Science Center/ ; }, mesh = {Animals ; *Motor Neurons/physiology ; Male ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy/genetics/pathology ; Mice ; Mice, Transgenic ; *Superoxide Dismutase/genetics ; *Excitatory Postsynaptic Potentials/physiology ; Superoxide Dismutase-1 ; Receptors, AMPA/metabolism ; *Synapses/physiology ; Spinal Cord/physiopathology ; Electric Stimulation ; }, abstract = {An imbalance between cells' intrinsic excitability and synaptic excitation levels underlies the spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a transient restoration of the deficient Ia synaptic excitation of spinal MNs in the presymptomatic SOD1 G93A mice was achieved by applying a single trans-spinal direct current stimulation (tsDCS) session. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 G93A animals can permanently alter spinal MN synaptic excitation levels and in this way affect intracellular metabolic pathways and cellular burden of the disease. Anodal, cathodal, or sham polarization of 100 μA was applied to P30-P35 SOD1 G93A male mice, and passive membrane properties and Ia excitatory post-synaptic potential (EPSP) characteristics were investigated by intracellular recordings of spinal MNs in vivo. A second cohort of animals was used to test the impact of our intervention on Ia synapse morphology, intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs amplitudes, coupled with a significant upregulation of GluR4 subunits of AMPA receptors at the Ia synapse. The cathodal polarization failed to induce any alteration to Ia synapse morphology, but increased the input resistance of MNs. However, changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular molecular pathways activity and did not decrease the cellular burden of the disease. Our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which however does not alleviate disease burden.}, }
@article {pmid41450148, year = {2026}, author = {Li, A and Cao, SQ and Fang, EF and Su, H}, title = {Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.}, journal = {Autophagy}, volume = {22}, number = {3}, pages = {637-639}, doi = {10.1080/15548627.2025.2610450}, pmid = {41450148}, issn = {1554-8635}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *Mitophagy/drug effects ; Animals ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; Mitochondria/metabolism/drug effects ; Caenorhabditis elegans ; Mice ; *Nerve Degeneration/pathology/drug therapy ; Protein Kinases/metabolism ; Disease Models, Animal ; }, abstract = {Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.}, }
@article {pmid41450325, year = {2026}, author = {Gamez, J and Carmona, F and Syriani, EE and Morales-Fuciños, M and Gamez, A}, title = {Early Dropped Head Syndrome Is More Prevalent in C9orf72 and FUS/TLS ALS.}, journal = {Muscle &amp; nerve}, volume = {73}, number = {4}, pages = {551-558}, doi = {10.1002/mus.70126}, pmid = {41450325}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/epidemiology ; *C9orf72 Protein/genetics ; Male ; Female ; *RNA-Binding Protein FUS/genetics ; Middle Aged ; Aged ; Adult ; Prevalence ; Cohort Studies ; *Muscle Weakness/genetics/epidemiology ; Dropped Head Syndrome ; }, abstract = {INTRODUCTION/AIMS: Dropped head syndrome (DHS) is common in advanced stages of amyotrophic lateral sclerosis (ALS), but infrequently reported among the early symptoms. We explored the frequency of DHS in a genetic ALS cohort harboring pathogenic variants to determine whether DHS is a prognostic factor for survival, particularly when appearing at an early stage.<br><br>METHODS: We collected the following variables to investigate a phenotype/genotype correlation: pathogenic variant (PV), sex, age at clinical ALS onset, time between ALS onset and DHS onset, and between DHS onset and death. DHS appearing within 12&#x2009;months of clinical onset was classified as early DHS (EDHS); otherwise, as late DHS (LDHS).<br><br>RESULTS: We observed DHS in 62 of 93 patients with genetic ALS, with a median of 26.5&#x2009;months between ALS clinical onset and identification of DHS. DHS was present in 72.1% of the 43 patients with C9orf72 expansions, 52.9% of the 34 with SOD1 , 100% of the 10 with FUS/TLS, and 50% of the 6 with other ALS gene PVs. EDHS appeared in 16 patients. Ten EDHS patients were C9orf72, and six were FUS/TLS . DHS was a significant factor for survival in the age-adjusted Cox regression model. The hazard ratio was 11.63 times higher for patients with DHS, with age as a concomitant variable.<br><br>DISCUSSION: Our results suggest that DHS is more prevalent in patients with C9orf72 and FUS/TLS than in those with SOD1 and other ALS-linked genes, and a risk factor for short survival, especially when appearing within 12&#x2009;months of ALS onset.}, }
@article {pmid41452185, year = {2025}, author = {Wilson, J and Toriumi, DM}, title = {Invited Commentary on: Uzunoğlu et al.'s "The Effect of Subperiosteal Drain Placement on Periorbital Edema and Ecchymosis Following Ultrasonic Piezoelectric-Assisted Rhinoplasty: A Prospective Comparative Study".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {26893614251407595}, doi = {10.1177/26893614251407595}, pmid = {41452185}, issn = {2689-3622}, }
@article {pmid41453576, year = {2026}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Paradkar, P and Suleiman, LA and Wendt, CD and Xu, C and An, H and Wang, M and Nishimune, H and Santin, JM and Arnold, WD}, title = {Reduced cortico-muscular output is associated with intrinsic hypoexcitability and reduced persistent inward currents in motor cortex neurons of TDP-43[Q331K] ALS mice.}, journal = {Neurobiology of disease}, volume = {218}, number = {}, pages = {107247}, doi = {10.1016/j.nbd.2025.107247}, pmid = {41453576}, issn = {1095-953X}, support = {R01 AG067758/AG/NIA NIH HHS/United States ; R01 AG078129/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Motor Cortex/physiopathology/metabolism ; Mice ; *DNA-Binding Proteins/genetics ; Mice, Transgenic ; *Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; Male ; Disease Models, Animal ; *Muscle, Skeletal/physiopathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by spinal and cortical motor neuron loss and progressive neuromuscular decline. When ALS pathology involves the primary motor cortex (PMC), cortical excitability is often disrupted, yet how these alterations map onto motor deficits during symptomatic ALS remains unclear. To investigate this, we examined the neuromuscular function, cortico-muscular output, and neuronal excitability of symptomatic 4-month-old TDP-43[Q331K] mice. TDP-43 mice exhibited reduced neuromuscular excitability and impaired strength compared to WT mice. Cranial motor evoked potentials were significantly reduced in TDP-43 mice, indicating decreased cortical output to muscle. Compared to WT mice, whole-cell patch-clamp recordings from TDP-43 PMC layer V pyramidal neurons revealed intrinsic hypoexcitability, diminished persistent inward currents (PICs), and decreased excitatory synaptic activity. Corroborating PIC findings, immunohistochemical analysis showed that PMC layer V neurons exhibited reduced signal intensity of the PIC-associated proteins Nav1.6 and 5-HT2C. Bulk RNA-seq of the cortex showed distinct transcriptional profiles in TDP-43 mice, with enrichment analysis indicating altered pathways relating to ion transport, synaptic signaling, and neuronal excitability. These results suggest that cortex-wide transcriptional changes may reflect broader and additional molecular mechanisms underlying cortical hypoexcitability in ALS. Together, our results demonstrate that symptomatic TDP-43[Q331K] mice exhibit a reduction in cortico-muscular output and PMC neuron excitability, accompanied by reduced PICs and PIC-associated proteins within these neurons. These findings identify cortical hypoexcitability as a defining feature of the TDP-43[Q331k] ALS mouse model and establish multi-level associations between cortical cellular-level dysfunction and impaired motor systems output.}, }
@article {pmid41454086, year = {2025}, author = {Mi, X and Shan, K and Ye, X and Cheng, R}, title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3371}, pmid = {41454086}, issn = {2045-2322}, support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; }, mesh = {*Spinal Cord Injuries/drug therapy/metabolism/pathology/physiopathology ; Animals ; *Hydrogen Peroxide/metabolism ; *Astrocytes/drug effects/metabolism ; *Nerve Regeneration/drug effects ; Cell Proliferation/drug effects ; Mice ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Disease Models, Animal ; Cells, Cultured ; }, abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.}, }
@article {pmid41454317, year = {2025}, author = {Abdi, M and Sooudi, OK and Milota, M}, title = {Professional identity formation for underrepresented groups in medicine: challenges and interventions for Dutch medical schools: a systematic scoping review.}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {1715}, pmid = {41454317}, issn = {1472-6920}, mesh = {Humans ; Netherlands ; *Schools, Medical/organization &amp; administration ; *Students, Medical/psychology ; *Social Identification ; *Minority Groups/psychology/education ; Cultural Diversity ; *Ethnicity ; }, abstract = {BACKGROUND: The concept of intersectionality is important when considering the professional identity formation (PIF) of students who are racially and ethnically underrepresented in medicine (URiM), as they must navigate race and ethnicity within the medical landscape. Despite a growing body of studies that shed light on the challenges that URiM students face in their PIF, there remains a notable lack of practical interventions for medical schools to address these challenges. Our objective is to highlight the challenges faced by URiM students and identify interventions in the literature that would be most suitable for Dutch medical schools to address them.<br><br>METHODS: This study builds upon Teo et al.'s (2022) scoping review. We examined articles from January 1, 2000, to December 31, 2021, and conducted an extended search from January 1, 2022, to November 30, 2023. Our focus was on articles exploring the intersectionality of PIF, perspectives of minoritized groups, and diversity, equity, and inclusion (DEI) within the context of PIF in medical education. We used the Systematic Evidence-Based Approach (SEBA) guided systematic scoping review, encompassing four stages: Systematic Approach, Structured Summary and Synthesis, Jigsaw Perspective, and Literature Analysis.<br><br>RESULTS: A total of 692 abstracts were reviewed, 36 full-text articles were evaluated, and 22 articles were included. URiM students encounter multiple challenges in their PIF journeys such as a lack of role models and representation, experiences of microaggressions, and pressure to assimilate into the majority culture. The proposed interventions for medical schools included diversifying recruitment practices to create more role models, developing curricula to address these challenges, and establishing a supportive network for URiM students.<br><br>CONCLUSIONS: Our study highlights the pressing need for Dutch medical schools to address the challenges faced by URiM students in PIF. The identified interventions offer actionable strategies to cultivate a more supportive and equitable learning environment. The implementation of these interventions has the potential to enhance URiM students' educational experiences, reduce disparities, and promote diversity within the medical profession. These findings underscore the importance of ongoing efforts to prioritize inclusivity and equity in medical education.}, }
@article {pmid41454587, year = {2025}, author = {Coulton, JB and He, Y and Budelier, MM and Barthélemy, N and Ireland, MD and Hu, M and Graham, D and Ferguson, T and Berry, JD and Bateman, RJ and Miller, TM and Ly, CV}, title = {Neurofilament Proteoforms in Amyotrophic Lateral Sclerosis Are Different in Cerebrospinal Fluid and Blood.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78138}, pmid = {41454587}, issn = {1531-8249}, support = {R01 NS138499/NS/NINDS NIH HHS/United States ; }, abstract = {We used targeted immunopurification-mass spectrometry (IP-MS) to characterize human neurofilament light chain (NfL) proteoforms across various compartments to assess their alterations in amyotrophic lateral sclerosis (ALS). NfL is truncated in cerebrospinal fluid (CSF) and blood in patients with sporadic ALS (sALS) and these proteoforms differ between compartments. Mid-domain species were elevated in CSF whereas plasma NfL proteoforms were mostly comprised of the tail subdomain region. Our results suggest NfL isoforms are proteolyzed and differentially distributed between ALS biofluid compartments and that analyzing by these specific regions or in ratios between regions can provide improvements in biomarker utility. These insights enhance the understanding of NfL and its potential for disease monitoring and therapeutic targeting in ALS. ANN NEUROL 2025.}, }
@article {pmid41454699, year = {2026}, author = {Feng, B and Xiang, W and Shan, T and Chen, X and Zheng, S and Shen, S and Wang, C}, title = {Low-Temperature Aluminum-Zinc Hydrogen-Aided Battery.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {65}, number = {7}, pages = {e24485}, doi = {10.1002/anie.202524485}, pmid = {41454699}, issn = {1521-3773}, abstract = {The need for reliable power sources in cold environments drives the development of efficient low-temperature batteries. While zinc-air batteries (ZABs) are promising due to low cost, high safety, and environmental compatibility, their performance at low temperatures is limited by sluggish kinetics. Here, we report an aluminum-zinc hydrogen-aided battery (AZ-HAB) that overcomes this limitation through a synergistic redesign of both electrodes. At the cathode, the kinetically favorable hydrogen oxidation reaction (HOR) replaces the oxygen evolution reaction (OER), reducing the charging potential and enhancing high-rate performance at low temperatures. The anode uses a composite structure (Al@Zn) with Zn pre-deposited on Al, leveraging Al's high activity and low deposition overpotential. This design reduces the full-cell resistance to one-third that of bare Zn, promotes uniform Zn deposition, and lowers polarization by 200 mV at 150 mA cm[-] [2]. The synergistic effect of both electrodes accelerates reaction kinetics, enabling an 11-fold longer cycle life than conventional ZABs at -20 °C. This work presents a viable strategy for high-performance energy storage and electric vehicles in extremely cold environments.}, }
@article {pmid41454905, year = {2025}, author = {Gómez-Tortosa, E and Agüero-Rabes, P and Roa-Escobar, J and Sainz, MJ and Viñas, J and Téllez, R and Martínez-Ulloa, P and Pérez-Pérez, J}, title = {MAPT p.V363I mutation in a patient with presenile dementia and late amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2025.2604238}, pmid = {41454905}, issn = {2167-9223}, abstract = {There are limited reports of motor neuron disease associated with MAPT mutations. We present a woman, carrier of the pathogenic MAPT V363I mutation, who developed a presenile dementia and, after 7 years, amyotrophic lateral sclerosis affecting both bulbar and spinal segments. This mutation has been reported in ten previous cases with various cognitive phenotypes and corticobasal syndrome, but not motor neuron disease. We also review the handful of MAPT mutations associated with motor neuron disease.}, }
@article {pmid41455134, year = {2026}, author = {Du, O and Wu, YJ and Li, MY and Du, JR}, title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.}, journal = {Cytokine}, volume = {198}, number = {}, pages = {157099}, doi = {10.1016/j.cyto.2025.157099}, pmid = {41455134}, issn = {1096-0023}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Central Nervous System Diseases/metabolism/therapy/pathology ; Animals ; Biomarkers/metabolism ; }, abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.}, }
@article {pmid41455150, year = {2026}, author = {Akkaya, HE and Kaya, E and Gökmen, R and Gedik, MS and Akpınar, D&#x130;}, title = {Global trends and collaboration networks in radiology: A bibliometric analysis of the 500 most-cited articles in web of science.}, journal = {Clinical imaging}, volume = {130}, number = {}, pages = {110700}, doi = {10.1016/j.clinimag.2025.110700}, pmid = {41455150}, issn = {1873-4499}, mesh = {*Bibliometrics ; *Radiology/trends ; Humans ; *Diagnostic Imaging ; Periodicals as Topic ; }, abstract = {OBJECTIVE: This study examined global research trends in Radiology, Nuclear Medicine, and Medical Imaging by analyzing the 500 most-cited articles in the Web of Science (WoS) Core Collection.<br><br>METHODS: A bibliometric search was conducted on June 15, 2025. Biblioshiny and VOSviewer 1.6.20 were used for network visualization, including institutional collaboration, co-authorship, keyword co-occurrence, and country-level contributions. Temporal patterns were analyzed with Python 3.13.3, and descriptive statistics summarized publication data.<br><br>RESULTS: Harvard University led institutional contributions with 54 publications, followed by Massachusetts General Hospital (n&#xa0;=&#xa0;49), University of Oxford (n&#xa0;=&#xa0;35), Washington University (n&#xa0;=&#xa0;29), and University of Texas (n&#xa0;=&#xa0;26). The United States accounted for 53.4&#xa0;% of all outputs, followed by the United Kingdom (21.6&#xa0;%), Germany (12&#xa0;%), Canada (9&#xa0;%), and France (8&#xa0;%). Among authors, Stephen M. Smith contributed most (19 publications), followed by Jenkinson, M (n&#xa0;=&#xa0;14), and Friston, KJ (n&#xa0;=&#xa0;13). The most frequent keywords were "MRI" (n&#xa0;=&#xa0;65), "Brain" (n&#xa0;=&#xa0;43), "fMRI" (n&#xa0;=&#xa0;37), "Segmentation" (n&#xa0;=&#xa0;25), and "PET" (n&#xa0;=&#xa0;24). In addition to leading all journals in citation impact (citations per article), Neuroimage was also identified as the most productive journal overall. Regarding the average citation impact, the top-performing entities in their respective categories were: the University of Oxford (among organizations), Germany (among countries), Smith Stephen M (among authors), and the journal Neuroimage (among journals). Emerging terms included "deep learning" and "artificial intelligence." The most-cited article was Ronneberger et al.'s U-Net (2015), cited 63,448 times.<br><br>CONCLUSION: High-impact radiology research is concentrated in North America and Western Europe, with neuroimaging and artificial intelligence representing key emerging domains. These insights provide a roadmap for research prioritization and collaboration strategies.}, }
@article {pmid41455589, year = {2026}, author = {Ruiz-Ortiz, M and Esteban-Pérez, J and Gómez-Grande, A and Martínez-Albero, E and Benito-León, J}, title = {Motor band sign in [18]F-FDG PET/CT studies: a biomarker of degenerative upper motor neuron disease? A study of three cases and literature review.}, journal = {Neurologia}, volume = {41}, number = {2}, pages = {501931}, doi = {10.1016/j.nrleng.2025.501931}, pmid = {41455589}, issn = {2173-5808}, mesh = {Humans ; *Positron Emission Tomography Computed Tomography ; Fluorodeoxyglucose F18 ; *Motor Neuron Disease/diagnostic imaging ; Male ; Middle Aged ; Female ; Aged ; Biomarkers ; Amyotrophic Lateral Sclerosis/diagnostic imaging ; Radiopharmaceuticals ; }, abstract = {INTRODUCTION: Motor neuron diseases (MND) encompass conditions like amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), marked by progressive degeneration of upper and/or lower motor neurons. The identification of specific biomarkers is crucial to reduce diagnostic delays.<br><br>METHODS: This study presents three clinical cases evaluated at the Hospital Universitario 12 de Octubre, where the motor band sign on brain 18&#x202f;F-FDG PET/CT aided the diagnosis of MND. The studies were conducted using a SIEMENS Biograph True Point 6, with a review of relevant literature.<br><br>RESULTS: In all three patients, PET/CT revealed hypometabolism in the prerolandic region, indicative of the motor band sign, contributing to the diagnosis of PLS or ALS.<br><br>DISCUSSION: The motor band sign on 18F-FDG PET/CT emerges as a potential marker of upper motor neuron involvement, though the heterogeneity of MNDs and variability across studies call for further research to establish its specificity and sensitivity.<br><br>CONCLUSION: The motor band sign on 18F-FDG PET/CT is a promising biomarker for MNDs, although further studies are required to confirm its diagnostic validity.}, }
@article {pmid41456082, year = {2025}, author = {Erro, ME and Zelaya, MV and Eraña, H and de Gordoa, JSR and García-Amigot, F and Simonovska-Serra, A and Caballero, MC and Ferrer, I and Gelpi, E and Jericó, I and Castilla, J}, title = {Variably Protease-Sensitive Prionopathy: Two New Cases With Motor Neuron-Dementia Syndrome.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70294}, pmid = {41456082}, issn = {2328-9503}, support = {19-2021//Health Department of Navarre Government/ ; //European Regional Development Fund/ ; //Federal Ministry Labour, Social Affairs, Health, Care and Consumer Protection/ ; PID2021-122201OB-C21//Agencia Estatal de Investigaci&#xf3;n, Ministerio de Ciencia e Innovaci&#xf3;n/ ; PID2024-160022OB-I00//Agencia Estatal de Investigaci&#xf3;n, Ministerio de Ciencia e Innovaci&#xf3;n/ ; CEX2021-001136-S//Severo Ochoa Excellence accreditation/ ; }, abstract = {We describe two patients with variably protease-sensitive prionopathy (VPSPr) who developed progressive upper motor neuron symptoms, insomnia, behavioral and cognitive decline, compatible with primary lateral sclerosis associated with frontotemporal dementia (FTD). Neuropathology revealed a spongiform encephalopathy with frontotemporal and pronounced thalamic involvement, associated with fine synaptic abnormal prion protein conformer (PrP[Sc]) deposits, microplaques, and intraneuronal aggregates. Western blot analysis revealed a characteristic VPSPr proteolytic profile, lacking the diglycosylated band. Both patients were methionine homozygous at PRNP codon 129 and carried no pathogenic mutations. These cases illustrate that VPSPr can present with a prominent motor neuron syndrome and FTD features.}, }
@article {pmid41456636, year = {2026}, author = {Kopalli, SR and Vadia, N and Varma, P and Mishra, S and Joshi, N and Bansal, P and Al-Hasnaawei, S and Chauhan, AS and Jain, H and Nathiya, D and Devi, A and Jayasingh Chellammal, HS and Gupta, P and Wal, P and Koppula, S}, title = {Neurodevelopmental origins of neurodegeneration: a lifespan perspective on brain vulnerability.}, journal = {Brain research}, volume = {1873}, number = {}, pages = {150134}, doi = {10.1016/j.brainres.2025.150134}, pmid = {41456636}, issn = {1872-6240}, mesh = {Humans ; *Brain/growth &amp; development ; *Neurodegenerative Diseases/etiology/genetics ; Pregnancy ; Prenatal Exposure Delayed Effects ; Animals ; Female ; *Neurodevelopmental Disorders ; Gastrointestinal Microbiome ; Longevity/physiology ; }, abstract = {Neurodegenerative disorders-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.}, }
@article {pmid41457335, year = {2026}, author = {Nicolaou, N and Nicolaou, D and Christou, S}, title = {Letter to the Editor: Comment on Palmieri et al.'s "Uveitis Following Intravitreal Injections of Faricimab: A Case Report".}, journal = {Ocular immunology and inflammation}, volume = {34}, number = {2}, pages = {443-444}, doi = {10.1080/09273948.2025.2610665}, pmid = {41457335}, issn = {1744-5078}, mesh = {Humans ; Intravitreal Injections/adverse effects ; *Uveitis, Anterior/chemically induced/diagnosis ; Antibodies, Bispecific ; }, abstract = {The article provides valuable insight on presentation and management of isolated anterior uveitis and with vitritis following intravitreal (IVT) faricimab. We highlight additional points. First sterile intraocular inflammation (IOI) onset ranges from 1-35 days; however, two patterns have been described: acute onset within 5 days and delayed onset at approximately 14 days following a mean of four IVT injections, although it may occur after the first. Sterile IOI may be recognised by delayed onset, suggestive of a type IV hypersensitivity reaction rather than infectious causes and by absence of hypopyon, although may present in severe cases. Second, faricimab's dual inhibition may alter ocular immune surveillance, potentially facilitating herpes simplex virus reactivation. Increased vigilance for dendritic ulcers is therefore warranted, and antiviral therapy should be initiated prior to corticosteroids. Finally, management should be guided by severity, with anterior or vitreous tap considered to exclude exogenous endophthalmitis. Resolution typically occurs within 15 days.}, }
@article {pmid41458376, year = {2025}, author = {Qian, G and Ding, L and Tan, C and Wang, L and Long, C}, title = {Mucosal immune response modulated by secreted and membrane-bound hydrolases of Candida albicans in vulvovaginal candidiasis.}, journal = {Frontiers in fungal biology}, volume = {6}, number = {}, pages = {1692795}, pmid = {41458376}, issn = {2673-6128}, abstract = {Vulvovaginal candidiasis (VVC) affects the physical and mental health of millions of women worldwide. The leading cause of VVC, Candida albicans, can induce a strong mucosal inflammatory reaction during the VVC infection, where secreted and membrane-bound adhesion and hydrolases seem to be the key virulent factors to promote the mucosal antifungal immunity and immunopathology. Several hydrolases, such as Saps, Als, candidalysin, lipases, and phospholipases, have been identified in vaginal secretions isolated from VVC patients; however, the immune impacts of some hydrolases have not been well documented. In this review, we focus on the literature that addresses the immunopathogenic roles of the Als adhesin family or proteinase, such as Sap and candidalysin, in VVC. Our goal is to expand our knowledge of VVC pathogenesis in order to provide new strategies for VVC treatment.}, }
@article {pmid41459056, year = {2025}, author = {Auclair-Ouellet, N and Kassem, O and Bronner, S and Oula, ML and Binda, S}, title = {Leveraging microbiome-based interventions to improve the management of neurodegenerative diseases: evidence for effects along the microbiota-gut-brain axis.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1699884}, pmid = {41459056}, issn = {2296-861X}, abstract = {The microbiota-gut-brain axis (MGBA) has recently emerged as a useful model for the understanding of the onset and progression of neurodegenerative diseases (NDDs). Microbiome-based interventions using biotic supplements (probiotics, prebiotics, synbiotics, postbiotics) can modulate the MGBA and constitute relevant solutions to help reduce the risk of neurological changes associated with NDDs and manage symptoms. This narrative review provides a summary of the functioning of the MGBA and of its interactions with disease processes involved in the onset and progression of NDDs. Microbiome-based interventions and their mechanisms of action are reviewed, and important considerations for the design of interventions are discussed. Next, preclinical and clinical studies on the potential of microbiome-based interventions in Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are reviewed. Evidence related to biomarkers of pathology (e.g., beta-amyloid or alpha-synuclein protein depositions), neuroinflammation, and metabolic activity is summarized, along with emerging evidence for the improvement of clinical symptoms and disease trajectories. Overall, preclinical studies show that microbiome-based supplements have significant positive effects on mechanisms and pathways involved in the pathophysiology of NDDs. Clinical studies show that these interventions provide important benefits both in terms of biomarkers and clinical symptoms. However, evidence is limited in some key clinical areas, such as mental wellbeing in AD and cognition in PD, and for the management of clinical symptoms in ALS and HD overall. Gaps in knowledge and open questions as well as perspectives for future research are discussed.}, }
@article {pmid41460923, year = {2025}, author = {Korada, S and Tam, OH and Greco, HC and Hammell, MG and Dubnau, J and Sher, RB}, title = {LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.}, journal = {PLoS genetics}, volume = {21}, number = {12}, pages = {e1012007}, pmid = {41460923}, issn = {1553-7404}, support = {R01 AG076493/AG/NIA NIH HHS/United States ; R01 AG078788/AG/NIA NIH HHS/United States ; R01 AG079898/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/genetics/metabolism ; *Long Interspersed Nucleotide Elements/genetics ; *Motor Cortex/pathology/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology ; Humans ; Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Retroelements/genetics ; Endogenous Retroviruses/genetics ; Mice, Transgenic ; Neuroglia/metabolism/pathology ; }, abstract = {A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs/ERVs are mobile virus-like genetic elements that constitute about 45% of our genome and encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. A causal role of RTEs/ERVs has been demonstrated in Drosophila in mediating both intracellular toxicity of TDP-43 and the intercellular spread of toxicity from glia to neurons. RTEs/ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer's Disease (AD) patients, but the role of RTEs/ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. We utilized established transgenic mouse models that overexpress moderate levels of human wild-type TDP-43 or a mutant version with a specific ALS-causal Q331K amino acid substitution, together with a LINE-1-EGFP retrotransposon indicator line. We found that TDP-43 animals exhibit broad expression of RTEs/ERVs with LINE-1 retrotransposition in glia and neurons in the motor cortex. Expression begins with onset of neurological phenotypes, earlier in hTDP-43-Q331K animals and later in hTDP-43-WT. The LINE-1-EGFP retrotransposition reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms, while EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with cell non-autonomous effects on nearby neurons and glial cells.}, }
@article {pmid41461417, year = {2026}, author = {Palma-Bautista, C and Rojano-Delgado, AM and Rey, MD and Gherekhloo, J and Domínguez-Valenzuela, JA and Jorrín-Novo, JV and Plaza, G and Osuna, MD and De Prado, R}, title = {Understanding cross- and multiple-herbicide resistance in Setaria adhaerens from olive orchards with two decades of multiple herbicides use.}, journal = {Pesticide biochemistry and physiology}, volume = {217}, number = {}, pages = {106883}, doi = {10.1016/j.pestbp.2025.106883}, pmid = {41461417}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Herbicide Resistance ; *Olea ; Glutathione Transferase/metabolism ; Glycine/analogs &amp; derivatives/pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; }, abstract = {Two populations of Setaria adhaerens (resistant [R] and susceptible [S]) have been identified in Spanish olive orchards. The R population shows multiple resistance to chlorotoluron (PSII inhibitor), diclofop-methyl (ACCase inhibitor), tribenuron-methyl (ALS inhibitor), glyphosate (EPSPS inhibitor), and oxyfluorfen (PPO inhibitor), along with potential natural tolerance to diflufenican (PDS inhibitor). This study evaluated herbicide efficacy at field rates, enzyme activity (ALS, ACCase, EPSPS, PPO, PSII), and the role of cytochrome P450 and glutathione-S-transferases using malathion and NBD-Cl, respectively. The S population was fully controlled by all herbicides except diflufenican, which showed only ∼45 % control in both populations, indicating possible innate tolerance. In the R population, chlorotoluron, diclofop-methyl, tribenuron-methyl, and glyphosate had no effect on enzyme activity, suggesting non-target site resistance (NTSR). In contrast, oxyfluorfen inhibited PPO activity only in the S population, indicating target-site resistance (TSR). NBD-Cl showed no activity, ruling out glutathione-S-transferases-mediated metabolism. However, malathion restored over 50 % sensitivity to chlorotoluron, diclofop-methyl, and tribenuron-methyl in the R population, suggesting enhanced metabolism likely mediated by cytochrome P450 monooxygenases. Metabolic profiling further confirmed enhanced herbicide detoxification in the R population as a key resistance mechanism. These findings highlight the complexity of resistance in S. adhaerens and underline the urgent need to incorporate metabolic resistance monitoring into weed management programs. Future studies will focus on unraveling the molecular basis of these resistance mechanisms.}, }
@article {pmid41461594, year = {2026}, author = {Lee, WT and Varghese, P and Gaunt, A}, title = {Post-Operative C-Reactive Protein as a Predictor of Anastomotic Leak Following Robotic Colorectal Surgery.}, journal = {World journal of surgery}, volume = {50}, number = {2}, pages = {424-431}, doi = {10.1002/wjs.70217}, pmid = {41461594}, issn = {1432-2323}, mesh = {Humans ; Male ; *C-Reactive Protein/analysis/metabolism ; *Anastomotic Leak/diagnosis/blood/etiology ; Female ; Aged ; Retrospective Studies ; Middle Aged ; *Robotic Surgical Procedures/adverse effects ; Predictive Value of Tests ; Biomarkers/blood ; *Colectomy/methods/adverse effects ; Postoperative Period ; Anastomosis, Surgical ; Colorectal Neoplasms/surgery ; }, abstract = {AIM: Postoperative C-reactive protein (CRP) levels are good predictors of anastomotic leak (AL) following colorectal surgery, with postoperative day-3 CRP thresholds ranging between 162 and 195 mg/L in open and laparoscopic resections. This study aims to determine a cut-off CRP value that predicts ALs following robotic colorectal surgery and identifies patients suitable for safe early discharge.<br><br>METHODS: A single-center retrospective analysis of patients who underwent an elective robotic colorectal resection, with primary anastomosis, between February 2017 and December 2024, was conducted. Primary outcome measure was clinically and radiologically confirmed AL (graded). Data were analyzed using IBM SPSS v30.0.0.<br><br>RESULTS: Seven hundred eighty-four elective robotic colorectal resections with anastomosis were performed. Median age was 69&#xa0;years (IQR 60-77), 448 male, 336 female, and BMI 27.5 (IQR 24.4-31.1), indication for surgery was cancer in 681 (86.9%) patients. 51 (6.5%) patients had an AL, of which 12/51 (23.5%) had a grade &#x2265;&#xa0;3 leak. A POD-3 CRP level of 136.0&#xa0;mg/L (73% sensitivity, 79% specificity, and AUC 0.788) and POD-4 CRP level of 94.4&#xa0;mg/L (84% sensitivity, 62% specificity, and AUC 0.806) were predictive of AL. At POD-5, a cut-off CRP of 243&#xa0;mg/L (88% sensitivity, 73% specificity, and AUC 0.818) was predictive of ALs requiring re-operation and/or escalation to level 2-3 care. Male sex, colo-rectal anastomoses, and resections performed before 2020 were associated with higher AL rates.<br><br>CONCLUSION: Postoperative CRP levels have high predictive value in early detection and exclusion of AL, facilitating early patient discharge under the enhanced recovery after surgery (ERAS) pathways. CRP thresholds in robotic colorectal resections are lower than previously reported thresholds in open and laparoscopic surgery.}, }
@article {pmid41462890, year = {2025}, author = {Fajkić, A and Belančić, A and Lam, YW and Rački, V and Pilipović, K and Janković, T and Mežnarić, S and Mršić-Pelčić, J and Vitezić, D}, title = {Novel Translational Concept: Axon-to-Muscle Exosomal Signaling as an Emerging Therapeutic Target in Spinal Muscular Atrophy.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462890}, issn = {2227-9059}, abstract = {Spinal muscular atrophy (SMA) has transitioned from a uniformly fatal disease to a treatable condition, yet incomplete neuromuscular recovery underscores the limits of current SMN-restorative therapies. Emerging data implicate disrupted axon-to-muscle exosomal signaling as an important, overlooked driver of residual dysfunction. Exosomes, nanovesicles mediating bidirectional neuronal-muscular communication, carry synaptic organizers, trophic factors, and microRNAs essential for neuromuscular junction integrity. SMN deficiency alters exosomal biogenesis and cargo, leading to loss of agrin-MuSK signaling, impaired β-actin transport, and muscle atrophy. Comparative insights from amyotrophic lateral sclerosis and muscular dystrophy reveal that stem-cell-derived or engineered exosomes restore synaptic stability, enhance regeneration, and cross biological barriers safely. Thus, we speculate herein on a translational model integrating exosome-based therapies with existing genetic interventions to achieve durable, systems-level recovery in SMA. Exosomal profiling may further yield minimally invasive biomarkers for disease monitoring and treatment optimization, establishing vesicle-mediated communication as a novel therapeutic axis in neuromuscular medicine.}, }
@article {pmid41462986, year = {2025}, author = {Vauti, F and Eilers, L and Kroll, A and Köster, RW}, title = {Genomic Organization, Evolutionary Conservation and Expression of Ataxin-2 and Ataxin-2-like Genes Underscore the Suitability of Zebrafish as a Model Organism for SCA2 and Related Diseases.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462986}, issn = {2227-9059}, support = {11-76251- 2714/2024 (ZN4545)//This project was supported by the BrightBrain initiative, which is funded by zu-kunft.niedersachsen, the joint science funding program of the Lower Saxony Ministry of Science and Culture and the Volkswagen Foundation/ ; }, abstract = {Background/Objectives: The Ataxin-2 protein (ATXN2) plays an essential role in RNA metabolism and many cellular processes. Dysregulation or mutation of the Ataxin-2 gene (ATXN2) can lead to neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Despite numerous efforts in this field in other animal models, little is known about Atxn2 in zebrafish. In this study, we aim to investigate the potential suitability of zebrafish as a model for Atxn2-related diseases by performing basic analyses on Atxn2. Methods: We performed a bioinformatic protein analysis of Atxn2 from zebrafish and its paralog Atxn2l in relation to human and other vertebrate homologues. Based on a structural analysis of the atxn2 and atxn2l genes, the expression of the predicted transcripts was detected by RT-PCR and the spatiotemporal expression pattern was determined by whole-mount in situ hybridization. Results: We found similarities between the protein sequences of Atxn2 and Atxn2l in zebrafish and their functional domains with those of orthologs in humans and other vertebrates. The predicted transcripts of atxn2 and atxn2l were experimentally verified and their spatiotemporal expression patterns were determined during zebrafish development. Splicing variants were detected for both genes, suggesting a different role for the isoforms in different tissues. Conclusions: These findings provide new insights into the atxn2 and atxn2l genes, suggesting the zebrafish as a suitable animal model for functional studies and research on disease modeling of SCA2 and ALS.}, }
@article {pmid41463070, year = {2025}, author = {Goyal, NA and Andrews, JA and Oskarsson, BE and Wiedau, MH and Kasarskis, EJ and Forrest, BD and Zhang, R and Bracci, PM and Davis, MW and Azhir, A and McGrath, MS}, title = {Quantitative Measures of Time to Loss of 15% Vital Capacity and Survival Extension in Slowly Progressive Amyotrophic Lateral Sclerosis (ALS) Patients Treated with the Immune Regulator NP001 Suggests an Immunopathogenic Subset of ALS.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463070}, issn = {2227-9059}, support = {Neuvivo - NP001//Ari Azhir/ ; }, abstract = {Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.}, }
@article {pmid41463293, year = {2025}, author = {Xie, V and Franco, MC and Martin, LJ}, title = {Human Mutant Dynactin Subunit 1 Causes Profound Motor Neuron Disease Consistent with Possible Mechanisms Involving Axonopathy, Mitochondriopathy, Protein Nitration, and T-Cell-Mediated Cytolysis.}, journal = {Biomolecules}, volume = {15}, number = {12}, pages = {}, pmid = {41463293}, issn = {2218-273X}, support = {R01 NS102479/NS/NINDS NIH HHS/United States ; 1R01NS107417-04A1/NH/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Anterior Horn Cells/metabolism/pathology ; *Axons/pathology ; *Dynactin Complex/genetics ; Mice, Transgenic ; *Mitochondrial Diseases/genetics ; *Motor Neuron Disease/genetics ; *Motor Neurons/metabolism/pathology ; Mutation ; *Protein Processing, Post-Translational/genetics ; Quinazolinones/pharmacology ; Spinal Cord Diseases ; T-Lymphocytes/immunology ; *Tyrosine/metabolism/analogs &amp; derivatives ; Mitochondrial Dynamics/drug effects ; Male ; Female ; }, abstract = {Mutations in the gene encoding the p150 subunit of the dynactin complex (DCTN1) are linked to amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Perry syndrome. These neurodegenerative diseases can cause muscle weakness and atrophy, parkinsonian-like symptoms, and paralysis. To examine the evolution of neuropathology caused by a mutation in DCTN1 and cellular mechanisms of disease for therapeutic discovery, we characterized mice expressing either human wildtype or mutant (G59S) DCTN1. Neuron-specific expression of mutant, but not wildtype, DCTN1 caused fatal age-related paralytic disease and motor neuron (MN) degeneration in the spinal cord with axonopathy and chromatolysis without apoptotic morphology. MNs became positive for cleaved caspase-3, cleaved caspase-8, and nitrated Hsp90. Mitochondria accumulated and appeared fragmented and dysmorphic and then were lost. This pathology was accompanied by invasion of CD95- and CD8-positive mononuclear T cells into the ventral horn and accumulation of TNFα and IL9. Administration of the mitochondrial division inhibitor-1 (Mdivi-1) protected MNs and extended the lifespan of G59S-DCTN1 mice. A mitochondrial permeability transition pore inhibitor also extended lifespan. Thus, mutant DCTN1 causes degeneration of MNs associated with axonopathy, mitochondriopathy, nitrative stress, and caspase activation. It appears as retrograde neurodegeneration and inflammatory T-cell-like cytolysis. Mitochondria are possible therapeutic targets in DCTN1-linked neurodegenerative disorders.}, }
@article {pmid41463333, year = {2025}, author = {Tendero-Lopez, D and Dominguez, M and Aguilar-Aragon, M}, title = {Modelling Neural Disorders with the D. melanogaster Larval Peripheral and Adult Dopaminergic Systems.}, journal = {Biomolecules}, volume = {15}, number = {12}, pages = {}, pmid = {41463333}, issn = {2218-273X}, mesh = {Animals ; *Drosophila melanogaster/metabolism ; Larva/metabolism ; *Disease Models, Animal ; Humans ; *Dopamine/metabolism ; *Dopaminergic Neurons/metabolism/pathology ; *Nervous System Diseases/metabolism ; Parkinson Disease/metabolism ; }, abstract = {The increasing prevalence of neurological disorders highlights the need for disease animal models to elucidate the underlying biomolecular and cellular mechanisms of disease and to facilitate studies aimed at developing effective treatments. The fruit fly Drosophila melanogaster, at both larval and adult stages, can serve as an effective model for different human-relevant neurological diseases. Larvae are particularly suited for studying peripheral nervous system disorders, such as Charcot-Marie-Tooth and amyotrophic lateral sclerosis, while adults enable investigations of higher-order cognitive functions and age-related conditions, including Parkinson's disease and depression-like behaviours. Combining larval and adult models offers a complementary framework to dissect the biomolecular pathways of neurological disorders and accelerate preclinical research.}, }
@article {pmid41464612, year = {2025}, author = {Klumb, S and Haley, L and Hathaway, C and Irby, J and Cheng, J and Rumley, J}, title = {Degenerative Cervical Myelopathy Diagnosis and Its Differentiation from Neurological Mimics, MS and ALS: A Literature Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {24}, pages = {}, pmid = {41464612}, issn = {2077-0383}, abstract = {Multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and degenerative cervical myelopathy (DCM) share features that may confound diagnosis. DCM is caused by degenerative changes in the cervical spine leading to spinal cord compression and injury, resulting in significant disability. Misdiagnosis of DCM for a similar neurological condition can lead to further spinal cord damage from delayed surgical treatment. Here we review the diagnostic criteria, clinical signs and symptoms, and imaging typical for DCM, and two of its clinical mimics, MS and ALS. Shared motor symptoms of all three conditions can make diagnosis difficult, especially early in disease course. Noteworthy differences include neck and shoulder pain in DCM, visual disturbances in MS, and bulbar symptoms and the absence of sensory deficits in ALS. In DCM and MS, MRI is used to support the diagnosis, with specific findings on MRI that differentiate DCM versus MS. In ALS, MRI is used to rule out differential diagnoses. Applying the diagnostic criteria for MS and ALS, as well as understanding the typical presentation and MRI findings of DCM, is crucial. Through discussion of these conditions, this review aims to help limit misdiagnosis rates, allowing for early management, which can improve long-term patient outcomes.}, }
@article {pmid41464650, year = {2025}, author = {Sonaglioni, A and Nicolosi, GL and Lombardo, M and Baravelli, M and Muti, P}, title = {Comparative Meta-Analysis of Left Ventricular Mechanics in Takotsubo Syndrome and Anterior STEMI Due to Left Anterior Descending Artery Occlusion.}, journal = {Journal of clinical medicine}, volume = {14}, number = {24}, pages = {}, pmid = {41464650}, issn = {2077-0383}, support = {N/A//Ministero della Salute/ ; }, abstract = {Background: Takotsubo syndrome (TTS) often mimics anterior ST-elevation myocardial infarction (STEMI) caused by left anterior descending (LAD) occlusion, yet the two entities differ fundamentally in pathophysiology and mechanical behavior. Two-dimensional speckle-tracking echocardiography (2D-STE) enables detailed assessment of left ventricular (LV) deformation beyond conventional ejection fraction (LVEF). This meta-analysis compared global and regional LV strain patterns in TTS versus LAD-related anterior STEMI during the acute phase. Methods: A systematic search of PubMed, Embase, and Scopus through October 2025 identified observational case-control studies directly comparing TTS and angiographically confirmed anterior STEMI, with LV mechanics assessed by 2D-STE. Random-effects models were used to pool standardized mean differences (SMDs) for LVEF; global longitudinal strain (GLS); apical, mid-ventricular, and basal longitudinal strain (ALS, MLS, BLS); and global radial strain (GRS). Heterogeneity (I[2]), publication bias (funnel plots, Egger's test), meta-regression, and leave-one-out sensitivity analyses were performed. Results: Six studies comprising 221 TTS and 290 anterior STEMI patients met the inclusion criteria. TTS patients were older, predominantly female, and had fewer metabolic risk factors, while LV size was comparable. LVEF was significantly lower in TTS (SMD -1.149; 95% CI -2.20 to -0.10; p = 0.032), with stable findings across sensitivity analyses and no evidence of publication bias. GLS, ALS, MLS, and BLS showed only a non-significant trend toward greater impairment in TTS, and these comparisons were limited by marked inter-study heterogeneity. In contrast, GRS was significantly and consistently more reduced in TTS (SMD -1.284; 95% CI -1.59 to -0.98; p < 0.001), indicating more profound global radial dysfunction. Meta-regression showed no significant influence of demographic factors or vendor-specific software on LVEF or GLS differences. Conclusions: Compared with LAD-related anterior STEMI, TTS is associated with more severely depressed LVEF and markedly impaired radial strain, while longitudinal strain differences remain inconclusive and suggest only a potential trend toward greater dysfunction, reflecting the limited and heterogeneous evidence. These findings are consistent with diffuse, stress-induced myocardial stunning in TTS and suggest that 2D-STE may aid differentiation between stress cardiomyopathy and ischemic infarction in the acute setting, although longitudinal strain parameters should be interpreted cautiously and regarded as hypothesis-generating.}, }
@article {pmid41465278, year = {2025}, author = {Marzetti, E and Di Lorenzo, R and Calvani, R and Coelho-Júnior, HJ and Landi, F and Pesce, V and Picca, A}, title = {Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465278}, issn = {1422-0067}, support = {D1.2024//Universit&#xe0; Cattolica del Sacro Cuore/ ; D1.2025//Universit&#xe0; Cattolica del Sacro Cuore/ ; Ricerca Corrente 2025//Italian Ministry of Health/ ; DM 1557 11.10.2022//European Commission/ ; 2022YNENP3//Italian Ministry of University and Research/ ; }, mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Intermediate Filaments/metabolism/pathology ; *Signal Transduction ; Neurons/metabolism/pathology ; }, abstract = {Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.}, }
@article {pmid41465496, year = {2025}, author = {López-Royo, T and Gascón, E and Moreno-Martínez, L and Macías-Redondo, S and Zaragoza, P and Manzano, R and Osta, R}, title = {Region-Specific Expression Patterns of lncRNAs in the Central Nervous System: Cross-Species Comparison and Functional Insights.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465496}, issn = {1422-0067}, support = {PI21/00372//Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa" from the European Union/ ; CB18/05/0037//CIBERNED/ ; A19_23R//Consolidated Groups from Gobierno de Arag&#xf3;n/ ; PRTR-C17.I1//The Spanish Ministry of Science and Innovation with funds from the European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan/ ; FPU19/05625//Ministerio de Universidades from Gobierno de Espa&#xf1;a/ ; PT20/00109//Instituto de Salud Carlos III/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; Humans ; Male ; Female ; Mice ; *Central Nervous System/metabolism ; Spinal Cord/metabolism ; Species Specificity ; Brain/metabolism ; Gene Expression Profiling ; Organ Specificity ; }, abstract = {Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) are crucial for brain evolution and proper development and function of the central nervous system (CNS), exhibiting specific time-, spatial-, and sex-biassed expression patterns. This study investigated whether region-specific spatial expression patterns of brain-relevant lncRNAs are conserved between the mouse and human CNS. Demonstrating such cross-species conservation informs the translational value of mouse models for lncRNA biology. To test this, the expression of 14 lncRNAs was studied in the adult CNS of mice and humans across three different regions (spinal cord, brainstem, and frontal cortex), and age effects were assessed in mice. The results demonstrated conserved expression patterns between the two species, with region-specific changes. The frontal cortex exhibited high expression of Meg3, Miat, and Pvt1 lncRNAs, while the spinal cord showed high levels of Hotair and Gas5. Additionally, Malat1 displayed lower levels in females compared to males in the spinal cord compared to other regions. Finally, through GO functional enrichment analysis and literature review, this study emphasizes the role of lncRNAs in CNS physiology and disease, suggesting their involvement in neurological processes and conditions such as cortical development, neuronal synapsis, schizophrenia, Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Overall, this research highlights the importance of further investigating the role of lncRNAs in brain function and their potential as key players in neurological disorders, opening the door to explaining the high region- and sex-specific effects of these disorders.}, }
@article {pmid41465514, year = {2025}, author = {Riku, Y and Brion, JP and Ando, K and Uchihara, T and Iwasaki, Y}, title = {The Determinant of Tau Spreading in Alzheimer's Disease: Dependent on Senile Plaque, Neural Circuits, or Spatial Proximity?.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465514}, issn = {1422-0067}, support = {JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; 23K06935, 25K22597, and 25K10781//JSPS-KAKENHI/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Plaque, Amyloid/metabolism/pathology ; Animals ; Neurofibrillary Tangles/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is neuropathologically characterized by tau-immunopositive neurofibrillary tangles (NFTs) and amyloid-β (Aβ)-immunopositive senile plaques. According to the widely accepted amyloid cascade hypothesis, Aβ pathology represents the upstream event in AD pathophysiology and induces tau aggregation. However, numerous studies have suggested that tau aggregates correlate more closely with neuronal loss and regional brain atrophy than with Aβ depositions. Tau aggregation in AD demonstrates a hierarchical spreading pattern beginning in the transentorhinal cortex, but the mechanisms underlying this spreading manner of lesions remain to be elucidated. This review aims to address current controversies regarding tau pathology in AD from the perspectives of both the 'amyloid cascade' and 'tauopathy' hypotheses. From the 'amyloid cascade' viewpoint, Aβ deposition prominently involves distal axon and axon terminals, and in some regions, there are anatomical correspondences between axonal Aβ pathology and cytoplasmic tau aggregations (e.g., a close relationship between senile plaques in the molecular layer of the hippocampal dentate gyrus and NFTs in the transentorhinal cortex). Nevertheless, this model cannot explain the whole body of hierarchical spreading of tau aggregation because notable spaciotemporal discrepancies also exist in many regions. From the 'tauopathy' perspective, the distribution of tau aggregates in AD involves key nodes within the memory circuits. Also, experimental studies have suggested that patient-derived tau exhibits seeding and neuron-to-neuron propagation properties. Interestingly, tau aggregation in AD appears to spread laterally in a proximity-dependent, cortico-cortical fashion rather than along long-range memory circuits. This contrasts with the system-selective, poly-nodal degenerations seen in four-repeat tauopathies, amyotrophic lateral sclerosis, or spinocerebellar degenerations. Moreover, the proportions of three-repeat and four-repeat isoforms shift during the maturation of NFTs in AD. Overall, spreading patterns of tau-pathology in AD cannot be fully explained by Aβ pathology and also differ from the system degeneration seen in other tauopathies.}, }
@article {pmid41466038, year = {2025}, author = {Cauchi, RJ and Tosolini, AP}, title = {ALS: a field in motion.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {44791}, pmid = {41466038}, issn = {2045-2322}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder driven by complex interactions among genetic, environmental, developmental, and resilience-related factors. The studies in this Scientific Reports’ Collection highlight major advances across diverse domains that collectively broaden our understanding of ALS pathogenesis. Genetic insights emphasise the need for functional validation, as shown by the non-pathogenic behaviour of the KIF5A P986L variant in Drosophila. Neuroimaging findings reveal hypothalamic atrophy in primary lateral sclerosis, underscoring widespread extra-motor involvement. Epidemiological analyses propose that early-life exposures may form the initial steps in a multistage pathway to ALS, while geographic correlations between ALS and multiple sclerosis suggest shared environmental determinants. Experimental model innovations demonstrate selective muscle preservation in SOD1-G93A mice and introduce electrical impedance myography as a sensitive detection method in zebrafish. Mechanistic work shows that stress influences ALS through PI3K/Akt and focal adhesion pathways, linking environment to cellular vulnerability. Finally, cognitive and brain reserve emerge as important modifiers of disease expression and progression. Together, these studies illustrate ALS as a multisystem, lifespan-spanning disorder shaped by both vulnerability and resilience. Their integration offers a forward-looking framework for advancing biomarker discovery, mechanistic research, and therapeutic development in ALS.}, }
@article {pmid41466416, year = {2026}, author = {Howard, I and Simmons, Z}, title = {Does the ACT Have ImpACT for ALS?.}, journal = {Muscle &amp; nerve}, volume = {73}, number = {3}, pages = {377-379}, doi = {10.1002/mus.70117}, pmid = {41466416}, issn = {1097-4598}, }
@article {pmid41466523, year = {2025}, author = {Watabe, K}, title = {Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70383}, pmid = {41466523}, issn = {1742-4658}, abstract = {Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki et al. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.}, }
@article {pmid41467385, year = {2025}, author = {Zhou, Z and Zhao, Y and Fan, X and Zhang, J and Niu, R and Ma, Y and Xie, F and Tang, P and Mei, X and Zhang, L and Deng, J}, title = {CD11c+ microglia: From basic research to clinical application.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00868}, pmid = {41467385}, issn = {1673-5374}, abstract = {CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c+ microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c+ microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c+ microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules (DAMPs) and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c+ microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c+ microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, IFN-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c+ biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases.}, }
@article {pmid41467421, year = {2025}, author = {Huerta, TJ and Urbina-Muñoz, V and Urra-Alvarez, V and Villablanca, C and Gomez-Perez, LS and Saavedra, B and Contreras, T and Vidal, RL}, title = {Cell-based immunotherapy for neurodegenerative disease: A promising avenue.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00816}, pmid = {41467421}, issn = {1673-5374}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are characterized by progressive neuronal loss and chronic neuroinflammation, with current treatments remaining largely symptomatic. This review explores the potential of cell-based immunotherapy as a disease-modifying strategy. Advances in stem cell biology and immune engineering have facilitated the development of therapies using mesenchymal stem cells, chimeric antigen receptor T cells, macrophages, regulatory T cells, modified macrophages, and monoclonal antibodies. These approaches aim to regulate immune mechanisms implicated in neurodegeneration, such as microglial activation, systemic inflammation, and immune checkpoint dysregulation. Notably, macrophage-mediated delivery systems, such as genetically modified cells expressing neurotrophic factors or antioxidant enzymes, have demonstrated neuroprotective effects. Likewise, emerging data support T-cell modulation and monoclonal antibody development as therapeutic targets in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. We highlight current preclinical findings, underlying mechanisms, and translational challenges, emphasizing that immunomodulatory cell therapies represent a promising avenue for precision medicine in neurodegenerative diseases.}, }
@article {pmid41467429, year = {2025}, author = {Liang, X and Qin, R and Qin, Q and Xu, W and Xu, H and Lai, X and Shao, L and Li, C and Xie, M and Xiong, X and Tang, Q and Chen, L}, title = {Therapeutic potential of astrocyte transdifferentiated neurons.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00554}, pmid = {41467429}, issn = {1673-5374}, abstract = {The permanent functional deficits resulting from the inability of adult mammalian central nervous system neurons to regenerate after injury present a significant clinical challenge. While traditional stem cell transplantation strategies continue to encounter ethical concerns and the risk of immune rejection, this impasse has shifted regenerative medicine research toward targeting endogenous astrocytes. Due to their intrinsic plasticity, widespread distribution throughout the central nervous system, and affinity for neurodevelopmental lineage, astrocytes are a unique target for in situ neuronal regeneration. This review systematically elucidates the core regulatory network governing astrocyte transdifferentiation, identifying 10 key signaling pathways, such as Wnt signaling pathway, that form a cascade regulatory system. Directed overexpression of transcription factors such as NeuroD1, Ascl1, or Neurog2 can directly initiate neuronal phenotypic conversion. Meanwhile, small molecule compounds such as valproic acid combined with CHIR99021 activate endogenous neurogenic programs by inhibiting the bone morphogenetic protein signaling axis. Notably, polypyrimidine tract binding protein 1 (PTB) gene silencing significantly enhances transdifferentiation efficiency by suppressing the microRNA 124/re1 silencing transcription factor (miR-124/REST) feedback loop. From a translational perspective, a multidimensional evaluation system based on morphological, molecular marker, and electrophysiological properties has demonstrated considerable therapeutic potential. In stroke models, NeuroD1-mediated transdifferentiation replenished approximately 30% of lost cortical neurons and improved motor coordination, evidenced by enhanced performance in food pellet retrieval, grid walking, and cylinder tests compared with controls. In spinal cord injury studies, SOX2-induced glutamatergic neurons moderately reduced glial scar density by about 25%, permitting regenerating axons to pass through while preserving the supportive structure of scar. In neurodegenerative contexts, PTB inhibition yielded functionally mature dopaminergic neurons and reconstructed nigrostriatal pathways in Parkinson's disease models. In Alzheimer's disease models, adeno-associated virus-delivered NeuroD1 induced whole-brain neural circuit remodeling, generating 500,000 new neurons widely distributed across the cortex and hippocampus, accompanied by improved cognitive performance. Current technical limitations include off-target effects of adeno-associated virus vectors, which cause nonspecific gene expression and require rigorous validation via Cre-loxP lineage tracing. Transdifferentiation efficiency is also highly influenced by regional microenvironments: gray matter astrocytes show higher conversion rates than those in white matter, and oxidative stress increases apoptosis among newly generated neurons. Clinical translation is further constrained by the safety of delivery systems and the aging tissue microenvironment, where transforming growth factor beta 1 is often elevated. Ferroptosis inhibitors have been shown to nearly double the survival rate of transdifferentiated cells, offering a novel strategy to mitigate oxidative damage. Based on current evidence, astrocyte transdifferentiation enables neural functional recovery across multiple disease models through endogenous repair mechanisms. Future advances should focus on optogenetically inducible vectors for spatiotemporal precision, non-viral delivery systems to mitigate vector-related risks, and integration of long-term safety validation in non-human primates with single-cell multi-omics technologies to facilitate the clinical translation of personalized regenerative therapies.}, }
@article {pmid41467438, year = {2025}, author = {Zhao, J and Wang, J and Guo, X}, title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00924}, pmid = {41467438}, issn = {1673-5374}, abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.}, }
@article {pmid41467439, year = {2025}, author = {Dong, T and Zhang, T and Wang, H and Zhang, J and Abdullah, R and Sun, B and Peng, G}, title = {Microbiota-gut-brain axis and bile acids-driven neuromodulation.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00927}, pmid = {41467439}, issn = {1673-5374}, abstract = {Bile acids emerge as multifunctional signaling molecules with dual hepatic and microbial origins, acting through farnesoid X receptor and Takeda G protein coupled receptor 5 to influence inflammation and metabolism. Their dysregulation is consistently observed across various neurodegenerative diseases. The microbiota-gut-brain axis is a pivotal conduit for bile acids-driven neuromodulation, while sex-specific bile acid profiles and signaling pathways introduce critical biological heterogeneity. Emerging translational evidence indicates the promise of bile acids as biomarkers and therapeutic targets, yet highlights the critical hurdles that need to be addressed to realize precision interventions. Our core findings are: (1) Bile acids are far more than mere metabolic byproducts. They orchestrate core pathological processes such as neuroinflammation and energy metabolism. Their functions, whether neuroprotective or neurotoxic, are highly context-dependent, varying with cell type and disease-specific pathological backgrounds, thus exhibiting a potent "double-edged sword" effect. (2) The "microbiota-bile acids-brain axis" serves as a crucial bridge linking peripheral metabolic dysregulation to central nervous system pathology. (3) Sexual dimorphism emerges as a fundamental biological variable essential for understanding the heterogeneity in bile acid profiles and disease susceptibility. The primary contribution of this work is the proposal of an integrated "microbiota-bile acids-sex" framework that systematically describes the key scientific challenge of the context-dependent, dual roles of bile acids. Ultimately, this review champions a paradigm shift from a traditional brain-centric view to a systemic, metabolic perspective, establishing the bile acid system as a promising target for future precision therapeutic interventions.}, }
@article {pmid41467440, year = {2025}, author = {Akbergenov, R and Wolfer, DP and Gillingham, D and Shcherbakov, D}, title = {Error-prone translation as a driver of proteostasis collapse and neurodegeneration.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00795}, pmid = {41467440}, issn = {1673-5374}, abstract = {Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular "tipping point" initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration.}, }
@article {pmid41467443, year = {2025}, author = {Yang, Y and Chen, M and Ding, L and Liu, J and Luo, J and Yan, R and Ning, J and Xie, S and Li, X and Ren, Z and Zhou, R and Chen, Z}, title = {Mitochondria-associated endoplasmic reticulum membranes and calcium ion exchange: A novel direction for aging and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00857}, pmid = {41467443}, issn = {1673-5374}, abstract = {Mitochondria-associated endoplasmic reticulum membranes serve as crucial signaling hubs mediating communication between the endoplasmic reticulum and mitochondria, and play a central role in calcium ion exchange. This dynamic interface regulates key cellular processes including bioenergetic metabolism, apoptosis, autophagy, and stress responses. Dysregulation of calcium transport associated with mitochondria-associated endoplasmic reticulum membranes can disrupt intracellular homeostasis, leading to mitochondrial dysfunction, oxidative stress, and neuronal death, which are hallmarks of aging and neurodegenerative diseases. This review systematically examines the functions of protein complexes within mitochondria-associated endoplasmic reticulum membranes and the pathogenic mechanisms of calcium signaling regulated by these membranes in neurodegenerative disorders. It places particular emphasis on structural alterations in calcium ion transport machinery as a common mechanism underlying various neurodegenerative diseases. In Alzheimer's disease, mitochondria-associated endoplasmic reticulum membranes exhibit a hyperactive state, promoting the generation of amyloid-β and enhancing calcium ion flux from the endoplasmic reticulum to the mitochondria. In contrast, in Parkinson's disease and amyotrophic lateral sclerosis, the activity of mitochondria-associated endoplasmic reticulum membranes is reduced, leading to a decline in mitochondrial calcium ion buffering capacity and exacerbating excitotoxicity. Proteins residing in mitochondria-associated endoplasmic reticulum membranes are disrupted across various neurodegenerative diseases, resulting in abnormal communication between the endoplasmic reticulum and mitochondria. Recent studies indicate that mitochondria-associated endoplasmic reticulum membranes play a bidirectional role in disease progression, and compensatory mechanisms often exacerbate the pathological process. Therapeutic strategies aimed at preserving the integrity of mitochondria-associated endoplasmic reticulum membranes hold promise for alleviating neurodegenerative damage. Therefore, calcium ion exchange mediated by mitochondria-associated endoplasmic reticulum membranes plays a key role in aging and neurodegenerative diseases, making it a highly promising therapeutic target.}, }
@article {pmid41467445, year = {2025}, author = {Dikwella, N and Lingor, P and Tzeplaeff, L}, title = {Seeing amyotrophic lateral sclerosis in a multi-omic perspective.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01010}, pmid = {41467445}, issn = {1673-5374}, }
@article {pmid41468379, year = {2025}, author = {Spencer, BE and Irwin, DJ and Van Deerlin, VM and Suh, E and Lee, EB and Elman, L and Quinn, CC and Amado, D and Baer, M and Grossman, M and Wolk, DA and McMillan, CT}, title = {Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies.}, journal = {PloS one}, volume = {20}, number = {12}, pages = {e0338398}, pmid = {41468379}, issn = {1932-6203}, support = {RF1 NS145263/NS/NINDS NIH HHS/United States ; F32 AG079618/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Multifactorial Inheritance ; *TDP-43 Proteinopathies/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Male ; Female ; *DNA-Binding Proteins/genetics ; Aged ; Phenotype ; Middle Aged ; Genetic Predisposition to Disease ; }, abstract = {TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies. We used weighted correlation analysis of GWAS summary statistics for ALS, FTLD-TDP, and hippocampal sclerosis of aging (HS-Aging) to identify data-driven clusters of highly correlated single nucleotide polymorphisms (SNPs). We performed gene ontology enrichment analysis for each identified cluster. We derived cluster-specific polygenic scores and evaluated their association with clinical and neuropathological traits in an independently evaluated sample of individuals who met neuropathological and/or genetic criteria for FTLD-TDP or ALS (n = 260). We identified 5 distinct data-driven clusters, including 3 GWAS phenotype-specific clusters (FTLD-TDP, ALS, HS-Aging) and 2 clusters representing the overlap between a pair of GWAS phenotypes (ALS-FTLD and FTLD-HS). Pathway analysis revealed biologically meaningful associations including distinct GWAS phenotype-specific processes within clusters. Cluster-specific ALS and FTLD-TDP polygenic risk each associated with individual-level clinical traits, even within the context of autosomal dominant mutation carriers, where higher ALS polygenic risk associated with neuromuscular impairment and higher FTLD-TDP polygenic risk associated with cognitive-behavioral impairment. Moreover, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden within characteristic FTLD-TDP brain regions. We suggest that there are polygenic modifiers of clinical and neuropathological traits across TDP-43 proteinopathies that may contribute to individual-level differences, including likelihood for developing FTLD or ALS.}, }
@article {pmid41468784, year = {2026}, author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D}, title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.}, journal = {Neuropeptides}, volume = {115}, number = {}, pages = {102583}, doi = {10.1016/j.npep.2025.102583}, pmid = {41468784}, issn = {1532-2785}, mesh = {Humans ; *Neuropeptide Y/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; Signal Transduction/physiology ; Oxidative Stress/physiology ; Receptors, Neuropeptide Y/metabolism ; }, abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.}, }
@article {pmid41471389, year = {2025}, author = {Gershoni Emek, N and Tan, AM and Geva, M and Fekete, A and Abate, C and Hayden, MR}, title = {Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {12}, pages = {}, pmid = {41471389}, issn = {1424-8247}, abstract = {Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca[2+] homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine's mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine's S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.}, }
@article {pmid41472414, year = {2026}, author = {Wu, J and Tao, Z and Cao, J and Hu, W and Jiang, M and Li, Y and Cao, H and Liao, M and Zhao, N}, title = {Cytochrome P450 and glutathione S-transferase may confer bensulfuron-methyl resistance in Cyperus iria.}, journal = {Pest management science}, volume = {82}, number = {4}, pages = {3708-3716}, doi = {10.1002/ps.70492}, pmid = {41472414}, issn = {1526-4998}, support = {2021YFD1700100//National Key Research and Development Program of China/ ; X202510364082//College Students' Innovation Training Project in Anhui Agricultural University/ ; }, mesh = {*Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Herbicides/pharmacology ; *Sulfonylurea Compounds/pharmacology ; *Cyperus/drug effects/genetics/enzymology/metabolism ; *Glutathione Transferase/metabolism/genetics ; *Plant Proteins/metabolism/genetics/chemistry ; Acetolactate Synthase/genetics ; }, abstract = {BACKGROUND: Rice flatsedge (Cyperus iria L.) is one of the most troublesome weeds infesting rice fields across China. Bensulfuron-methyl, an acetolactate synthase (ALS)-inhibiting herbicide, has been widely used for the control of Cyperaceae weeds in rice production. However, long-term and extensive use of this herbicide has resulted in the evolution of resistant C. iria populations. In this study, a suspected bensulfuron-methyl-resistant (R) population collected from a rice field that survived field-recommended applications was investigated to elucidate its resistance level and underlying mechanism.<br><br>RESULTS: Compared with a susceptible (S) population, the R population exhibited a high level of resistance to bensulfuron-methyl [resistance index (RI)&#x2009;=&#x2009;12.88] and cross-resistance to metazosulfuron (RI&#x2009;=&#x2009;11.66), bispyribac-sodium (RI&#x2009;=&#x2009;9.10) and penoxsulam (RI&#x2009;=&#x2009;6.35). No mutations were detected in the ALS gene, and ALS expression levels did not differ significantly between the R and S plants. Pretreatment with the cytochrome P450 inhibitor malathion and the glutathione S-transferase inhibitor 4-chloro-7-nitrobenzoxadiazole effectively reversed bensulfuron-methyl resistance in R plants. Liquid chromatography tandem mass spectrometry analysis showed that the R plants metabolized bensulfuron-methyl significantly faster than the S plants. RNA sequenccing analysis revealed remarkable upregulation of CYP97A3 and GSTF1 in the R population, while molecular docking indicated strong binding affinities between both enzymes and bensulfuron-methyl at their active sites.<br><br>CONCLUSION: These results reveal that enhanced expression of CYP97A3 and GSTF1 may contribute to bensulfuron-methyl resistance in C. iria, highlighting the role of metabolic detoxification in the evolution of non-target-site resistance in this species. &#xa9; 2025 Society of Chemical Industry.}, }
@article {pmid41474642, year = {2026}, author = {Luo, H and Yang, Y and Cao, X and Deng, C and Chen, H}, title = {Unveiling the Genetic Association Between Hemoglobin Concentration and Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {16}, number = {1}, pages = {e71152}, pmid = {41474642}, issn = {2162-3279}, support = {82171422//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/blood ; *Hemoglobins/genetics/metabolism ; Genome-Wide Association Study ; Motor Neurons/metabolism ; Mendelian Randomization Analysis ; Induced Pluripotent Stem Cells/metabolism ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Although previous studies have suggested an association between hemoglobin (Hb) concentration and amyotrophic lateral sclerosis (ALS), the precise cause-and-effect relationship between them is still unclear. This study aims to investigate the causal correlation between Hb concentration and ALS, and explore the potential genes related to their association.<br><br>METHODS: We extracted summary statistical data of Hb concentration and ALS from genome-wide association studies (GWAS), performed Mendelian randomization (MR) analyses, and conducted RNA sequencing of motor neurons different from ALS patient-derived induced pluripotent stem cells (iPSCs), followed by an intersection analysis between differentially expressed genes (DEGs) in ALS motor neurons and selected instrumental variables (IVs) associated with Hb concentration.<br><br>RESULTS: As a result, Hb concentration had a negative causal relationship with the risk of ALS, established through IVW (OR = 0.854; 95% CI: 0.767-0.951; p = 0.00418) of the univariable MR analysis. A multivariable MR further confirmed that this causal link remained robust, even when accounting for confounders including systolic blood pressure, total cholesterol levels, body mass index, LDL cholesterol, diastolic blood pressure, and smoking. Importantly, genetically predicted ALS did not show a causal connection to Hb concentration. Additionally, RNA sequencing analysis and qRT-PCR results revealed that transcripts for BACH1 and FLVCR1 were upregulated, while those for TRIM58 were downregulated in SOD1[D90A] ALS motor neurons, compared to the control. In motor neurons differentiated from a sporadic ALS patient-derived iPSCs, qRT-PCR showed increased transcript levels of BACH1, and decreased transcript levels of FLVCR1 and TRIM58. These three genes were intersected with harmonized SNPs between Hb concentration and ALS.<br><br>CONCLUSION: Our study concludes that genetically predicted Hb concentration exhibited an independent inverse causal association with the risk of developing ALS, with potential involvement of genes such as BACH1, FLVCR1, and TRIM58.}, }
@article {pmid41475066, year = {2026}, author = {Kaji, R and Nishi, Y and Ishida, T and Takase, T and Ueda, T and Maeda, T and Izumi, Y and , }, title = {Clinical safety of ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis: Open-label extension of a phase 2/3 randomized controlled study.}, journal = {Journal of the neurological sciences}, volume = {480}, number = {}, pages = {125701}, doi = {10.1016/j.jns.2025.125701}, pmid = {41475066}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; *Vitamin B 12/analogs &amp; derivatives/adverse effects/administration &amp; dosage/therapeutic use ; Female ; Middle Aged ; Aged ; Double-Blind Method ; Treatment Outcome ; Injections, Intramuscular ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {OBJECTIVE: To develop combined therapies for amyotrophic lateral sclerosis (ALS), we investigated the long-term safety of ultra-high-dose methylcobalamin (50-mg intramuscular, twice weekly) in patients with advanced ALS.<br><br>METHODS: As an open-label extension of a multicenter, randomized, double-blind, placebo-controlled phase 2/3 study, patients were enrolled and administered methylcobalamin 50&#xa0;mg intramuscularly twice weekly for up to 52&#xa0;weeks.<br><br>RESULTS: In total, 144 patients (mean age, 62.1&#xa0;years; 61.1&#xa0;% male) were included, and the overall disease duration was 53.2&#xa0;&#xb1;&#xa0;17.9&#xa0;months, with 85.4&#xa0;% of patients having an ALS severity stage &#x2265;3. The incidence of adverse events was 94.4&#xa0;%, and adverse drug reactions occurred in 3.5&#xa0;% of patients, which included proteinuria (2.1&#xa0;%) and single cases of supraventricular arrhythmia, increased blood urea, and hypertension (0.7&#xa0;% each). None led to discontinuation or death. The survival rate at 52&#xa0;weeks was 85.7&#xa0;%, and as shown for the following patient subgroups: by ALS severity (stage 1-2, 100&#xa0;%; 3, 85.3&#xa0;%; 4, 82.8&#xa0;%; 5, 82.0&#xa0;%) and by presence of tracheostomy (with, 88.8&#xa0;%; without, 84.1&#xa0;%). The median change in the ALS functional rating scale total score from baseline to 52&#xa0;weeks was -1.0.<br><br>CONCLUSION: There were no particular safety issues as reported in the phase 2/3 study and no clear deterioration in survival rate or physical function when ultra-high-dose methylcobalamin was administered intramuscularly in patients with advanced ALS. This regimen could be a candidate for initial therapy with further add-on to overcome ALS in the future.}, }
@article {pmid41475349, year = {2026}, author = {Dubey, SK and Chaubey, D and Ikenaga, C and Lin, WW and Bellen, HJ and Lloyd, TE}, title = {Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.}, journal = {Neuron}, volume = {114}, number = {5}, pages = {850-867.e8}, doi = {10.1016/j.neuron.2025.11.017}, pmid = {41475349}, issn = {1097-4199}, support = {R01 AG068043/AG/NIA NIH HHS/United States ; R01 AR076390/AR/NIAMS NIH HHS/United States ; }, mesh = {*Valosin Containing Protein/genetics/metabolism ; Animals ; Humans ; *Nuclear Pore/metabolism/genetics ; Drosophila Proteins/metabolism/genetics ; Drosophila ; *Nuclear Pore Complex Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Mutation ; Active Transport, Cell Nucleus ; Nuclear Proteins/metabolism ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants cause a reduction in nucleoporins in Drosophila, induced pluripotent stem cell (iPSC)-derived motor neurons, and muscle biopsies from patients, indicating a dominant gain-of-function mechanism. Mechanistically, disease-associated mutations in VCP result in increased recruitment to NPCs through interactions with Ufd1-Npl4, leading to the removal of a subset of nucleoporins from NPCs and disrupting NCT. These findings show that the VCP-Ufd1-Npl4 pathway regulates NPC quality control and that disease-associated variants aberrantly activate the VCP-Ufd1-Npl4 complex to degrade NPCs and disrupt NCT.}, }
@article {pmid41475669, year = {2026}, author = {Mirzalieva, O and Reed, RE and Haas, AL and Juncker, MA and Logarbo, P and Klein, JM and Worthylake, D and Desai, SD}, title = {ISG15 dysregulates endoplasmic reticulum-mitochondrial contacts and calcium homeostasis in Ataxia telangiectasia.}, journal = {Cellular signalling}, volume = {139}, number = {}, pages = {112347}, doi = {10.1016/j.cellsig.2025.112347}, pmid = {41475669}, issn = {1873-3913}, mesh = {*Mitochondria/metabolism ; *Endoplasmic Reticulum/metabolism ; Humans ; *Calcium/metabolism ; Homeostasis ; *Cytokines/metabolism/genetics ; *Ubiquitins/metabolism/genetics ; Fibroblasts/metabolism ; GTP Phosphohydrolases/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Mitochondrial Proteins/metabolism ; }, abstract = {Dysregulation of endoplasmic reticulum and mitochondrial (ER:Mit) contacts and mitochondrial calcium (mitCa[2+]) homeostasis are found in several neurodegenerative disorders, including Ataxia Telangiectasia (A-T). However, the cellular basis of these defects remains unclear. Previously, we demonstrated that the aberrantly elevated Interferon-Stimulated Gene 15 (ISG15) pathway inhibits protein polyubiquitylation, its dependent protein turnover, and mitophagy pathways in A-T. Literature indicates that silencing of mitochondrial ubiquitin ligase 1 (MUL1) stabilizes mitofusin2 (MFN2) and attenuates mitCa[2+] uptake from ER to Mit (mitCa[2+]influx) in primary neurons. We have replicated these findings in apparently healthy fibroblasts. We hypothesized that elevated ISG15 may inhibit ubiquitin-dependent MUL1-mediated degradation of MFN2 and dysregulate ER:Mit contacts and mitCa[2+] homeostasis in A-T fibroblasts. Concurrently, MFN2 is stabilized in A-T, MUL1-silenced A-T, MUL1/ISG15-silenced A-T vs ISG15-silenced A-T fibroblasts. Moreover, the number of ER:Mit contacts is increased in A-T vs ISG15-silenced A-T fibroblasts. Notably, mitCa[2+]efflux is significantly attenuated in A-T vs ISG15-silenced A-T fibroblasts in which mitCa[2+]efflux is restored to levels comparable to those observed in normal fibroblasts. The mitCa[2+]efflux remains attenuated in MUL1 and MUL1/ISG15-silenced A-T fibroblasts. We conclude that ISG15 impairs MUL1/MFN2-mediated regulation of ER:Mit contacts and attenuates mitCa[2+]efflux, which may, in turn, cause Ca[2+] overload-mediated mitochondrial damage in A-T. These findings suggest that ISG15 silencers may correct mitochondrial abnormalities and improve mitochondrial health in A-T patients and in those with other neurodegenerative disorders in which ISG15 is elevated, such as ALS.}, }
@article {pmid41476266, year = {2026}, author = {Cai, F and Xu, D and Yang, D and Huang, F and Song, X and Jiang, Q and Wan, S and Zhao, Y and Zhou, J}, title = {Multidimensional predictors of fatigue in amyotrophic lateral sclerosis: a cross-sectional study in China.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3294}, pmid = {41476266}, issn = {2045-2322}, support = {Grant No. ZY2025Q006//Hubei Provincial Administration of Traditional Chinese Medicine/ ; Grant No. 82575246//National Natural Science Foundation of China/ ; GZY-KJS-2025-008 and Joint Fund, 2023AFD128//Science and Technology Special Project of State Administration of Traditional Chinese Medicine and Hubei Provincial Natural Science Foundation/ ; }, abstract = {UNLABELLED: This study aims to identify key predictors of fatigue in patients with amyotrophic lateral sclerosis (ALS) and examine the interaction of physiological, psychological, and social factors to inform management strategies. A descriptive cross-sectional study. Between June 2023 and June 2024, a cohort of 239 patients diagnosed with ALS enrolled at the Integrated Traditional Chinese and Western Medicine Center, Hubei Provincial Hospital of Traditional Chinese Medicine. The participants were evaluated using validated instruments that assessed motor function, depressive symptoms, sleep quality, and social determinants. Stepwise multiple regression analysis was conducted to identify independent predictors of fatigue. The ALS Functional Rating Scale-Revised (ALSFRS-R), depression (PHQ-9), sleep quality (PSQI), and residential status were significant predictors of fatigue, accounting for 28.6% of the variance (R[2]= 0.286). The use of traditional Chinese medicine was associated with a reduction in fatigue, whereas muscle strength exhibited an inverse correlation with the severity of fatigue. Fatigue in ALS is influenced by multiple factors, extending beyond motor decline to include psychological well-being, sleep quality, and the social environment. These findings highlight the need for multidisciplinary, personalized strategies that integrate both biomedical and supportive care approaches to enhance the quality of life for ALS patients.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-33192-3.}, }
@article {pmid41476438, year = {2025}, author = {Oza, R}, title = {Physical Activity as an Intervention for Frailty Syndrome: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100293}, pmid = {41476438}, issn = {2168-8184}, abstract = {Frailty is a geriatric syndrome characterised by a decline in functional reserves as the body ages, resulting in increased disability, comorbidity, and mortality. With trends towards ageing populations, frailty syndrome becomes more clinically relevant, highlighting the importance of appropriately preventing and managing the characteristics of frailty syndrome. Risk factor modification is recommended to delay or prevent the onset of frailty, including physical activity alongside other modifiable behaviours such as diet. Ageing is associated with chronic low-grade inflammation, resulting in reduced muscle protein synthesis and increased resistance to insulin, which both contribute to sarcopenia. Sarcopenia underpins key characteristics of frailty, including weakness and slow speed. Physical activity stimulates anabolic pathways and improves insulin resistance, reducing sarcopenia. Moreover, aerobic exercise is responsible for increasing the VO2 peak, whilst resistance exercise improves muscle strength, both of which are known to decrease in frail elders. This narrative review primarily explored the effectiveness of physical activity in reducing the risk of the onset of frailty syndrome through a narrative review of the relevant literature concerning this subject. A secondary focus of this narrative review is to compare the success of alternative interventions for preventing frailty, relative to physical activity. Physical activity interventions have been shown to improve components of frailty scoring and selected biological markers of frailty, with evidence suggesting physical activity is an effective single-domain intervention for frailty; however, multidomain approaches may result in a greater overall improvement in frailty prevention. Further research is required to identify the types of exercise that modify specific aspects of Fried et al.'s frailty criteria (FFC), as well as what interventions can be used alongside physical activity, to holistically treat all characteristics of frailty syndrome.}, }
@article {pmid41476442, year = {2025}, author = {Kato, N and Hashida, G and Sahara, W}, title = {Short-Term Effects of Exercise Therapy on Muscle Characteristics in Patients With Mild-to-Moderate Amyotrophic Lateral Sclerosis: A Preliminary Case Series Study.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100383}, pmid = {41476442}, issn = {2168-8184}, abstract = {BACKGROUND: Exercise therapy is recommended for patients with amyotrophic lateral sclerosis (ALS), but its effects on muscle mass and intramuscular conditions remain unclear. In recent years, ultrasonography has enabled the simple and non-invasive estimation of muscle mass and intramuscular conditions. This study aimed to investigate the short-term effects of exercise therapy on muscle characteristics in patients with mild-to-moderate ALS using ultrasonography.<br><br>METHODS: &#xa0;Ambulatory patients with ALS and an ALS Functional Rating Scale-Revised (ALSFRS-R) score of &#x2265;30 underwent moderate-intensity exercise therapy for 3-4 weeks. Primary outcome measures included muscle strength (handgrip strength (HGS) and ankle dorsiflexion strength (ADFS)), muscle thickness (MT), echo intensity (EI), and the ratio of muscle strength to muscle thickness for both the forearm muscles and the tibialis anterior muscle. The Bayesian Wilcoxon signed-rank test was used to compare outcomes before and after the intervention.<br><br>RESULTS: &#xa0;Six consecutive patients with ALS (median age: 75.5 years; three males&#xa0;(50%) and three females&#xa0;(50%); four with bulbar onset&#xa0;(66.7%) and two with upper limb onset&#xa0;(33.3%)) were included. Following the intervention, the muscle thickness of the forearm muscles and the tibialis anterior muscle decreased. However, qualitative muscle characteristics were partially maintained or improved: the echo intensity of the forearm muscles was maintained, and the ratio of ankle dorsiflexion strength to muscle thickness of the tibialis anterior muscle showed a large increase.<br><br>CONCLUSION: &#xa0;In patients with mild-to-moderate ALS, exercise therapy resulted in short-term qualitative changes in muscle, while a concurrent reduction in muscle mass may have attenuated these effects. The benefits of exercise therapy may have been counteracted by muscle mass loss, suggesting the need for future studies to investigate the combined effects of exercise and nutritional therapy on muscle characteristics and activities of daily living (ADL).}, }
@article {pmid41477139, year = {2025}, author = {Syamal, M}, title = {Treatment of Neurogenic Voice Disorders.}, journal = {World journal of otorhinolaryngology - head and neck surgery}, volume = {11}, number = {4}, pages = {541-547}, pmid = {41477139}, issn = {2589-1081}, abstract = {This overview serves as a foundational resource for clinicians caring for neurologically complex patients presenting with voice complaints. Neurogenic voice disorders are diverse in their clinical presentations and therapeutic approaches. A thorough medical history, including family history, detailed laryngeal examination, voice assessments, and neuroimaging, are imperative, as well as a multidisciplinary, collaborative approach with neurologists, speech language pathologists, and patient caregivers. Disorders such as amyotrophic lateral sclerosis (ALS), cerebrovascular accidents (strokes), Huntington's disease, myasthenia gravis (MG), Parkinson's disease (PD), and voice tremor should be understood by otolaryngologists. Each condition presents unique challenges and requires tailored treatment strategies ranging from supportive therapies and pharmacological interventions to surgery. Voice management techniques, including the use of botulinum toxin for hyperkinetic disorders and deep brain stimulation for refractory cases, are highlighted as promising interventions.}, }
@article {pmid41477570, year = {2025}, author = {Almalki, MG and Abdel-Aziem, AA}, title = {Validation and cross-cultural adaptation of an Arabic version of the chronic pain self-efficacy scale.}, journal = {Hong Kong physiotherapy journal : official publication of the Hong Kong Physiotherapy Association Limited = Wu li chih liao}, volume = {45}, number = {2}, pages = {143-155}, pmid = {41477570}, issn = {1013-7025}, abstract = {BACKGROUND: Self-efficacy in pain sufferers includes beliefs about one's capacity to tolerate pain. For usage by Arabic-speaking individuals, the Chronic Pain Self-Efficacy Scale (CPSS), which was initially developed in English, must be translated and modified into the Arabic language.<br><br>OBJECTIVE: To assess the CPSS's psychometric qualities for subjects suffering from chronic pain in Arabic.<br><br>METHODS: This was a cross-sectional survey that followed Beaton et&#xa0;al.'s guidelines. The CPSS underwent cross-cultural adaptation and Arabic translation in the initial phase. Then, the reliability and validity of the Arabic version of CPSS were examined. A total of 329 patients completed the questionnaire (40.7% males and 59.3% females).<br><br>RESULTS: The subscales had good internal consistency, the Cronbach's alpha was 0.870 for subscale 1 (self-efficacy for managing pain), 0.935 for subscale 2 (physical function self-efficacy), and 0.925 for subscale 3 (coping with other symptoms self-efficacy). Test-retest total scores had an acceptable intraclass correlation coefficient (ICC) of 0.743 (95% CI -0.29 to -0.196, p = 0 . 92). When performing principal component analysis with varimax rotation [exploratory factor analysis (EFA)> 0 . 4 ], the test is helpful. Regarding construct validity, the correlation between the total score of Beck depression inventory (BDI) and CPSS subscales and total score have significant moderate negative correlations (r =- 0 . 479 ; p = 0 . 001) except the pain management subscale has significantly weak negative correlations (r =- 0 . 345 ; p = 0 . 001).<br><br>CONCLUSION: The Arabic version seems to be a reliable and valid instrument for evaluating a person's self-efficacy in chronic pain among Arabic-speaking individuals making it a good and acceptable instrument.}, }
@article {pmid41478512, year = {2026}, author = {Strohmer, B and Grosh, K and Montañana-Rosell, R and Mora, S and Ausborn, J and Allodi, I}, title = {Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107253}, pmid = {41478512}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/pathology ; *Motor Neurons/physiology ; Animals ; *Spinal Cord/physiopathology ; Computer Simulation ; Interneurons/physiology ; Mice ; Humans ; *Models, Neurological ; *Nerve Net/physiopathology ; Disease Models, Animal ; *Neural Networks, Computer ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1-motoneuron connections improved motor function and saved motoneurons in the SOD1[G93A] ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor-extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1[G93A] ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.}, }
@article {pmid41479097, year = {2026}, author = {Stamatelopoulos, D and Papakonstantinou, E and Bacopoulou, F and Vlachakis, D}, title = {Polyphenols from Olive Oil: A Promising Therapeutic Approach for Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1490}, number = {}, pages = {343-349}, pmid = {41479097}, issn = {0065-2598}, mesh = {*Olive Oil/chemistry/therapeutic use ; Humans ; *Polyphenols/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use ; Animals ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use ; Diet, Mediterranean ; Anti-Inflammatory Agents/therapeutic use ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, and Huntington's disease pose a growing global health challenge due to their prevalence in aging populations and their devastating impact on cognitive and motor functions. Current treatments focus on symptom management, with no options available to reverse neuronal damage. Emerging evidence highlights the potential role of extra virgin olive oil (EVOO) polyphenols in neuroprotection, particularly in the context of the Mediterranean diet, which is associated with lower rates of neurodegenerative disorders. EVOO's rich polyphenolic compounds, including hydroxytyrosol, oleuropein, tyrosol, and oleocanthal, exhibit potent antioxidant, anti-inflammatory, and neuroprotective properties. These bioactive molecules have shown potential in modulating disease-specific pathways, such as reducing oxidative stress, inhibiting abnormal protein aggregation, and regulating neuroinflammation. This paper explores the therapeutic potential of olive oil polyphenols for neurodegenerative diseases, detailing their mechanisms of action across different conditions. Our findings suggest that incorporating EVOO into dietary and medical interventions could serve as a promising strategy for mitigating neurodegenerative disease progression and enhancing cognitive health.}, }
@article {pmid41479703, year = {2025}, author = {Wan, P and Zhou, SQ and Ke, QH}, title = {Very early recurrence after pancreatic cancer resection: Unmasking the "biological R2" enigma and rethinking prognostic paradigms.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {12}, pages = {114403}, pmid = {41479703}, issn = {1948-9366}, abstract = {Pancreatic ductal adenocarcinoma (PDAC), a "silent killer" with elusive early symptoms and poor prognosis, sees nearly half of patients experience recurrence within a year post-curative-intent surgery. Very early recurrence (VER), defined as recurrence within 12 weeks postoperatively and first termed "biological R2 resection" by Belfiori et al, remains a clinical puzzle. Martlı et al's recent retrospective cohort study offers crucial insights into this understudied issue, identifies predictive factors that challenge long-held beliefs, and calls for a rethink of risk stratification and postoperative management for PDAC patients. Martlı et al studied 303 PDAC patients at a high-volume center from 2019 to 2024, with VER affecting 9.24% (28 patients) of the cohort. The study's strength lies in combining traditional statistical analyses and machine learning (random forest modeling) to capture nonlinear relationships between clinicopathological factors and VER risk. Key findings include: (1) Poorly differentiated (G3) tumors are the strongest VER predictor (OR = 2.43, P < 0.001; random forest importance score = 0.35), with 92.85% of VER patients having G3 tumors (vs 45.81% of non-VER patients); (2) Contrary to prior studies, pancreatic head tumors (89.28% of VER patients vs 83.66% of non-VER patients, P = 0.031) were linked to VER; (3) Elevated red cell distribution width is a weaker predictor (random forest importance score = 0.20, P = 0.03 for group difference, P = 0.079 in multivariate analysis); and (4) VER correlates with significantly higher 6-month mortality (32.44% vs 14.77% in non-VER patients, P = 0.032).}, }
@article {pmid41479723, year = {2025}, author = {Jing, C and Liu, K}, title = {Taming colonic anastomotic leakage: Wisdom from the ancient Chinese legend of Yu the Great.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {12}, pages = {113423}, pmid = {41479723}, issn = {1948-9366}, abstract = {Colonic anastomotic leakage (AL) remains the most severe complication of colorectal surgery, significantly increasing morbidity, mortality, and healthcare burdens. The ideal solution - complete AL prevention without a defunctioning stoma - has long eluded surgeons and patients. Hu et al proposed total enteric flow diversion using a modified ileostomy tube with an inflatable balloon, demonstrating its efficacy in completely preventing AL in porcine models. This innovation echoes the ancient legend of Yu the Great, a Chinese hero renowned for taming the Yellow River's catastrophic floods. Unlike his father, who failed by merely building embankments to block water, Yu succeeded by dredging channels to redirect floods seaward. This paradigm of "diversion over obstruction" applies equally to AL prevention. Beyond Hu et al's balloon technique, alternatives like the C-seal, the SafeHeal Colovac+ anastomosis protection device and Tong et al's biodegradable stent-based diverting techniques show promise in clinical trials. Key challenges remain: Diversion efficiency, device migration risks, and patient tolerance. We must accelerate such like breakthroughs in non-stoma diversion strategies to transform AL management.}, }
@article {pmid41479929, year = {2025}, author = {Bagrodia, A and Vaithiyam, V and Laguduva Mohan, S}, title = {Large colorectal lesions: Expanding the boundaries of endoscopic management.}, journal = {World journal of gastrointestinal endoscopy}, volume = {17}, number = {12}, pages = {115008}, pmid = {41479929}, issn = {1948-5190}, abstract = {Large colorectal lesions (≥ 3 cm) present a significant therapeutic challenge due to their potential for malignancy and the technical difficulties they encounter. Endoscopic resection techniques, including endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection, have revolutionized the management of these lesions by offering organ-preserving alternatives to surgery with favorable outcomes. We read with great interest and commended Zhu et al for their valuable study on the endoscopic treatment of large colorectal lesions. Zhu et al's study provides crucial real-world evidence regarding the safety and effectiveness of advanced endoscopic resection techniques in this challenging patient group. These findings support the possibility of achieving high rates of complete resection with acceptable adverse event profiles, reinforcing the role of endoscopic mucosal resection and submucosal dissection in routine practice. This editorial also offers a comprehensive review of the current literature, discusses its clinical implications, explores future directions, and compares endoscopic resection methods with surgical options. Zhu et al's study findings not only validate the efficacy of advanced endoscopic resection but also signify a paradigm shift from surgical to organ-preserving strategies in colorectal oncology, a transformation that requires deliberate system-wide training and capacity building.}, }
@article {pmid41479978, year = {2025}, author = {Chang, X}, title = {The impact of phrasing on advice-taking under gain and loss frames in a reinforcement learning paradigm.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1693546}, pmid = {41479978}, issn = {1664-1078}, abstract = {INTRODUCTION: Grounded in Behrens et al.'s (2008) advice-taking paradigm, this study investigates how advice phrasing (positive vs. negative) and task framing (gain vs. loss) influence the extent to which individuals integrate advice during decision-making. Rather than focusing on isolated choice outcomes, we examined the cognitive processes underlying advice use through a reinforcement learning (RL) framework.<br><br>METHODS: Across two experiments (N = 38 and N = 74), participants completed probabilistic decision-making tasks while receiving trial-by-trial advice. Computational modeling was used to estimate the latent advice reference weight (&#x3c9;), reflecting reliance on advice throughout the learning process, as well as the advice-specific learning rate (&#x3b1; a). Behavioral measures of advice-taking (advice-choice consistency) were analyzed alongside modeling-derived parameters.<br><br>RESULTS: Both behavioral indices and parameter estimates showed that participants relied more on positively phrased advice than negatively phrased advice. Moreover, advice phrasing interacted with task framing: positively phrased advice exerted a stronger influence under the gain frame, whereas negatively phrased advice was more influential under the loss frame. This interaction was robustly captured by the modeled advice-weight parameter (&#x3c9;), although not consistently evident in behavioral choice patterns. Modeling results further showed that the advice-specific learning rate (&#x3b1; a) was significantly higher for positively phrased advice, suggesting greater updating from such information.<br><br>DISCUSSION: These findings provide a mechanistic understanding of how social (advice phrasing) and contextual (task framing) features jointly shape advice integration and inform more effective communication strategies in decision-making contexts.}, }
@article {pmid41480190, year = {2025}, author = {Ganzetti, M and Valsasina, P and Barkhof, F and Rocca, MA and Filippi, M and Prados, F and Craveiro, L}, title = {SynSpine: an automated workflow for the generation of longitudinal spinal cord synthetic MRI data.}, journal = {Frontiers in neuroinformatics}, volume = {19}, number = {}, pages = {1649440}, pmid = {41480190}, issn = {1662-5196}, abstract = {BACKGROUND: Spinal cord atrophy is a key biomarker for tracking disease progression in neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and spinal cord injury. Recent MRI advancements have improved atrophy detection, particularly in the cervical region, facilitating longitudinal studies. However, validating atrophy quantification algorithms remains challenging due to limited ground truth data.<br><br>OBJECTIVE: This study introduces SynSpine, a workflow for generating synthetic spinal cord MRI data (i.e., digital phantoms) with controlled levels of artificial atrophy. These phantoms support the development and preliminary validation of spinal cord imaging pipelines designed to measure degeneration over time.<br><br>METHODS: The workflow consists of two phases: (1) generating synthetic MR images by isolating, extracting and scaling the spinal cord, simulating atrophy on the PAM50 template; (2) performing non-rigid registration to align the synthetic images with the subject's native space, ensuring accurate anatomical correspondence. A proof-of-concept application utilizing the Active Surface and Reg methods implemented in Jim demonstrated its effectiveness in detecting atrophy across various levels of simulated atrophy and noise.<br><br>RESULTS: SynSpine successfully generates synthetic spinal cord images with varying atrophy levels. Non-rigid registration did not significantly affect atrophy measurements. Atrophy estimation errors, estimated using Active Surface and Reg methods, varied with both simulated atrophy magnitude and noise level, exhibiting region-dependent differences. Increased noise led to higher measurement errors.<br><br>CONCLUSION: This work presents a novel and modular framework for simulating spinal cord atrophy data using digital phantoms, offering a controlled setting for testing spinal cord analysis pipelines. As the simulated atrophy may over-simplify in vivo conditions, future research will focus on enhancing the realism of the synthetic dataset by simulating additional pathologies, thus improving its application for evaluating spinal cord atrophy in clinical and research contexts.}, }
@article {pmid41480315, year = {2025}, author = {Wang, CL and Zeng, M and Luo, Y}, title = {Unmasking the high-risk phenotype in autoimmune gastritis: A pathologist's roadmap for the clinician.}, journal = {World journal of gastroenterology}, volume = {31}, number = {48}, pages = {115244}, pmid = {41480315}, issn = {2219-2840}, mesh = {Humans ; *Stomach Neoplasms/pathology/diagnosis/immunology ; *Autoimmune Diseases/pathology/immunology/diagnosis ; *Gastritis/pathology/immunology/diagnosis ; Biopsy ; *Neuroendocrine Tumors/pathology/immunology/diagnosis ; Phenotype ; Risk Factors ; *Precancerous Conditions/pathology/immunology/diagnosis ; *Gastric Mucosa/pathology/immunology ; Risk Assessment ; Pathologists ; Ki-67 Antigen/analysis ; Prognosis ; Disease Progression ; }, abstract = {Li et al's recent work on the risk factors for autoimmune gastritis provides clinical context for the vast majority of gastric neuroendocrine tumors (G-NETs). However, a deeper understanding of the underlying pathology is needed for precise clinical management. Our letter details the predictable stepwise progression of type 1 G-NETs from autoimmune-driven corporal atrophy and hypergastrinemia to a clear microscopic sequence of enterochromaffin-like cell precursor lesions, including linear hyperplasia, micronodular hyperplasia, and dysplasia. We highlight the definitive diagnostic thresholds that separate these precursors from overt neoplasia: The 0.5 mm size rule and the presence of submucosal invasion. We advocate for a "prognostic biopsy protocol" in which pathologists actively report these precursor lesions and use Ki-67 to grade G-NETs, providing a quantitative risk assessment. This pathology-centric approach transforms surveillance, allowing clinicians to act on objective microscopic milestones rather than waiting for macroscopically visible tumors.}, }
@article {pmid41480396, year = {2025}, author = {Arafat, A and Soliman, SMA and Farghaly, TA and Ebrahim, NAA}, title = {Exercise with induced pluripotent stem cells enhances Wnt1-Lmx1a signaling and dopaminergic neurogenesis to alleviate Parkinsonian symptoms.}, journal = {World journal of stem cells}, volume = {17}, number = {12}, pages = {113924}, pmid = {41480396}, issn = {1948-0210}, abstract = {This article focused on the recent contribution by Jiang et al, who demonstrated that voluntary exercise can significantly potentiate the effects of induced pluripotent stem cell transplantation in a Parkinson's disease (PD) model through activation of the Wnt1-Lmx1a signaling cascade. Jiang et al's findings highlight the role of exercise as a molecular modulator of neurogenesis and support the development of integrated strategies combining physical activity, stem cell transplantation, and biomaterials to improve outcomes in PD. We highlight exercise as a molecular modulator that fosters a neurogenic milieu, recommend examining additional developmental signals (sonic hedgehog, fibroblast growth factor 8, bone morphogenetic protein), and suggest biomaterial-based strategies to support graft survival and integration. We also stress the need to optimize exercise regimens in relation to transplantation, framing these insights within a translational strategy for advancing regenerative therapies in PD.}, }
@article {pmid41480618, year = {2025}, author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE}, title = {Extracellular vesicle-based therapies for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {4}, pages = {377-390}, pmid = {41480618}, issn = {2750-6665}, support = {R01 MH121402/MH/NIMH NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.}, }
@article {pmid41480876, year = {2026}, author = {Majumdar, T and Das, PK and Bisoi, A and Jana, B and Singh, PC}, title = {Three-State Unfolding of Telomeric G-Quadruplexes through Conformational Switching in Crowded Cell-like Conditions.}, journal = {Biochemistry}, volume = {65}, number = {2}, pages = {195-206}, doi = {10.1021/acs.biochem.5c00486}, pmid = {41480876}, issn = {1520-4995}, mesh = {*G-Quadruplexes ; *Telomere/chemistry ; Humans ; Circular Dichroism ; Nucleic Acid Conformation ; Potassium Chloride/chemistry ; Hydrophobic and Hydrophilic Interactions ; Molecular Dynamics Simulation ; }, abstract = {The unfolding of telomeric G-quadruplexes (G4s) is a key step in telomere elongation and regulation. Within cells, the highly crowded intracellular milieu significantly influences the structural stability and dynamics of G4s; however, the molecular mechanism governing their unfolding under such conditions remains poorly understood. In this study, we have investigated the thermal unfolding of various human telomeric G4 sequences in KCl, both in the absence and presence of molecular crowders, using temperature-dependent circular dichroism (CD) spectroscopy combined with singular value decomposition, multivariate curve resolution alternating least-squares (MCR-ALS), and well-tempered metadynamics simulations. In KCl alone, telomeric G4s exhibit a two-state unfolding mechanism, where the hybrid-type topology directly converts into the unfolded random-coil state. In contrast, under crowded conditions, particularly in the presence of hydrophobic crowders, the unfolding follows a three-state pathway involving a distinct intermediate. The hybrid structure initially transitions to a parallel-type topology at elevated temperatures before fully unfolding. This stabilization of the parallel topology arises from preferential interactions between hydrophobic crowders and the exposed loop nucleobases of the parallel G4 form. On the other hand, hydrophilic crowders exert minimal influence on the unfolding pathway, which remains similar to that observed in KCl solution. Overall, these findings provide molecular-level insights into the unfolding process of telomeric G4 DNA in crowded cell-like environments and may be useful in understanding the complex telomere elongation process.}, }
@article {pmid41481411, year = {2026}, author = {Ortholand, J and Gensollen, N and Durrleman, S and Du Montcel, ST}, title = {Joint model with latent disease age: Overcoming the need for reference time.}, journal = {Statistical methods in medical research}, volume = {}, number = {}, pages = {9622802251399917}, doi = {10.1177/09622802251399917}, pmid = {41481411}, issn = {1477-0334}, abstract = {Heterogeneity of the progression of neurodegenerative diseases is one of the main challenges faced in developing therapies. Thanks to the increasing number of clinical databases, progression models have allowed a better understanding of this heterogeneity. Joint models have proven their effectiveness by combining longitudinal and survival data. Nevertheless, they require a reference time, which is ill-defined for neurodegenerative diseases, where biological underlying processes start before the first symptoms. In this work, we propose a joint non-linear mixed-effect model with a latent disease age, to overcome this need for a precise reference time. We used a longitudinal model with a latent disease age as a longitudinal sub-model. We associated it with a survival sub-model that estimates a Weibull distribution from the latent disease age. We validated our model on simulated data and benchmarked it with a state-of-the-art joint model on data from patients with Amyotrophic Lateral Sclerosis (ALS). Finally, we showed how the model could be used to describe ALS heterogeneity. Our model got significantly better results than the state-of-the-art joint model for absolute bias on ALS functional rating scale revised score (4.21(SD 4.41) versus 4.24(SD 4.14)(p-value=1.4×10-17)), and mean-cumulative-AUC for right-censored events on death (0.67(0.07) versus 0.61(0.09)(p-value=1.7×10-03)). To conclude, we propose a new model better suited in the context of unreliable reference time.}, }
@article {pmid41481500, year = {2026}, author = {Leon, AM and Sucasaca, A and Choque-Quispe, BM and Medina, WT}, title = {Physical and nutritional properties of meat analogues obtained by high-moisture extrusion with the inclusion of high Andean algae flours: Llaska (Cladophora crispata) and Cushuro (Nostoc sphaericum).}, journal = {Food science and technology international = Ciencia y tecnologia de los alimentos internacional}, volume = {}, number = {}, pages = {10820132251409012}, doi = {10.1177/10820132251409012}, pmid = {41481500}, issn = {1532-1738}, abstract = {Environmental impact of the meat industry and the adverse effects of excessive meat consumption, has prompted the search for sustainable and healthy protein alternatives. This study assessed the physical and textural properties and nutritional profile of two meat analogues processed by high-moisture extrusion, including Llaska (Cladophora crispata) (AL) and Cushuro (Nostoc sphaericum) (AC) flours. Color was evaluated by digital image analysis; textural profile analysis (TPA) was determined by compression tests. The nutritional profile was determined by proximate analysis, spectrophotometric, and chromatographic techniques. AL and AC were green and dark brown, respectively. The luminosity and hue of AC are similar to chicken meat. TPA shows that ALs had a greater degree of hardness and texturization than ACs. AL and AC, processed at a temperature of 135 °C and moisture level of 75% and 65%, respectively, exhibited textures comparable to that of chicken meat. Nutritionally, ACs showed higher antioxidant capacity (∼15,382 μMol Trolox/100 g), ∼30 times higher than chicken meat. Amino acid profiles indicate that both samples provide essential amino acids comparable to chicken meat, which are indispensable in a healthy diet. Consequently, these algae have potential to enrich the nutritional profile of meat analogues as a possible healthy and sustainable alternative to conventional meats.}, }
@article {pmid41481541, year = {2026}, author = {Lehto, A and Zapf, A and Hermann, A and Machts, J and Vielhaber, S and Koppenbrink, J and Edbauer, D and Kasper, E and Prudlo, J}, title = {Homozygosity for the C allele at UNC13A rs12608932 seems to compromise cognition in ALS independently of the cognitive domains.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2025.2608238}, pmid = {41481541}, issn = {2167-9223}, abstract = {The common single nucleotide polymorphism (SNP) rs12608932 located at a cryptic splice in the UNC13A gene has been reported to modify the clinical phenotype of ALS, but it is unclear whether homozygosity for the C-allele at UNC13A rs12608932 modifies specific domains of cognition in ALS. We analyzed retrospective data from a German cohort and found that the proportion of cognitively or behaviorally impaired patients was higher in the high-risk group of homozygous C-allele carriers. Patients with C/C alleles had lower scores than controls on verbal fluency, executive functioning, and delayed memory recall, but did not differ significantly from other ALS genotypes. Furthermore, informant ratings suggested higher disinhibition in the C/C carriers. These findings indicate that the C/C risk variant of UNC13A rs12608932 may contribute to general cognitive vulnerability rather than domain-specific deficit.}, }
@article {pmid41482475, year = {2026}, author = {Bernsen, S and Weydt, P}, title = {Hereditary transthyretin amyloidosis with hand weakness and bulbar involvement.}, journal = {Practical neurology}, volume = {}, number = {}, pages = {}, doi = {10.1136/pn-2025-004950}, pmid = {41482475}, issn = {1474-7766}, abstract = {A 76-year-old man developed progressive motor weakness, bulbar symptoms and hand muscle atrophy, initially suspected to be due to motor neurone disease. Unexpected findings on cardiological evaluation identified amyloidosis, and genetic testing confirmed the TTR p.Val50Met mutation, indicating late-onset hereditary transthyretin amyloidosis with a mixed neuropathic and cardiac phenotype. The diagnosis was delayed and complicated by minimal sensory symptoms and the atypical presentation.}, }
@article {pmid41483413, year = {2026}, author = {Khan, T and Mahboob, H and Zehra, M and Saqib, HW and Ahmad, M}, title = {Super excitability at 7 ms: a superior prognostic biomarker beyond CMAP in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {71}, pmid = {41483413}, issn = {1590-3478}, }
@article {pmid41484230, year = {2026}, author = {Schneider, K and Spekking, L and Azimi, S and Peltanová, B and Rösel, D and Brown, JS and Gatenby, RA and Brábek, J and Staňková, K}, title = {Migrastatic therapy as a potential game-changer in adaptive cancer treatment.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3929}, pmid = {41484230}, issn = {2045-2322}, support = {24-11903S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; 24-10672S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; LX22NPO5102//National Institute for Cancer Research/ ; 955708//European Union's Horizon 2020 research and innovation program/ ; VI.Vidi.213.139/NWO_/Dutch Research Council/Netherlands ; }, mesh = {Humans ; Male ; *Neoplasms/pathology/therapy ; Neoplasm Metastasis ; Game Theory ; Drug Resistance, Neoplasm ; *Prostatic Neoplasms, Castration-Resistant/pathology ; }, abstract = {Adaptive therapy, which anticipates and counters the evolution of resistance in cancer cells, has gained significant traction, especially following the success of the Zhang et al.'s protocol in treating metastatic castrate-resistant prostate cancer. While several adaptive therapies have now advanced to clinical trials, none currently incorporates migrastatics, i.e. treatments designed to inhibit cancer cell metastasis. In this study, we propose integrating migrastatics into adaptive therapy protocols and evaluate its potential benefits through a spatial game-theoretic model. Our results demonstrate that combining adaptive therapy with migrastatics effectively delays the onset of metastases and reduces both the number and size of metastases in most cancer scenarios analyzed. Including migrastatics to adaptive therapy not only extends the time to the first metastasis, but also enhances the overall efficacy of adaptive therapies. Our findings suggest a promising new direction for cancer treatment, where adaptive therapy, in combination with migrastatic agents, can target both the evolution of resistance and the metastatic spread of cancer cells.}, }
@article {pmid41484575, year = {2026}, author = {Luo, J}, title = {Revisiting MASLD-based pregnancy risk stratification: a critical appraisal of Jung et al.'s nationwide cohort study.}, journal = {Hepatology international}, volume = {}, number = {}, pages = {}, pmid = {41484575}, issn = {1936-0541}, }
@article {pmid41484784, year = {2026}, author = {Katzenschlager, S and Kaltschmidt, N and Dietrich, M and Fiedler-Kalenka, M and Klemm, S and Kofler, O and Mohr, S and Eisner, C and Neuhaus, C and Simon, C and Weigand, MA and Weilbacher, F and Popp, E}, title = {Prehospital transesophageal echocardiography versus conventional advanced life support in out-of-hospital cardiac arrest (PHTEE-OHCA) - a randomized controlled pilot study.}, journal = {Critical care (London, England)}, volume = {30}, number = {1}, pages = {45}, pmid = {41484784}, issn = {1466-609X}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Echocardiography, Transesophageal/methods/standards/statistics &amp; numerical data ; Emergency Medical Services/methods/standards/statistics &amp; numerical data ; *Advanced Cardiac Life Support/methods/standards/statistics &amp; numerical data ; Cardiopulmonary Resuscitation/methods ; }, abstract = {BACKGROUND: Transesophageal echocardiography during out-of-hospital cardiac arrest can be performed during ongoing chest compressions and may improve resuscitation quality, but its prehospital use has not been systematically evaluated. To assess the feasibility, diagnostic yield, and impact of prehospital TEE on resuscitation metrics and advanced life support (ALS) interventions during OHCA.<br><br>METHODS: We conducted a randomized controlled trial in a physician-staffed two-tiered emergency medical service (EMS). Adults with ongoing non-traumatic OHCA were randomized 1:1 to standard ALS or ALS plus TEE. The primary endpoints were hands-off time and chest compression fraction (CCF) from EMS arrival to return of spontaneous circulation (ROSC) or resuscitation termination. Secondary endpoints included ROSC at hospital admission, survival to hospital discharge, neurological status at hospital discharge, and TEE findings. Analyses followed the intention-to-treat principle.<br><br>RESULTS: Of 249 screened patients, 35 were randomized and 32 analyzed (TEE n&#x2009;=&#x2009;15; control n&#x2009;=&#x2009;17). Median hands-off time was 4&#xa0;s in both groups. Mean CCF was higher in the TEE group (96.2%) than the control group (91.6%), with a mean difference of 4.6% (95% confidence interval 2.5-6.7; p&#x2009;<&#x2009;0.001). Sustained ROSC occurred in 40% (TEE) versus 71% (control; p&#x2009;=&#x2009;0.083). The control group had an eCPR rate of 41%, compared to 20% in the TEE group. Using TEE, an incorrect area of maximal compression or inadequate depth was identified in 23% and 14%, respectively.<br><br>CONCLUSION: Prehospital TEE during OHCA was feasible without negatively interfering with CPR metrics, and provided clinically relevant diagnostic information and procedural guidance, warranting further evaluation in larger trials.<br><br>TRIAL REGISTRATION: German Clinical Trials Register DRKS00028695 registered on 28 April 2022.}, }
@article {pmid41485061, year = {2026}, author = {Waldherr, SM and Eck, RJ and Hincks, JC and Currey, HN and Goldberg, M and McMillan, PJ and Saxton, AD and Hulsey-Vincent, HJ and Latimer, CS and Kraemer, BC and Liachko, NF}, title = {Calcineurin depletion coincides with phosphorylated TDP-43 deposition in a mouse model of ALS/FTLD-TDP.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {33}, pmid = {41485061}, issn = {2051-5960}, support = {F99AG088436/NH/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; F99 AG088436/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; IK6BX006467//U.S. Department of Veterans Affairs/ ; P30 AG066509/AG/NIA NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; I01BX005762//U.S. Department of Veterans Affairs/ ; R01SN0064131/NH/NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Mice ; *Brain/metabolism ; Caenorhabditis elegans ; *Calcineurin/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Phosphorylation ; *TDP-43 Proteinopathies/metabolism ; Primary Cell Culture ; Mice, Inbred C57BL ; DNA-Binding Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) exhibit predominantly cytoplasmic phosphorylated inclusions of the protein TDP-43 as the major neuropathological lesion. Phosphorylated TDP-43 can modify protein aggregation and promote neuronal dysfunction and neurodegeneration in models of ALS and FTLD-TDP. The phosphatase calcineurin has previously been shown to directly dephosphorylate TDP-43 in vitro and prevent accumulation of phosphorylated TDP-43 in vivo in C. elegans. However, it is unknown whether dysregulation of calcineurin contributes to increased TDP-43 phosphorylation and neurodegeneration in the mammalian brain. Here we show in an inducible mouse model of ALS/FTLD-TDP driven by expression and cytoplasmic mislocalization of human TDP-43 (rNLS8 mice), calcineurin protein decreases dramatically in the brain. This depletion coincides with increased levels of the TDP-43 kinase CDC7 and accumulation of phosphorylated TDP-43, and precedes frank neurodegeneration. Using brain-wide single nucleus RNA sequencing (snRNAseq) in symptomatic rNLS8 mice, we find cell-type selective reduced expression of catalytic and regulatory subunits of calcineurin predominantly in GABAergic and glutamatergic neurons. In mouse primary neuron culture and C. elegans models of ALS/FTLD-TDP, we demonstrate activation or overexpression of calcineurin protects against accumulation of phosphorylated TDP-43, neurotoxicity, and neurodegeneration. Taken together, our data suggests calcineurin dysregulation may be a major contributor to loss of brain resilience mechanisms against phosphorylated TDP-43. Restoring calcineurin activity may present a new target for intervening in TDP-43 proteinopathies, including ALS and FTLD-TDP.}, }
@article {pmid41485128, year = {2026}, author = {Mordes, DA and Smeyers, J}, title = {TBK1 orchestrates autophagy and endo-lysosomal pathways in human neurons.}, journal = {Autophagy}, volume = {22}, number = {3}, pages = {632-634}, pmid = {41485128}, issn = {1554-8635}, support = {R01 AG089849/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Autophagy/physiology ; *Lysosomes/metabolism ; *Endosomes/metabolism ; *Neurons/metabolism ; Phosphorylation ; rab GTP-Binding Proteins/metabolism ; rab7 GTP-Binding Proteins ; Sequestosome-1 Protein/metabolism ; Signal Transduction ; }, abstract = {Haploinsufficiency of TBK1 causes familial ALS and frontotemporal dementia (FTD), yet the mechanisms by which TBK1 loss leads to neurodegeneration remain unclear. Using deep proteomics and phospho-proteomics, we demonstrate that TBK1 regulates select macroautophagy/autophagy factors, targeting cargo receptors and autophagy initiation factors, and also sustains the phosphorylation of the late endosomal marker RAB7A in stem cells and stem cell-derived excitatory neurons. We further uncovered novel TBK1-dependent phosphorylation sites in the key autophagy protein SQSTM1/p62. Loss of TBK1 function results in a cell-autonomous neurodegenerative phenotype characterized by impaired neurite outgrowth and lysosomal dysfunction.}, }
@article {pmid41486180, year = {2026}, author = {Tarutani, A and Nonaka, T and Ohtani, R and Imai, K and Ito, Y and Tsuji, H and Mochizuki, A and Tamaoka, A and Arai, T and Robinson, AC and Mann, DMA and Kosaka, T and Takahashi, H and Kakita, A and Yoshida, M and Hasegawa, M}, title = {Co-aggregation of annexin A11 and TDP-43 in FTLD/MND with primary lateral sclerosis phenotype.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {34}, pmid = {41486180}, issn = {2051-5960}, support = {JP24wm0625120//Japan Agency for Medical Research and Development/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP24dk0207074h0001//Japan Agency for Medical Research and Development/ ; JP20K16482//Japan Society for the Promotion of Science/ ; JP25K21773//Japan Society for the Promotion of Science/ ; JP24H00624//Japan Society for the Promotion of Science/ ; JPMJCR18H3//Japan Science and Technology Agency/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Aged ; Middle Aged ; *Annexins/metabolism ; *Motor Neuron Disease/pathology/metabolism ; *Frontotemporal Lobar Degeneration/pathology/metabolism ; Phenotype ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Brain/pathology/metabolism ; }, abstract = {TDP-43 proteinopathies, such as frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are classified into five neuropathological subtypes, Types A to E, according to the morphology of TDP-43 inclusions. Recent cryo-electron microscopy analysis of FTLD-TDP cases demonstrated that TDP-43 filaments composing the inclusions are structurally different depending on the subtype, and remarkably, co-assembled heteromeric filaments of TDP-43 and annexin A11 (ANXA11) were identified in Type C. Therefore, the involvement of ANXA11 in TDP-43 proteinopathy should be further examined. Here, we pathologically and biochemically analyzed four cases of primary lateral sclerosis-phenotype FTLD/motor neuron disease (MND) with TDP-43 pathology (PLS-TDP), and found that ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP. Immunoblot analysis of the PLS-TDP cases revealed that the banding patterns of C-terminal and chymotrypsin-resistant fragments of TDP-43 are distinct from those of FTLD-TDP Types A, B and C. In addition, the N-terminal fragments of ANXA11 appear to be different from those of FTLD-TDP Type C. Filaments extracted from PLS-TDP cases were TDP-43- and ANXA11-immunopositive, suggesting the presence of TDP-ANXA11 heteromeric filaments. These results suggest that co-aggregation of ANXA11 and TDP-43 may serve as a neuropathological and biochemical indicator distinguishing PLS from ALS in FTLD/MND.}, }
@article {pmid41486306, year = {2026}, author = {Zhuang, SP and Huang, HW and Zeng, JY and Shi, JY and Lin, HY and Chen, S and Wu, Y and Huang, NX and Zou, ZY and Chen, HJ}, title = {Superficial white matter microstructural impairments correlate with functional alterations and disease severity in early-stage amyotrophic lateral sclerosis.}, journal = {La Radiologia medica}, volume = {}, number = {}, pages = {}, pmid = {41486306}, issn = {1826-6983}, support = {Nos. 2023CXA009//Fujian Provincial Health Technology Project/ ; Nos. 2024QNA011//Fujian Provincial Health Technology Project/ ; No.2024J01625//Fujian Provincial Natural Science Foundation of China/ ; Nos. 2024Y9253//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; Nos. 2024Y9256//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; No. S202410392033//College Student Innovation Training Program of Fujian Medical University/ ; }, abstract = {PURPOSE: White matter (WM) damage is a key pathophysiological process in amyotrophic lateral sclerosis (ALS). However, alterations in superficial WM (SWM) have not been systematically explored. This study aimed to assess SWM microstructural changes in early-stage ALS and their associations with cortical functional alterations and disease severity.<br><br>METHODS: Forty-two early-stage ALS patients and 48 healthy controls were included. Disease severity was evaluated using the revised ALS Functional Rating Scale (ALSFRS-R). The SWM was identified by sampling voxels along the cortical surface, maintaining a fixed distance (2&#xa0;mm) from the gray matter/WM interface and removing deep white matter regions. SWM microstructural impairments were evaluated via neurite orientation dispersion and density imaging. Functional disturbances in the cortical regions corresponding to impaired SWM were measured by assessing regional homogeneity (ReHo) that reflects local synchronization of neuronal activity.<br><br>RESULTS: Patients showed a decreased neurite density index (NDI) in specific SWM regions, primarily including the bilateral precentral gyrus, supplementary motor area, paracentral lobule, and postcentral gyrus (family-wise error-corrected P&#x2009;<&#x2009;0.05). Additionally, significant ReHo reductions were observed in cortical regions corresponding to compromised SWM. Both SWM NDI and cortical ReHo values significantly correlated with the ALSFRS-R score. Cortical ReHo alterations mediated the relationship between the SWM NDI value and the ALSFRS-R score (mediation effect&#x2009;=&#x2009;0.103). SWM NDI assessments effectively identified ALS (area under the curve&#x2009;=&#x2009;0.725-0.926).<br><br>CONCLUSION: Our findings highlight the SWM disruption as a crucial neurobiological substrate involved in early-stage ALS neuropathological mechanisms.}, }
@article {pmid41486410, year = {2026}, author = {Wang, F and Zhang, KY and Zhu, LJ and Li, WJ and Wu, Y and Gao, X and Ma, XR and Yin, XH and Wu, JB and Ye, XK and Dong, ZJ and Wang, DX and Zhou, Z and Wang, SD and Han, L and Jiang, ZN and Zhao, JW}, title = {Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1[G93A] ALS Mice by Enhancing Microglial Migration and Neuroprotection.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {13}, pages = {e12149}, pmid = {41486410}, issn = {2198-3844}, support = {STI2030-MajorProjects2021ZD0201705//National Key R&amp;D Program of China/ ; NSFC82371576//National Natural Science Foundation of China/ ; BZZ19J005//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Microglia/metabolism ; Mice ; Disease Models, Animal ; *Neuroprotection/physiology/genetics ; Motor Neurons/metabolism ; *Cell Movement/genetics ; Humans ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease characterized by progressive loss of motor neurons. Current clinically available drugs targeting neurons show minor survival extension and no motor improvement in ALS patients. This shifts the focus of ALS research toward non-neuronal cells, particularly microglia, a critical driver of ALS pathogenesis. Highly druggable ion channels are key regulators of microglia function. Here, Hydrogen voltage gated channel 1 (HVCN1) was screened out as the most highly expressed ion channel in microglia, and was upregulated in microglia of SOD1[G93A] mice and patients. Deletion of HVCN1 in microglia increased motor neuron survival, rescued the innervated neuromuscular junctions in the muscle, reduced glial activation and decreased the level of both misfolded protein and myelin debris in the ALS mice. Importantly, these pathological improvements were translated into significant motor improvement and survival extension in the ALS mice, exhibiting better effects than the current clinical drugs. HVCN1 deletion enhanced microglia migration and their homeostatic state with elevated neurotrophic functions. Mechanistically, HVCN1 ablation promoted microglial migration via suppressing Akt signaling. Our results identify HVCN1 as a novel promising therapeutic target for ALS, opening a new avenue to further develop specific inhibitors for HVCN1 to alleviates ALS.}, }
@article {pmid41488323, year = {2025}, author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R}, title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1733659}, pmid = {41488323}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.}, }
@article {pmid41488805, year = {2026}, author = {Klassen, P and Alexudis, C and Klose, V and de San José, NG and Huss, A and Bachhuber, F and Soylu, &#xd6; and Fazeli, B and Erhart, D and Laible, M and Anderl-Straub, S and Jesse, S and Otto, M and Ludolph, AC and Tumani, H and Halbgebauer, S}, title = {Increased transmembrane protein 119 (TMEM119) levels in the cerebrospinal fluid of patients with mild cognitive impairment due to Alzheimer's disease suggest early microglial involvement.}, journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)}, volume = {18}, number = {1}, pages = {e70240}, pmid = {41488805}, issn = {2352-8729}, abstract = {INTRODUCTION: We aimed to evaluate the potential of the microglial marker transmembrane protein 119 (TMEM119) in the cerebrospinal fluid (CSF) as a (differential) diagnostic biomarker for neurodegenerative diseases.<br><br>METHODS: Following assay validation, we used enzyme-linked immunosorbent assay to measure CSF TMEM119 in 174 patients from six diagnostic groups: Alzheimer's disease (AD, n&#xa0;=&#xa0;35), amyotrophic lateral sclerosis (ALS, n&#xa0;=&#xa0;33), cerebral microangiopathy (CM, n&#xa0;=&#xa0;25), frontotemporal lobar degeneration (FTLD, n&#xa0;=&#xa0;28), Lewy body diseases (n&#xa0;=&#xa0;21), and non-neurodegenerative controls (n&#xa0;=&#xa0;33).<br><br>RESULTS: CSF TMEM119 levels were elevated in the AD group compared to the control (p&#xa0;=&#xa0;0.004), CM (p&#xa0;=&#xa0;0.005), and FTLD (p&#xa0;=&#xa0;0.023) groups. Levels were higher in both mild cognitive impairment (MCI-AD) and dementia (ADD) subgroups when compared to controls. For the discrimination of AD from controls, the area under the curve (AUC) was 0.78.<br><br>DISCUSSION: Our results indicate that CSF TMEM119 may have potential as a biomarker representing microglial involvement in early and later stages of AD.<br><br>HIGHLIGHTS: Elevated levels of TMEM119 were observed in the CSF of patients with AD.Increased CSF TMEM119 was seen in MCI-AD patients compared to controls.Elevated levels in MCI-AD underscore early microglial involvement in AD.In the AD group, an association was found between CSF TMEM119 and CSF total tau.CSF TMEM119 may provide valuable information on neuroinflammation.}, }
@article {pmid41489058, year = {2026}, author = {Pilotto, F and Toth, TD and Bond, S and Schmitz, A and Diab, R and Tenlep, SYN and Mooney, B and Erni, S and Schobesberger, M and Scheidegger, O and Peitsch, C and Saxena, S}, title = {Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e14128}, doi = {10.1002/advs.202514128}, pmid = {41489058}, issn = {2198-3844}, support = {31ER30_179595//E-Rare/ ; 725825/ERC_/European Research Council/International ; //InnoMedica Schweiz AG/ ; 179436/SNSF_/Swiss National Science Foundation/Switzerland ; //Swiss Foundation for Research on Muscle Diseases/ ; //Spinal Cord Injury/Disease Research Program (SCIDRP), University of Missouri/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal condition marked by the degeneration of motor neurons. ALS has been linked to numerous genes with diverse biological roles, reflecting a highly intricate and multifaceted disease process. This diversity poses significant challenges in developing universally effective and bioavailable treatments. Advancing therapeutic strategies require uncovering molecular pathways that are major drivers of ALS. We conducted proteomic analyses of human iPSC-derived motor neurons carrying C9ORF72 mutations, alongside spinal ventral horns from mice with pathogenic C9orf72-mutations. This cross-species approach revealed disruptions in synaptic vesicle release, endoplasmic reticulum (ER) and mitochondrial stress responses as conserved ALS pathogenic mechanisms. Disease progression was associated with accumulation of cytotoxic protein aggregates and oxidative stress. We analyzed the potential of GM1, an established neuroprotective molecule, to reverse these pathogenic features. To enhance the pharmacokinetics of GM1, we developed Talineuren (TLN), a nanoliposome-based formulation of the active pharmaceutical ingredient GM1 ganglioside that improves its bioavailability. GM1 stabilized mitochondrial Ca[2][+] handling, improved energy metabolism, and alleviated ER stress, preventing protein aggregation and restoring cellular proteostasis and counteracted behavioral deficits in C9orf72 and SOD1-G93A mouse models. Together, these findings underscore the central, convergent role for cellular disruptions in ALS and position TLN as a promising therapeutic candidate.}, }
@article {pmid41490046, year = {2026}, author = {Maheswari Jawahar, V and Zeng, Y and Armour, EM and Yue, M and Citrano, K and Lovchykova, A and Reeves, MM and Rawlinson, B and DeTure, M and Dunmore, JA and Song, Y and Ball, SK and Wszolek, ZK and Graff-Radford, NR and Boeve, BF and Knopman, DS and Day, GS and Small, SA and Dickson, DW and Ward, ME and Gendron, TF and Zhang, Y and Prudencio, M and Gitler, AD and Petrucelli, L}, title = {TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia.}, journal = {PLoS biology}, volume = {24}, number = {1}, pages = {e3003573}, pmid = {41490046}, issn = {1545-7885}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Polyadenylation/genetics ; Female ; *Vesicular Transport Proteins/genetics/metabolism ; Male ; Aged ; 3' Untranslated Regions/genetics ; Middle Aged ; Aged, 80 and over ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region lengthening events in the brains of individuals with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), focusing on the functional impact of APA dysregulation. To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex. We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset. Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA. Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits.}, }
@article {pmid41490238, year = {2025}, author = {Ni, S and Chen, K and Wang, H and Chen, S and Qiu, Y and Wang, T and Mo, F and Wang, S and Li, B and Bai, Y and Zhao, J and Zhai, X and Li, Z}, title = {A new paradigm of bidirectional regulation of the gut-spinal cord axis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01016}, pmid = {41490238}, issn = {1673-5374}, abstract = {The bidirectional interactions of spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis with the gut operate through a distinct gut-spinal cord axis, rather than being fully explained by the conventional gut-brain axis. The spinal cord, with its unique anatomical and physiological features, serves as a central hub of communication. The gut and spinal cord communicate through various pathways, including the immune system and the autonomic and enteric nervous systems. This review summarizes existing clinical and basic research on the relationship between gut homeostasis and spinal cord diseases. First, we present findings from epidemiological studies showing that patients with spinal cord disorders often exhibit altered gut function, which may be influenced by antibiotic exposure and environmental factors. Second, we review the key physiological and anatomical structures of the gut-spinal cord axis, including the intestinal barrier, gut microbiota, and enteric nervous system, all of which are involved in maintaining gut health, as well as sensory neurons, motor neurons, and interneurons in spinal nerve regulation. Third, we describe the roles of the three axes (microbial, immune, and neural) in bidirectional regulation and their pathological mechanisms. Moreover, vicious cycles involving these axes can exacerbate spinal cord disorders. Fourth, we outline potential biomarkers in the gut-spinal cord axis, such as uridine, hypoxanthine, and 5-methoxytryptophan. Fifth, we propose several treatment strategies with potential clinical applications, including fecal microbiota transplantation and the use of probiotics and prebiotics. Finally, this review emphasizes the gut-spinal cord axis as a promising therapeutic target, highlighting the need for multi-omics integration, longitudinal cohort studies, and individualized interventions to resolve existing debates. Overall, the recognition of the gut-spinal cord axis provides a conceptual shift that extends beyond the gut-brain framework.}, }
@article {pmid41491573, year = {2026}, author = {Kuramitsu, Y and Itou, J and Munakata, Y and Okazaki, K}, title = {Transverse incisions improve scar outcomes in anterolateral supine approach total hip arthroplasty: a patient observer scar assessment scale-based study.}, journal = {Arthroplasty (London, England)}, volume = {8}, number = {1}, pages = {2}, pmid = {41491573}, issn = {2524-7948}, abstract = {BACKGROUND: This study compared transverse and longitudinal skin incisions in anterolateral supine (ALS) total hip arthroplasty (THA), focusing on cosmetic and sensory outcomes using the Patient Observer Scar Assessment Scale (POSAS).<br><br>METHODS: A retrospective analysis was conducted on 132 hips that underwent primary ALS THA performed by a single surgeon between 2019 and 2024. Longitudinal incisions were used until December 2022, and transverse incisions aligned with relaxed skin tension lines were used thereafter. POSAS 3.0 was used to evaluate scar quality across satisfaction, appearance, and sensory domains.<br><br>RESULTS: Baseline characteristics were similar between groups, except for follow-up duration and incision length. No significant differences were found in POSAS scores. However, regression analysis revealed that transverse incision significantly improved satisfaction (P&#x2009;=&#x2009;0.04) and appearance (P&#x2009;<&#x2009;0.05). Sensory scores were significantly affected by follow-up duration (P&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: Transverse incisions in ALS THA may enhance cosmetic satisfaction without compromising sensory outcomes. These findings support the potential role of personalized incision planning for improving patient-reported outcomes following THA. Video Abstract.}, }
@article {pmid41492782, year = {2026}, author = {Dallaire, JS and Bachand, MP and Shaul, J and Lareau-Trudel, E}, title = {Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/cjn.2025.10510}, pmid = {41492782}, issn = {0317-1671}, abstract = {BACKGROUND: Installation of a percutaneous gastrostomy tube is often needed for patients with amyotrophic lateral sclerosis (ALS) who develop severe dysphagia. However, there is uncertainty regarding the optimal timing for this procedure, especially with regard to the decline in respiratory function. Several guidelines suggest that gastrostomy should be placed before the forced vital capacity (FVC) drops below 50%, since the procedural risks are heightened. However, multiple studies argue that this procedure could be safe in patients with an FVC of less than 50%.<br><br>METHODS: In this retrospective study, we reviewed the medical records of all patients with ALS who had a gastrostomy at our center between 2010 and 2023. Our primary objective was to identify the 30-day mortality rate and the incidence of complications after this procedure. Also, we investigated whether predictive factors of adverse outcomes could be identified, particularly to evaluate if there was an association with pulmonary function.<br><br>RESULTS: We included 54 patients. The 30-day mortality rate was 9.3%, and the incidence of major complications was 16.7%. There was no statistical difference in complications between percutaneous endoscopic and radiologically inserted gastrostomy procedures. Predictive factors for complications were pre-existing pulmonary disease, pre-procedural CO2 levels and, although not statistically significant, diabetes. There was no association between FVC and the occurrence of adverse outcomes, although only 70% of patients had a measure of pulmonary function.<br><br>CONCLUSION: In our study, there was no correlation between FVC and the occurrence of adverse events from the gastrostomy procedure. This suggests that the traditional cutoff of 50% FVC level should be re-examined and explored further in future studies.}, }
@article {pmid41493066, year = {2026}, author = {De Vocht, J and Costello, E and McHutchison, C and Radakovic, R and Foucher, J and McMackin, R and Peelo, C and van den Berg, L and Hardiman, O and Van Damme, P and Pender, N and Abrahams, S and Lulé, D and , }, title = {Prioritizing neuropsychological research and care in Amyotrophic Lateral Sclerosis (ALS): building an international neuropsychological framework for ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2025.2610290}, pmid = {41493066}, issn = {2167-9223}, }
@article {pmid41493706, year = {2026}, author = {Hashemi, M and Shafiei Asheghabadi, P and Moassesfar, M and Mashhadikhan, S and Nasirzade, S and Vasheghani Farahani, A and Mehdizadeh, S and Minaei, S and Rahmani, M and Jamshidian, F and Farahani, N and Reiter, RJ and Taheriazam, A and Hasani Sadi, F and Hushmandi, K and Alimohammadi, M and Rahimzadeh, P and Entezari, M}, title = {MicroRNAs and Long Non-Coding RNAs Affect the Mechanisms Involved in Age-Related Neurodegeneration in a Manner Depending on RNA-Binding Proteins.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {343}, pmid = {41493706}, issn = {1559-1182}, mesh = {Humans ; *RNA, Long Noncoding/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Aging/genetics/pathology/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are marked by progressive neuronal loss and aberrant protein aggregation, presenting substantial global healthcare challenges. Recent research has illuminated the pivotal roles of RNA-binding proteins (RBPs) and non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the molecular pathogenesis of age-related neurodegeneration. RBPs orchestrate RNA metabolism and engage extensively with miRNAs and lncRNAs to modulate gene expression at the post-transcriptional level. Dysregulation of these interactions precipitates pathological phenomena such as protein misfolding, stress granule formation, and disrupted RNA processing, thereby exacerbating neuronal dysfunction and death. Specific miRNAs have been implicated in regulating key neurodegenerative biomarkers, including tau and amyloid-β in AD, motor neuron maintenance in ALS, and survival pathways in HD. Elucidating the intricate interplay between RBPs and ncRNAs holds significant promise for the development of therapeutic strategies aimed at ameliorating RNA-mediated mechanisms in neurodegenerative disorders.}, }
@article {pmid41493797, year = {2026}, author = {Esteve, D and Bresque, M and Okhuevbie, D and Ramachandran, S and Pehar, M and Vargas, MR}, title = {Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes.}, journal = {Glia}, volume = {74}, number = {3}, pages = {e70136}, pmid = {41493797}, issn = {1098-1136}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS122973/NS/NINDS NIH HHS/United States ; R01NS089640/NS/NINDS NIH HHS/United States ; R01NS122973/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Astrocytes/drug effects/metabolism/pathology/enzymology ; Humans ; *Fatty Acids/toxicity ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; *L-Lactate Dehydrogenase/antagonists &amp; inhibitors/metabolism/genetics ; Mice, Transgenic ; Mice ; Cells, Cultured ; Motor Neurons/drug effects/metabolism/pathology ; Coculture Techniques ; Phenotype ; Spinal Cord/pathology ; Mice, Inbred C57BL ; Disease Models, Animal ; Lipid Metabolism/drug effects ; Lipid Droplets/metabolism/drug effects ; Male ; }, abstract = {Astrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid-binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co-culture model, we examined the effect of FA overload and its impact on astrocyte-motor neuron interaction. LD accumulation was tightly coupled with an NF-κB-driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS-linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte-neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.}, }
@article {pmid41495602, year = {2026}, author = {Vahsen, BF and Pasterkamp, RJ}, title = {Microglia in C9orf72-associated amyotrophic lateral sclerosis: More or less active?.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01831}, pmid = {41495602}, issn = {1673-5374}, }
@article {pmid41495620, year = {2026}, author = {Li, Y and Feng, Y and Liu, X and Yuan, R and Chen, S and Wang, J and Pan, C and Li, G and Tang, Z}, title = {Functional near-infrared spectroscopy: Systematic mapping of abnormal brain function features in neurological disorders.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00595}, pmid = {41495620}, issn = {1673-5374}, abstract = {Functional near-infrared spectroscopy quantifies cerebral hemodynamic signals by capturing oxygenation-dependent changes in hemoglobin in a noninvasive, portable, and ecologically valid manner, providing a unique insight into neurovascular coupling. However, functional imaging biomarkers with high ecological validity for neurological disorders such as stroke, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, spinal cord injury, and traumatic brain injury are lacking, limiting the mechanistic understanding, treatment evaluations, and individualized interventions. The aim of this review is to systematically summarize evidence from the past decade on the use of functional near-infrared spectroscopy under the aforementioned conditions, synthesize its value for revealing neural mechanisms and assessing therapeutic responses, and identify current technical bottlenecks and future directions for advancement. Collectively, the findings demonstrate that functional near-infrared spectroscopy possesses substantial and far-reaching potential for uncovering the neural mechanisms underlying disease and for evaluating treatment-induced changes in brain function. Equipped with wearable probes, functional near-infrared spectroscopy can continuously and noninvasively monitor brain activity in naturalistic environments for extended periods, thereby overcoming the limitations of conventional imaging modalities that can only acquire data under restricted settings. This capability can furnish unprecedented objective neuroimaging evidence for neuroregenerative therapy research. Moreover, the portability of functional near-infrared spectroscopy allows it to be integrated into neurofeedback training systems: hemoglobin signals can be fed back to participants within milliseconds, enabling targeted, individualized, closed-loop modulation of brain function and considerably expanding the scope of hemodynamics-based neurofeedback. When combined with other brain function assays (such as electroencephalography) and intervention techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation), functional near-infrared spectroscopy also supplies high-temporal-resolution hemodynamic information, laying a critical foundation for the construction of high-precision noninvasive brain-computer interfaces, real-time cognitive-state decoding, and adaptive neuromodulation. Admittedly, almost all existing functional near-infrared spectroscopy studies are still observational and have small sample sizes, short follow-ups, and insufficient controls-shortcomings that together produce low-grade evidence. Therefore, there is still a significant gap before clinical translation can be achieved. Technically, the limited penetration depth of functional near-infrared spectroscopy restricts sampling to the superficial cortex, leaving deep nuclei largely unreachable. In addition, no consensus exists across devices regarding optode layout, light-source choice, motion-artifact correction, or analytical pipelines, creating pronounced heterogeneity that undermines reproducibility. With artificial intelligence and big data analytics advancing rapidly, functional near-infrared spectroscopy embedded within multimodal fusion frameworks is now poised to systematically map aberrant brain function signatures of neurological disorders, identify pathological regions suitable for targeted intervention, and provide real-time assessments of functional changes produced by neuroregenerative therapies.}, }
@article {pmid41496108, year = {2026}, author = {Wang, YW and Zhang, Y and Hu, X and Li, X and Han, L and Wang, DX and Ding, T}, title = {Recurarization after sugammadex reversal in a patient with amyotrophic lateral sclerosis: Case report.}, journal = {Medicine}, volume = {105}, number = {1}, pages = {e46928}, pmid = {41496108}, issn = {1536-5964}, mesh = {Humans ; *Sugammadex/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/complications/surgery ; Female ; Aged ; Rocuronium ; Neuromuscular Nondepolarizing Agents/adverse effects ; Neuromuscular Blockade/adverse effects/methods ; Gastrostomy/methods ; Respiratory Insufficiency ; *Delayed Emergence from Anesthesia ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) confers heightened and unpredictable sensitivity to nondepolarizing neuromuscular blocking agents and a high risk of postoperative respiratory failure. Although sugammadex reliably reverses rocuronium, recurarization may occur and is likely under-recognized in ALS. We report 2 ALS patients undergoing percutaneous endoscopic gastrostomy, one of whom developed delayed recurarization after apparent reversal.<br><br>PATIENT CONCERNS: Both women (67 and 68 years) presented with progressive dysphagia requiring percutaneous endoscopic gastrostomy. Case 1 had dyspnea, dysarthria, and long-standing noninvasive positive-pressure ventilation; Case 2 had bulbar signs without preoperative ventilatory support. The key perioperative concern in both cases was ventilatory failure from residual neuromuscular block.<br><br>DIAGNOSES: ALS had been established clinically. In Case 2, recurarization was diagnosed shortly after extubation when acute hypercapnic respiratory failure and clinical weakness followed an earlier recovery to a train-of-four (TOF) ratio of 92%.<br><br>INTERVENTIONS: Intravenous anesthesia with propofol and remifentanil was used. Case 1 received rocuronium 10&#x2009;mg (0.2&#x2009;mg/kg) and was reversed with sugammadex 90&#x2009;mg (2&#x2009;mg/kg) at TOF count 0, achieving a TOF ratio of 98% within 3 minutes before extubation and postoperative noninvasive ventilation. Case 2 received rocuronium 30&#x2009;mg (0.6&#x2009;mg/kg) and sugammadex 200&#x2009;mg (3.8&#x2009;mg/kg) at TOF count 1, recovered to a TOF ratio of 92% at 4 minutes, but developed respiratory failure 3 minutes after extubation; mask ventilation and neostigmine 2&#x2009;mg with atropine 0.25&#x2009;mg were given.<br><br>OUTCOMES: Case 1 recovered uneventfully and was discharged on postoperative day (POD) 6. Case 2 required intensive care unit admission, re-intubation on POD 1, and re-extubation on POD 3; she was discharged on POD 23 without new neurologic deficits.<br><br>LESSONS: In ALS, recurarization can occur despite seemingly adequate sugammadex reversal. When rocuronium is used, sugammadex is recommended for reversal, with vigilant quantitative neuromuscular monitoring and extended post-extubation observation to detect delayed weakness.}, }
@article {pmid41496184, year = {2026}, author = {Portaro, S and Latella, D and Manuli, A and Calderone, A and Calabrò, RS}, title = {Bridging the gap in sexuality and neuromuscular disorders: a scoping review of an overlooked but crucial topic.}, journal = {Sexual medicine reviews}, volume = {14}, number = {1}, pages = {}, doi = {10.1093/sxmrev/qeaf076}, pmid = {41496184}, issn = {2050-0521}, support = {//Current Research Funds 2024-2025/ ; //Ministry of Health, Italy/ ; }, mesh = {Humans ; *Neuromuscular Diseases/psychology ; *Quality of Life/psychology ; *Sexuality/psychology ; *Sexual Dysfunction, Physiological/psychology ; Social Stigma ; Female ; *Sexual Health ; }, abstract = {INTRODUCTION: Neuromuscular disorders (NMDs) comprise a group of conditions affecting the muscles and/or the nerves controlling them, resulting in progressive muscle weakness. Beyond the physical limitations, NMDs can significantly impact quality of life (QoL), including sexuality. Sexuality, as defined by the World Health Organization, encompasses physical, psychological, and social dimensions. However, research exploring the multifaceted impact of NMDs on sexual well-being remains limited, despite the potential influence of physical impairments, psychological distress, and social stigma.<br><br>OBJECTIVES: This scoping review aims to synthesize the existing literature on sexuality in individuals with NMDs, identifying the interplay of physical, psychological, and social factors affecting sexual QoL, highlighting research gaps, and informing future research and clinical practice.<br><br>METHODS: A scoping review was conducted using PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases (up to May 15, 2025) to identify studies examining sexuality in individuals with NMDs. Studies addressing physical, psychological, and social factors influencing sexual health in NMD patients were included. Data were extracted using a standardized form and synthesized narratively. The review was registered on Open OSF (DOI https://doi.org/10.17605/OSF.IO/RP9U2).<br><br>RESULTS: Fourteen studies with various conditions such as Duchenne muscular dystrophy, amyotrophic lateral sclerosis (ALS), myotonic dystrophy type 1, myasthenia gravis, and Charcot-Marie-Tooth&#x2002;disease were included, from interviews to surveys. One key theme that emerged was the extent to which&#x2002;personal narratives reveal the emotional weight of stigma, the struggle with body image, and how intimacy is peripheral in medical institutions. In surveys, many said their sexual activity had declined, particularly among people with progressive diseases like ALS and myotonic dystrophy. Many of these studies also pointed to how sexual health was directly associated with QoL, a good reminder that it's an important aspect of well-being that we need to pay more attention to in care and support.<br><br>CONCLUSION: This scoping review highlights a significant gap in research regarding sexuality in individuals with NMDs. The limited number of studies identified underscores the need for further research to understand the complex interplay of physical, psychosocial, and social factors affecting sexual well-being in this population.}, }
@article {pmid41496372, year = {2026}, author = {Fitriasari, E and Umasugi, MT}, title = {Reframing underserved young women's access to reproductive services: Extending Wier et al.'s review through a life-course, gender-inclusive and digital lens.}, journal = {Sexual &amp; reproductive healthcare : official journal of the Swedish Association of Midwives}, volume = {47}, number = {}, pages = {101177}, doi = {10.1016/j.srhc.2025.101177}, pmid = {41496372}, issn = {1877-5764}, }
@article {pmid41497595, year = {2025}, author = {Zhong, W and Scialò, C and Gatta, B and Häfliger, M and Leu, N and Lurati, F and Peter, M and Ramesh, N and Roschitzki, B and Jagannath, S and Manglunia, R and de Cecco, E and Lim, SM and Wilkins, OG and Aguzzi, A and Ward, M and Fratta, P and Petrucelli, L and Lagier-Tourenne, C and Polymenidou, M}, title = {Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41497595}, issn = {2692-8205}, support = {RM1 NS133601/NS/NINDS NIH HHS/United States ; }, abstract = {Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.}, }
@article {pmid41498281, year = {2026}, author = {Santamaria, MP and Mathias-Santamaria, IF and Tavelli, L and Barootchi, S and Prato, GPP}, title = {An updated evidence-based recommendation for the treatment of gingival recession associated with non-carious cervical lesions.}, journal = {Journal of periodontology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jper.70049}, pmid = {41498281}, issn = {1943-3670}, abstract = {BACKGROUND: Approximately 50% of the gingival recessions (GRs) are associated with non-carious cervical lesions (NCCLs), forming what are known as combined defects (CDs), which often require specific treatment protocols that differ from those used for GRs on teeth with an intact and sound surface. This narrative review aims to evaluate the current and relevant literature on the treatment of CDs and update the latest decision-making process with the new literature.<br><br>METHODS: Medline/PubMed, Embase, BIREME, and Google Scholar databases were searched. The NCCL portion of the CDs was classified according to Pini-Prato et&#xa0;al.'s classification (2010). The GR portion of the CDs was classified according to Cairo et&#xa0;al.'s classification (2011) and gingival phenotype. Based on these, a decision tree, supported by the current literature, was proposed.<br><br>RESULTS: Several approaches associating different surgical techniques/graft materials with different NCCL restoration protocols and materials are available. When A-, A+, and B- NCCL are present, only a surgical procedure for root coverage is needed based on GR characteristics. When either B+ or V-shaped NCCL is present, a composite restorative protocol and a root coverage procedure should be considered.<br><br>CONCLUSIONS: CDs are characterized by the coexistence of gingival recession and a non-carious cervical lesion. This updated decision-making process incorporated current literature, including new evidence on soft tissue grafts, which can guide clinicians in the treatment of CDs.<br><br>PLAIN LANGUAGE SUMMARY: Gum recession often occurs alongside defects in the tooth that are not caused by cavities. These two conditions can appear on the same tooth in about half of the cases. When that happens, treatment becomes more complex and requires careful planning. Choosing the best approach depends on the shape and severity of the tooth defect. This recommendation helps dentists and patients understand how to manage these combined problems. Most cases fall into mild categories (A-, A+, and B-; i.e., shallow tooth defects) and can be treated with standard procedures for gum recession alone. However, about 25% of cases have a more advanced defect (B+; i.e., deep tooth defects), which requires both a tooth restoration and gum surgery. The way gum recession is treated also depends on how thick the gum tissue is. If the tissue is thin, using the patient's own tissue for a graft usually gives the best results. If the tissue is already thick, a graft may not be necessary. In moderate cases, a graft using either patient tissue or commercial materials can improve long-term success. This recommendation summarizes the latest research and provides practical guidance to improve treatment outcomes for both patients and clinicians.}, }
@article {pmid41498289, year = {2025}, author = {Ram, J and Glickman, MH}, title = {The many faces of p97/Cdc48 in mitochondrial homeostasis.}, journal = {Essays in biochemistry}, volume = {69}, number = {5}, pages = {}, pmid = {41498289}, issn = {1744-1358}, mesh = {Humans ; *Valosin Containing Protein/metabolism/genetics ; *Mitochondria/metabolism ; *Homeostasis ; Animals ; *Adenosine Triphosphatases/metabolism/genetics ; Nuclear Proteins ; }, abstract = {Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.}, }
@article {pmid41498343, year = {2026}, author = {Spencer, C and Connon, CC and Seashols-Williams, SJ}, title = {Semen extraction efficiency and recovery before and after washing from reusable period underwear.}, journal = {Journal of forensic sciences}, volume = {71}, number = {2}, pages = {962-969}, doi = {10.1111/1556-4029.70255}, pmid = {41498343}, issn = {1556-4029}, mesh = {Humans ; Male ; *Semen/cytology/chemistry ; DNA Fingerprinting ; Microsatellite Repeats ; *Specimen Handling/methods ; Female ; *DNA/isolation &amp; purification ; Spermatozoa ; Acid Phosphatase/analysis ; *Laundering ; *Menstrual Hygiene Products ; }, abstract = {When sexual assault evidence kits do not yield biological evidence demonstrating sexual contact, clothing such as undergarments is evaluated for the presence of semen. Menstrual underwear is a new type of undergarment and feminine product encountered as evidence in sexual assaults. They are composed of absorbent and leak-proof layers and can be washed and re-worn multiple times. The objective of this work was to determine a best practice for semen and DNA recovery from reusable menstrual underwear. Simulated postcoital samples were deposited on three different brands of menstrual underwear, and alternate light source evaluation failed for two of the three brands tested, though acid phosphatase testing was positive for all three brands tested. Testing of individual layers versus cuttings of a portion of the stain found that a full-depth cutting results in optimal biological sample recovery. Mock postcoital deposits were then washed once or twice and subjected to serological and DNA workflows, with varying results in acid phosphatase and P30 testing after washing once or twice between brands. However, sperm recovery was successful in all samples, and complete short tandem repeat (STR) profiles were obtained from both sperm and nonsperm fractions from all samples, regardless of washing status. With these findings, while sperm recovery has the highest likelihood of success with a full-thickness cutting, forensic scientists should be cautious in depending on ALS for stain location. Additionally, biological materials remain in these brands of menstrual underwear after washing, and therefore, biological material from previous sexual contact could remain and be detectable.}, }
@article {pmid41498389, year = {2026}, author = {Wang, XC and Yang, C and Lv, H and Zhang, XJ and Zhou, WT and Lu, P and Yu, Y and Fu, H and She, Y}, title = {A GC-MS Data Analysis Platform for Untargeted Metabolomics with Enhanced Coeluting Peak Resolution.}, journal = {Analytical chemistry}, volume = {98}, number = {2}, pages = {1416-1426}, doi = {10.1021/acs.analchem.5c05471}, pmid = {41498389}, issn = {1520-6882}, mesh = {*Gas Chromatography-Mass Spectrometry/methods ; *Metabolomics/methods ; Algorithms ; Least-Squares Analysis ; Data Analysis ; }, abstract = {Gas chromatography-mass spectrometry (GC-MS) remains challenged by the accurate resolution of coeluting peaks and the correction of retention time shift in large-scale batch analysis. Here, we introduce AntDAS-CPR, an integrated data analysis platform tailored for untargeted GC-MS-based metabolomics. The platform incorporates modules for total ion chromatogram (TIC) peak resolution, retention time shift correction, component registration, chemometric analysis, and compound identification. In this work, the TIC peak resolution module was specifically optimized through the development of a dynamic elimination multivariate curve resolution-alternating least-squares (DEMCR-ALS) algorithm, which employs multiple initialization strategies to enhance the resolution of coeluting peaks and reduce dependence on initial estimates inherent in conventional methods. The performance of AntDAS-CPR was comprehensively evaluated using standard mixtures and complex food matrix data sets. It was compared with state-of-the-art GC-MS data analysis tools, including AMDIS, ADAP-GC, MS-DIAL, and eRah. Comparative results demonstrated that AntDAS-CPR consistently outperforms existing methods in both targeted and untargeted analysis. The platform is freely accessible at http://www.pmdb.org.cn/antdascpr.}, }
@article {pmid41498587, year = {2026}, author = {Maskell, KG and Cook, AL and King, AE and Dickson, TC and Blizzard, CA}, title = {Modeling amyotrophic lateral sclerosis (ALS) in vitro: from mechanistic studies to translatable drug discovery.}, journal = {Lab on a chip}, volume = {26}, number = {5}, pages = {1108-1122}, doi = {10.1039/d5lc00577a}, pmid = {41498587}, issn = {1473-0189}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Humans ; *Drug Discovery ; Animals ; *Models, Biological ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressing, fatal neurodegenerative disease that causes selective degeneration of the corticomotor system. Currently, ALS remains incurable, and the available treatment options offer little in the way of extending life or improving quality of life. This is due, at least in part, to a lack of representative disease models. In vitro modeling offers rapid, experimentally accessible platforms for mechanistic discovery research and drug screening, but modeling the complexity of ALS - a multicellular, multisystem disease - in a dish, is not without its challenges. Here, we review the current landscape of in vitro pre-clinical ALS research, with emphasis on the development of compartmentalised culture and the promise this holds for translatable modeling of ALS.}, }
@article {pmid41498748, year = {2026}, author = {Byrd, A and Marmorale, LJ and Marcinowski, S and Dykstra, MM and Addison, V and Barmada, SJ and Buchan, JR}, title = {Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.}, journal = {The Journal of cell biology}, volume = {225}, number = {2}, pages = {}, pmid = {41498748}, issn = {1540-8140}, support = {R01NS113943/NH/NIH HHS/United States ; T32 GM136536/GM/NIGMS NIH HHS/United States ; F31NS134123-01/NH/NIH HHS/United States ; R01 GM114564/GM/NIGMS NIH HHS/United States ; //University of Arizona/ ; R01GM114564/NH/NIH HHS/United States ; DGE-1746060//National Science Foundation/ ; P30 AG072931/AG/NIA NIH HHS/United States ; F31NS141379/NH/NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; T32GM136536/NH/NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; P330AG072931//Michigan Alzheimer's Disease Research Center/ ; F31 NS141379/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R56NS128110/NH/NIH HHS/United States ; R01NS097542/NH/NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; }, mesh = {*Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics/toxicity ; *Nedd4 Ubiquitin Protein Ligases/metabolism/genetics ; *Lysosomes/metabolism ; Ubiquitination ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ubiquitin-Protein Ligase Complexes/metabolism/genetics ; *Endosomes/metabolism ; HEK293 Cells ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; Multivesicular Bodies/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; }, abstract = {A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation, stability, and toxicity. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation induces giant MVB-like vesicles, within which TDP-43 accumulates in a NEDD4-dependent manner. Our studies shed light on endolysosomal-mediated cytoplasmic protein clearance, a poorly understood proteostasis mechanism, which may help identify novel ALS therapeutic strategies.}, }
@article {pmid41499157, year = {2026}, author = {Sousa-Leite, M and Gameiro, S}, title = {A multi-country study to co-design and evaluate digital educational resources to support conversations about ending fertility treatment.}, journal = {Human reproduction (Oxford, England)}, volume = {41}, number = {3}, pages = {381-393}, doi = {10.1093/humrep/deaf248}, pmid = {41499157}, issn = {1460-2350}, support = {//Research Wales Innovation Fund/ ; JA1710IF63//Higher Education Funding Council for Wales/ ; SFRH/BD/144429/2019//Portuguese Foundation for Science and Technology/ ; ES/Z503125/1//UK Economic and Social Research Council/ ; UIDB/04750/2020//FTC/ ; LA/P/0064/2020//FTC/ ; }, mesh = {Humans ; Female ; *Patient Education as Topic/methods ; Adult ; Male ; *Reproductive Techniques, Assisted/psychology ; *Infertility/therapy/psychology ; Communication ; }, abstract = {STUDY QUESTION: How can educational resources be feasibly co-designed and used to support conversations between staff and patients about ending fertility treatment?<br><br>SUMMARY ANSWER: Co-design workshops allow for the development of educational resources that account for all stakeholders' perspectives and are considered sensitive, informative, and helpful to support end-of-treatment conversations, but staff and patients have different views about how these can be used within the treatment pathway.<br><br>WHAT IS KNOWN ALREADY: Ending treatment without children is a common outcome but seldom discussed with patients. Preventive end-of-treatment care aims to promote healthy transitions at the end of treatment by preparing and helping patients cope with this possible outcome. Nine in ten patients want to receive such care, but only 3 in 10 report receiving it. Knowledge of perceived barriers to implementing preventive end-of-treatment care at clinics and whether digital educational resources can be developed to support its provision is lacking.<br><br>STUDY DESIGN, SIZE, DURATION: Co-design workshops with fertility staff (March 2022), patients, and patient advocates (March-December 2022) from Europe (Belgium, Finland, Germany, Italy, Portugal, Spain, and UK) and South America (Argentina, Brazil, and Chile). Staff were invited to participate through fertility professional and scientific associations, and patients and advocates via charities and social media. Eligibility criteria were being aged 18 or older and working in fertility care (for staff) or charity (for advocates) or being waiting to initiate, undergoing, or having undergone treatment within 6 months (for patients).<br><br>A preliminary specification and initial prototypes of digital educational resources to support staff and patients, respectively, in having conversations about ending treatment were developed with relevant stakeholders. Co-design workshops with study participants were conducted. A semi-structured script, following Bowen et al.'s (2009)feasibility framework, was used to guide the workshops. Questions covered: (i) experiences, views, and preferences on the provision of preventive end-of-treatment care at clinics and iterative prototypes of the resources to support this provision (acceptability); (ii) perceived need and benefits (demand); and (iii) perceived barriers and facilitators to its implementation at clinics (practicalities). Workshops were recorded and transcribed verbatim, and data were analysed using Framework Analysis.<br><br>Fifteen fertility staff, 34 patients, and 7 advocates participated. Staff were mainly psychologists/counsellors (40.0%) or clinicians (26.7%) working in the field for around 23&#x2009;years. Patients were mostly women (91.2%), on average aged 38&#x2009;years. Most were childless (73.5%) and trying to conceive for around 3 years. Framework analysis of data collected during the co-design workshops generated four themes and one meta-theme, reflecting a need for a normative shift across countries towards the routine implementation of preventive end-of-treatment care. Themes reflected: (i) demand for routine provision of holistic psychosocial care, including preventive end-of-treatment care; (ii) different views between staff and patients about the risks and extent of benefits of routinely implementing preventive end-of-treatment care; (iii) patient high clarity about the functions of preventive end-of-treatment care (ensuring patients feel prepared and supported in moving through the grief and cope with short-term challenges; explore other pathways to parenthood and re-orient one's life goals; and ensure informed consent for fertility treatment) versus staff lower clarity, with care being equated to signposting patients for timely psychological support; and (iv) co-designed digital educational resources are helpful to support the routine provision of preventive end-of-treatment care at clinics.<br><br>Non-probability sample. Although the patient sample was heterogeneous (heterosexual and same-sex couples; private and public sectors), patients were primarily White, well-educated, employed, and childless women, limiting the generalization and comparisons across gender and other personal characteristics (ethnicity, socioeconomically disadvantaged, and disabled), where access to and acceptance of psychosocial support are expected to be lower.<br><br>Routine discussions about the end of treatment are needed and beneficial, but staff will require reassurance and training on with whom, when, and how to engage in these. The final version of the digital educational resources is seen as valuable to support a cultural shift in implementing end-of-treatment preventive care at clinics. The co-designed webpages are freely available online in four languages (for staff: www.myjourney.pt/clinics, for patients: www.myjourney.pt/patients). Future research is needed to raise awareness and further investigate how best to support staff in such care provision and measure its impact.<br><br>This work was supported by a Research Wales Innovation Fund from the Higher Education Funding Council for Wales (HEFCW, grant No.: JA1710IF63). M.S.-L. was supported by the Portuguese Foundation for Science and Technology (FCT; fellowship No.: SFRH/BD/144429/2019) and the UK Economic and Social Research Council (ESRC; fellowship No.: ES/Z503125/1). The EPIUnit and ITR were funded by the FTC through the Portuguese State Budget (projects No.: UIDB/04750/2020 and LA/P/0064/2020 and DOI identifiers https://doi.org/10.54499/UIDB/04750/2020 and https://doi.org/10.54499/LA/P/0064/2020). S.G. reports grants from the European Society for Human Reproduction and Embryology (ESHRE), the Wellcome Fund (UK), and the Health and Care Research Wales (UK). Cardiff University holds the Intellectual Property rights for the tool www.myjourney.pt, licensed under a Creative Commons AttributionNonCommercial-ShareAlike 4.0 International Licence (CC BY-NCSA 4.0).<br><br>TRIAL REGISTRATION NUMBER: n/a.}, }
@article {pmid41499987, year = {2026}, author = {Poulidou, V and Tseriotis, VS and Bombaci, A and Vucic, S and Pavey, N and Papagiannopoulos, S and Kimiskidis, VK and Arnaoutoglou, M}, title = {The split elbow sign in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {56}, number = {2}, pages = {103134}, doi = {10.1016/j.neucli.2025.103134}, pmid = {41499987}, issn = {1769-7131}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) patients can exhibit split phenomena, with preferential weakness of specific muscle groups. The aim of this review is to investigate the split elbow (SE) phenomenon (different weakness/wasting pattern between biceps and triceps) as a potential clinical and neurophysiological feature in ALS.<br><br>METHODS: Our study was reported according to the PRISMA statement and registered in PROSPERO (CRD42024528359). MEDLINE, SCOPUS, Web of Science, and grey literature sources were searched using the terms "split elbow" and "amyotrophic lateral sclerosis" up to April 2025. English-written peer-reviewed, randomized, non-randomized, observational, diagnostic accuracy, and case-control studies were included. Study quality was assessed using Joanna Briggs Institute critical appraisal tool. Regarding muscle strength, we pooled the standardized mean difference of normalized Medical Research Council (MRC) scores using random effects. We used a bivariate random-effects model to evaluate SE index (SEICMAP, compound muscle action potential of biceps/triceps) in distinguishing ALS from controls.<br><br>RESULTS: Seven studies with 1941 ALS patients (61.8 % male) met inclusion criteria. Pooled standardized mean difference (triceps - biceps MRC scores) was -0.17 [95 % CI, -1.03 to 0.69], p = 0.63, indicating no significant difference in muscle strength between elbow flexion and extension. Between-study heterogeneity was high (I[2] = 97.1 % [95.5 %; 98.2 %], p < 0.0001). The SEICMAP demonstrated only moderate accuracy in distinguishing ALS from controls (pooled sensitivity, specificity, and AUC of 0.789 [0.655-0.880], 0.580 [0.487-0.668], and 0.661, respectively).<br><br>CONCLUSIONS: Current evidence does not support a consistent SE pattern in ALS. Methodological variability and small sample sizes limit the generalizability of available findings, indicating that the SE is unlikely to provide meaningful diagnostic utility in routine clinical practice.}, }
@article {pmid41500294, year = {2026}, author = {Zhang, Y and Wang, Y}, title = {Response letter to Chi-Tung Lu et al.'s Comment on "Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China".}, journal = {Pharmacological research}, volume = {224}, number = {}, pages = {108086}, doi = {10.1016/j.phrs.2026.108086}, pmid = {41500294}, issn = {1096-1186}, }
@article {pmid41500819, year = {2026}, author = {Zorotovich, J and Andrews, C}, title = {Multidisciplinary care for amyotrophic lateral sclerosis in rural Appalachia: Tales from the Clinic Coordinator.}, journal = {Palliative &amp; supportive care}, volume = {24}, number = {}, pages = {e29}, doi = {10.1017/S1478951525101454}, pmid = {41500819}, issn = {1478-9523}, }
@article {pmid41500873, year = {2026}, author = {Pérez-Bonilla, M and Borrego, PD and Mora-Ortiz, M and Fernández-Baillo, R and Mayordomo-Riera, FJ and López, EG}, title = {Voice-Based Prediction of Survival in Amyotrophic Lateral Sclerosis (ALS) Patients Using Biomechanical Acoustic Markers.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.12.014}, pmid = {41500873}, issn = {1873-4588}, abstract = {OBJECTIVE: To evaluate whether voice-derived acoustic and biomechanical features can serve as non-invasive biomarkers for mortality-risk prediction and survival stratification in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We conducted a retrospective study including 50 ALS patients evaluated in a phoniatrics consultation with available sustained vowel recordings, demographic data, and functional assessments. Nested logistic regression models were developed to predict clinical outcomes, progressively incorporating demographic variables, functional indices (Grade, Roughness, Breathiness, Asthenia, Strain, and Barthel), acoustic features (fundamental frequency, jitter, shimmer, harmonics-to-noise ratio), and biomechanical voice parameters (Pr1-Pr22). Model performance was assessed using receiver operating characteristic curves and area under the curve (AUC) comparisons via DeLong tests. Stepwise Akaike Information Criterion&#xa0;(StepAIC) was applied to optimize the final model. A Cox proportional hazards model was used to evaluate the association between voice parameters and survival time.<br><br>RESULTS: The final StepAIC model, which included a subset of biomechanical features, achieved excellent predictive performance (AUC&#xa0;=&#xa0;0.903, 95% confidence interval: 0.816-0.989), significantly outperforming baseline and acoustic-only models. Bootstrapping confirmed the model's robustness and generalizability. Cox regression analysis showed that the derived risk scores stratified patients into tertiles with significantly different survival probabilities (log-rank P&#xa0;<&#xa0;0.0001; hazard ratio for high vs. low-risk group&#xa0;=&#xa0;11.2).<br><br>CONCLUSION: Biomechanical voice features are strong predictors of mortality in ALS and outperform traditional clinical and acoustic indices. These findings support the integration of voice analysis into ALS monitoring protocols as a non-invasive, cost-effective, and scalable prognostic tool.}, }
@article {pmid41502663, year = {2025}, author = {Ma, Y and Tian, H and Xiao, W and Ma, Y and Su, H and Zhu, L and Jiang, Y and Ge, L and Li, Y and Yuan, M and Liu, X}, title = {Machine Learning Approaches for Optimizing Drug Combinations in Neurodegenerative Diseases: A Brief Review.}, journal = {ACS omega}, volume = {10}, number = {48}, pages = {57950-57973}, pmid = {41502663}, issn = {2470-1343}, abstract = {As the global population ages, the prevalence of neurodegenerative diseases (NDDs)(?)including Alzheimer's disease, Parkinson's disease, Huntington's disease, Multisystem Atrophy (multiple system atrophy), and amyotrophic lateral sclerosis(?)continues to rise, largely driven by environmental, metabolic, and lifestyle risk factors. Advances in computational technologies, particularly machine learning (ML) and deep learning, are reshaping research in this field. This review summarizes the major features of these diseases and emphasizes the role of ML in drug discovery, virtual screening, drug repurposing, and drug combination optimization. Representative approaches include support vector machines for classification, convolutional neural networks|convolutional neural network for imaging analysis, recurrent neural networks for temporal biomedical data, and transformers for multimodal integration. These methods highlight the potential of computational strategies to improve therapeutic development. In addition, the review underscores the substantial incidence rates and socioeconomic burden of these conditions, which have made them focal points for algorithmic innovation. With research evolving rapidly, the development of AI-driven approaches is expected to enable more effective, targeted interventions and improve patient outcomes. This Perspective provides a concise overview of current progress and identifies promising future directions in the fight against NDDs.}, }
@article {pmid41503832, year = {2026}, author = {Tuli, S and Patel, P and Shethji, A and Gau, D}, title = {Mitochondria and the Actin Cytoskeleton in Neurodegeneration.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/cm.70095}, pmid = {41503832}, issn = {1949-3592}, support = {CA267180/NH/NIH HHS/United States ; TL1 TR001858/NH/NIH HHS/United States ; }, abstract = {Mitochondrial dysfunction and cytoskeletal disorganization are widely recognized hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although these disorders differ in clinical presentation and etiology, accumulating evidence points to a shared cellular vulnerability at the intersection of mitochondrial dynamics and actin cytoskeletal regulation. In this review, we examine the emerging role of actin-mitochondria crosstalk as a convergent mechanism in neurodegeneration. We discuss how disruptions in actin filament remodeling, mitochondrial fission and fusion, organelle transport, and mitophagy contribute to neuronal dysfunction and loss across these diseases. Particular attention is given to disease-specific pathways, including cofilin-actin rod formation in AD, α-synuclein-driven actin disruption in PD, mutant huntingtin's effects on mitochondrial fragmentation in HD, and profilin-1-associated mitochondrial defects in ALS. By synthesizing findings from diverse models, we highlight how perturbations in the cytoskeleton-mitochondria interface may act as an upstream trigger and amplifier of neurodegenerative cascades. We also outline key knowledge gaps and propose future directions for research, with an emphasis on targeting actin-mitochondrial interactions as a potential therapeutic strategy across multiple neurodegenerative conditions.}, }
@article {pmid41504056, year = {2025}, author = {Lymperopoulos, A and M'Sadoques, AJ and Stoicovy, RA and Altsman, VL}, title = {Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β2-Adrenergic Receptor Activation.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {12}, pages = {47927}, doi = {10.31083/FBL47927}, pmid = {41504056}, issn = {2768-6698}, support = {R01 #HL155718-01//National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant/ ; #333609-2025//American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship/ ; }, mesh = {*Epinephrine/therapeutic use/pharmacology ; Humans ; *Heart Arrest/drug therapy ; *Receptors, Adrenergic, beta-2/metabolism ; *Vasoconstrictor Agents/therapeutic use/pharmacology ; Cardiopulmonary Resuscitation/methods ; Animals ; }, abstract = {Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β2-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β2AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β2AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.}, }
@article {pmid41504098, year = {2026}, author = {Aazmi, O and Aswale, AR and Chugh, J}, title = {H[+] Ions and ATP Reshape the Conformational Landscape of an RNA Recognition Motif and Regulate Its Fibrillation.}, journal = {Journal of the American Chemical Society}, volume = {148}, number = {2}, pages = {2295-2306}, doi = {10.1021/jacs.5c15374}, pmid = {41504098}, issn = {1520-5126}, mesh = {*Adenosine Triphosphate/chemistry/metabolism ; *RNA-Binding Protein FUS/chemistry/metabolism ; Hydrogen-Ion Concentration ; Humans ; Protein Conformation ; *RNA Recognition Motif ; Ions/chemistry ; Nuclear Magnetic Resonance, Biomolecular ; }, abstract = {Proteins exist as dynamic ensembles, with their native states comprising interconverting conformational substates critical to their physiological functions and participation in disease states. Fused in sarcoma (FUS), an RNA-binding protein implicated in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), contains an RNA recognition motif (RRM) known to form fibrillar aggregates. Here, we investigate the conformational plasticity of FUS-RRM in its native state using advanced NMR techniques, particularly [15]N chemical exchange saturation transfer and heteronuclear adiabatic relaxation dispersion experiments, to capture slow and fast microsecond (μs) time scale dynamics. We further examine the influence of environmental factors such as pH and ATP on the conformational plasticity and the aggregation behavior of FUS-RRM. Our findings show that both ATP and pH perturb the fast and slow μs time scale dynamics of FUS-RRM and thus the aggregation behavior. Specifically, a contrasting effect of ATP on slow and fast μs-ms dynamics at pH 6.4 and 4.6, along with the corresponding changes in aggregation behavior, suggests a complex relationship among ATP, pH, and protein aggregation kinetics. The study suggests that these environmental perturbations behave as kinetic regulators of FUS-RRM's propensity for aggregation.}, }
@article {pmid41504202, year = {2025}, author = {Wu, JY and Ye, S and Yin, TL and Zhang, S and Zheng, DF and Fu, JY and Ma, GW and Fan, DS}, title = {Amyotrophic Lateral Sclerosis With Concurrent LHON-associated m.14484T&gt;C Mutation: A Case Report and Literature Review.}, journal = {Revista de neurologia}, volume = {80}, number = {11}, pages = {44110}, pmid = {41504202}, issn = {1576-6578}, support = {81873784//National Natural Sciences Foundation of China/ ; 82071426//National Natural Sciences Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, mesh = {Adult ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mutation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that mostly presents as sporadic cases. Currently, no mitochondrial-related gene mutations have been identified as the cause of ALS. Mitochondrial gene mutations cause rare hereditary diseases, and the symptoms of pure muscle weakness and muscle atrophy are rarely observed.<br><br>CASE REPORT: We report the case of a young patient clinically diagnosed with ALS concurrently associated with a pathogenic mutation in the mitochondrially encoded nicotinamide adenine dinucleotide: ubiquinone oxidoreductase core subunit 6 (MT-ND6) gene. However, the pathogenic relationship between the MT-ND6 gene and ALS has not been confirmed.<br><br>CONCLUSION: We provide a case report and a literature review aimed at increasing the understanding of the connection between the two. It is essential to consider the potential modifying role of mitochondrial pathogenic genes in ALS.}, }
@article {pmid41504722, year = {2026}, author = {Bąkowska-Żywicka, K}, title = {[Erratum for: Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge, K. Kalkowski Postepy Biochem. 71(3):252-259].}, journal = {Postepy biochemii}, volume = {71}, number = {4}, pages = {435-436}, doi = {10.18388/pb.2025_643}, pmid = {41504722}, issn = {0032-5422}, }
@article {pmid41504787, year = {2026}, author = {de Barros, JAMM and Vasconcelos, AFB and Gomes, ALCB and de Sousa, LMG and Meira, AT}, title = {"Bright Tongue" and "Wine Glass" signs in amyotrophic lateral sclerosis.}, journal = {Neuroradiology}, volume = {}, number = {}, pages = {}, pmid = {41504787}, issn = {1432-1920}, abstract = {A 43-year-old male patient presented with monoparesis in his left leg, which had persisted for one year, then progressed to spastic dysarthria, tetraparesis, wide-based gait, muscle atrophy, weakness, fasciculations, and signs of pyramidal signs in all limbs. Brain MRI findings revealed hyperintensities on T2/FLAIR and diffusion-weighted imaging (DWI) along the corticospinal tracts, extending from the corona radiata and internal capsules to the brainstem, the "bright tongue sign" and the "wine glass sign,". This case highlights the classic findings in amyotrophic lateral sclerosis, which was confirmed by electroneuromyography.}, }
@article {pmid41504939, year = {2026}, author = {Evola, V and Parmar, MS}, title = {Targeting neuroinflammation in neurodegenerative disorders: the emerging potential of semaglutide.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {75}, number = {1}, pages = {13}, pmid = {41504939}, issn = {1420-908X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/immunology ; *Glucagon-Like Peptides/therapeutic use/pharmacology ; Animals ; *Neuroprotective Agents/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Glucagon-Like Peptide 1 ; Semaglutide ; }, abstract = {BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.<br><br>FINDINGS: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8[+]T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.<br><br>CONCLUSION: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.}, }
@article {pmid41505016, year = {2026}, author = {Bronovitsky, E and Chaprov, K and Khizeva, A and Ivanova, T and Pravdivceva, E and Bobkov, T and Morozova, O and Krayushkina, A and Nebogatikov, V and Ninkina, N and Ustyugov, A}, title = {Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {1}, pages = {8}, pmid = {41505016}, issn = {1559-1166}, support = {FFSG-2024-0020//Ministry of Science and Higher Education of the Russian Federation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/physiopathology/pathology ; Mice ; Mice, Transgenic ; Male ; *Dopamine/metabolism ; Female ; *RNA-Binding Protein FUS/genetics/metabolism ; Body Weight ; Spinal Cord/metabolism ; Disease Models, Animal ; Longevity ; Movement Disorders/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to disability and death. Genetic animal models, like transgenic mice, are critical for studying disease mechanisms and developing therapies. Model validity, experimental standardization, and predictability are key to successful research. This retrospective study analyzed physiological parameters of the S-FUS (1-359) transgenic mouse model over 10 years, focusing on lifespan, body weight dynamics, symptomatic stages, and molecular changes. Hemizygous mice had a mean lifespan of 137.8 days (males) and 125.1 days (females), longer than homozygous counterparts. The symptomatic stage, marked by motor deficits, began at ~ 123 days and lasted 10-15 days. Body weight loss correlated with disease progression, reaching 28.93% of baseline at death. Molecular analysis revealed regional FUS expression differences (midbrain > spinal cord), alongside proinflammatory cytokine activation (Il6, Tnf alpha) and oxidative stress. Dopaminergic dysregulation was evident, with striatal dopamine/metabolite levels rising 40-60%, linked to Maob downregulation and impaired GABAergic inhibition. Midbrain-selective caspase-3 suppression suggested a shift from apoptosis to necroptosis, while spinal cord astrogliosis indicated compensatory mechanisms. Heterogeneity in lifespan, symptom onset timing, and disease duration was observed, underscoring the need for rigorous experimental design, particularly for therapies aiming to delay symptoms or extend survival. Dopamine oxidation emerged as a novel neurotoxicity contributor, highlighting potential therapeutic targets: modulating dopaminergic signaling and reducing oxidative stress.}, }
@article {pmid41506565, year = {2026}, author = {Liang, HY and Huang, PH}, title = {Concerns regarding the causal inference and statistical methods in Laine et al's study on obstetric anal sphincter injuries.}, journal = {American journal of obstetrics and gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajog.2026.01.001}, pmid = {41506565}, issn = {1097-6868}, }
@article {pmid41508039, year = {2026}, author = {Kim, SH and So, JH and Kim, YH and Kim, HS and Park, NY and Kim, JB and Jo, DS and Yeom, E and Lee, JA and Bae, JE and Cho, DH}, title = {Proteasome inhibition by VR23 enhances autophagic clearance of FUS[P525L]-mediated persistent stress granule in SH-SY5Y cells.}, journal = {Molecular brain}, volume = {19}, number = {1}, pages = {10}, pmid = {41508039}, issn = {1756-6606}, support = {RS-2024-00463344//Ministry of Education/ ; P0025489//Ministry of Trade, Industry and Energy/ ; }, mesh = {*Autophagy/drug effects ; Humans ; *Stress Granules/metabolism/drug effects ; *Proteasome Inhibitors/pharmacology ; *Proteasome Endopeptidase Complex/metabolism ; Cell Line, Tumor ; *RNA-Binding Protein FUS/metabolism ; Lysosomes/metabolism/drug effects ; RNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; DNA Helicases/metabolism ; }, abstract = {Autophagy is a conserved catabolic pathway that preserves cellular homeostasis through lysosomal degradation. Beyond its general role in proteostasis, selective autophagy mediates the clearance of selective cellular targets such as persistent stress granules (SGs), in a process termed granulophagy. SGs are dynamic cytoplasmic assemblies that normally disassemble after stress relief; however, their aberrant persistence has arisen as a pathological feature of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, the molecular regulation of granulophagy remains incompletely understood. Here, we established a tandem fluorescent SG reporter system with mCherry-pHluorin-FUS[P525L], enabling live-cell visualization of granulophagic flux. Using this system, we screened a chemical library and identified VR23, a proteasome inhibitor, as a potent inducer of granulophagy. VR23 promoted SG clearance through autophagic mechanisms, as evidenced by enhanced LC3 colocalization, lysosome-dependent degradation, and Bafilomycin A1-sensitive flux. Notably, disruption of SG assembly via G3BP1 inhibition abolished VR23-induced clearance, confirming its SG selectivity. These findings suggest a link between proteasome inhibition and granulophagy, highlighting VR23 as a valuable tool compound to dissect the mechanisms of SG turnover, and provide a platform for discovering modulators of pathological SG clearance in protein aggregation.}, }
@article {pmid41509200, year = {2025}, author = {Mahendran, TS and Bremer, A and Gui, X and Singh, A and Basalla, JL and Chittori, S and Marzahn, MR and Das, T and Mittag, T and Banerjee, PR}, title = {Viscoelasticity and interface properties of multi-component condensates govern protein sequestration and suppression of amyloid formation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509200}, issn = {2692-8205}, support = {R01 NS121114/NS/NINDS NIH HHS/United States ; R35 GM138186/GM/NIGMS NIH HHS/United States ; }, abstract = {Stress granules (SGs) are multi-component protein-RNA condensates widely viewed as crucibles for fibril formation in neurodegenerative diseases such as amyotrophic lateral sclerosis. Here, we test this model by examining whether SG-mimics promote or suppress amyloid formation. Using multi-component programmable peptide-nucleic acid condensates, we show that condensates delay amyloid assembly by sequestering soluble proteins, and that fibrils grow in the dilute phase. Systematic tuning of condensate material properties reveals two key modulating mechanisms: the density of fibril-forming proteins at condensate interfaces dictates the lag phase of fibril assembly, and condensate viscoelasticity regulates protein efflux-driven fibril growth. These principles extend to SG-mimic condensates formed by G3BP1 and RNA, suggesting that SGs may function as potent suppressors rather than crucibles of pathological amyloid assembly.}, }
@article {pmid41509469, year = {2025}, author = {Park, J and Stepanova, A and Dash, J and Southwell, N and Zhao, D and Konrad, C and Tyagi, P and Kwan, JY and Shneider, NA and Mentis, GZ and Manfredi, G and Kawamata, H}, title = {A mouse model of CHCHD10 p.R15L familial ALS presents mild, age-related motor neuron degeneration without protein instability or mitochondrial dysfunction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.29.696888}, pmid = {41509469}, issn = {2692-8205}, support = {R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the mitochondrial protein CHCHD10 (D10) cause a spectrum of hereditary neurodegenerative disorders. Among these, the p.R15L variant is linked to a slowly progressive, late-onset familial form of amyotrophic lateral sclerosis (ALS) with unclear pathogenic mechanisms. To better understand this, we investigated a knock-in (KI) mouse model carrying the p.R15L mutation in the endogenous protein. Unlike previously described mutant D10 KI models, p.R15L KI mice exhibited normal D10 protein levels, with no evidence of large protein aggregates. Mitochondrial respiration and hydrogen peroxide emission in mitochondria isolated from muscle and brain were unaltered. Similarly, fibroblasts from human p.R15L carriers exhibited normal D10 levels and unchanged oxidative phosphorylation function. Histochemical analyses of p.R15L KI muscle revealed mild increases in mitochondrial enzymatic activity in a subset of muscle fibers and muscle transcriptomics showed elevated expression of PGC-1α, suggesting enhanced mitochondrial biogenesis. p.R15L KI mice developed subtle, late-onset phenotypes, including reduced body weight and motor activity and increased anxiety-like behavior. Importantly, in aged mice electrophysiological studies demonstrated decreased amplitude of the compound muscle action potential, commensurate with a moderate loss of spinal cord motor neurons and elevated serum neurofilament light levels, indicative of neurodegeneration. Together, these results indicate that the p.R15L mutation produces a mild, late-onset motor neuron phenotype in mice, partially recapitulating the human disease, without mitochondrial functional or morphological alterations. The findings indicate that p.R15L D10 selectively impairs mouse motor neurons through a gain-of-function mechanism, providing a genetically accurate yet mild in vivo model of familial ALS.}, }
@article {pmid41509476, year = {2025}, author = {Saez-Calveras, N and Verheijen, BM and Morgan, N and Hill, E and Taylor, S and Oyanagi, K and Kakita, A and Song, Y and Joachimiak, LA and Vaquer-Alicea, J and Diamond, MI and Lu, Y}, title = {Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.22.696002}, pmid = {41509476}, issn = {2692-8205}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disorder that was once hyperendemic in the island of Guam (Mariana Islands, US) and a few other Pacific locales. Despite extensive investigations into its origins, the etiology of ALS/PDC remains unclear. ALS/PDC is, at the neuropathology level, characterized by tau-dominant multiple proteinopathy in brain and spinal cord. It was recently reported that Guam ALS/PDC brain extracts exhibit tau seeding activity in fluorescence resonance energy transfer (FRET)-based biosensor cells. To build upon those findings and explore the nature of tau seeds in ALS/PDC in more detail, we used an alanine mutational scanning (Ala scan) approach to determine the seeding profile of tau in nervous tissues of Guam ALS/PDC cases. First, we confirmed the detection of tau seeding activity in ALS/PDC brain samples in tau biosensor cells. Notably, we could also detect potent tau seeding activity in spinal cord. Subsequent Ala scan assays demonstrated that ALS/PDC tau displays an aggregate incorporation pattern that resembles that of chronic traumatic encephalopathy (CTE)-type tau. This result is consistent with recent electron cryo-microscopy studies of tau, which revealed that ALS/PDC tau filaments are predominantly of the CTE-type. The structural characteristics and seeding behavior of ALS/PDC tau, as well as the regional distribution of tau pathology at post-mortem, suggest that ALS/PDC is a CTE-like tauopathy.<br><br>SIGNIFICANCE STATEMENT: Neurodegenerative tauopathies are characterized by proteinaceous deposits containing microtubule-associated tau in nervous tissue. Emerging evidence suggests that disease-associated tau proteins adopt abnormal, self-propagating conformations characteristic of prions. Here, we employed alanine mutational scanning (Ala scan) to determine the nature of prion-like tau seeds in ALS/PDC, a mysterious disorder that occurred formerly in high incidence in certain regions in the western Pacific. We show that the Ala scan incorporation profile of ALS/PDC tau is similar to that of abnormal tau proteins in chronic traumatic encephalopathy (CTE). The findings lend support to the idea that ALS/PDC can be classified structurally as a CTE-like tauopathy. This work may have important implications for our understanding of ALS/PDC as well as common neurological disorders beyond the Pacific.}, }
@article {pmid41510219, year = {2025}, author = {Moll, S and Tannemann, N and Gestmann, M and Brenner, T and Herbstreit, F and Szalai, C}, title = {Redesigning Advanced Life Support teaching and assessment using a constructive alignment approach.}, journal = {MedEdPublish (2016)}, volume = {15}, number = {}, pages = {48}, pmid = {41510219}, issn = {2312-7996}, abstract = {Advanced Life Support (ALS) is a crucial component of medical training. Previously, a single-person OSCE-Station (Objective Structured Clinical Exam) was used to assess these skills, focusing primarily on the team leader role and emphasizing theoretical knowledge. However, students demonstrated deficiencies in key algorithm-compliant practical skills, such as cardiac massage, mask ventilation and defibrillator use, and struggled to integrate into a team-based resuscitation approach. To address this, a constructive alignment approach was used to revise the course and offer a guideline-appropriate, three-person resuscitation model. Learning outcomes and assessment targets were aligned with the course activities to increase student engagement and increase desired skill attainment. In the summer semester 2023, students and lecturers were briefed on the new structure of the course and assessment, specific skills were highlighted, and a model video was provided. The OSCE format was adjusted to assess both practical and non-technical skills. In the new setup, each student was randomly assigned one of three roles and assessed using role-specific checklists with defined criteria, focusing on non-technical and practical abilities. Course activity included training and practice in the three-person resuscitation approach. A team OSCE (tOSCE) approach for assessment was used, with one student for each role being examined. Results indicated both subjective and objective markers of satisfaction in course activities and tOSCE results. A team-based OSCE station proves effective for teaching combined practical and non-technical competencies.}, }
@article {pmid41510529, year = {2026}, author = {Reedy, MB and Abdul Azeem, M and Subramaniam, T and Salamat, S and Rowley, H and Beinlich, B}, title = {Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report.}, journal = {Case reports in neurological medicine}, volume = {2026}, number = {}, pages = {5565739}, pmid = {41510529}, issn = {2090-6668}, abstract = {West Nile virus (WNV) is the most common mosquito-borne infection in North America; while most cases are asymptomatic, fewer than 1% develop neuroinvasive disease with significant morbidity and mortality. We report a 57-year-old man from rural Wisconsin who presented with a 10-week history of progressive asymmetric quadriparesis and severe intractable pain, preceded by fatigue, shoulder pain, and paresthesias. Neurologic examination demonstrated mild encephalopathy, bulbar involvement, and mixed upper and lower motor neuron signs. MRI showed patchy thoracic cord T2 hyperintensities and diffuse lumbar ventral root enhancement. Electrodiagnostic studies revealed diffuse active denervation and reduced compound muscle action potentials, initially raising concern for amyotrophic lateral sclerosis. Elevated WNV IgM and IgG titers in serum and cerebrospinal fluid confirmed neuroinvasive WNV infection. Despite treatment with corticosteroids and intravenous immunoglobulin, the patient deteriorated and was transitioned to hospice care. Autopsy demonstrated T-cell-mediated meningoencephalitis with widespread lymphocytic inflammation involving motor neurons, spinal cord, ventral rootlets, and peripheral nerves, consistent with diffuse axonopathy. This case underscores that neuroinvasive WNV may closely mimic motor neuron disease and emphasizes the importance of serologic testing for accurate diagnosis. Management remains supportive, and outcomes can be severe due to extensive central and peripheral nervous system involvement.}, }
@article {pmid41510716, year = {2026}, author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A}, title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575415521251021091530}, pmid = {41510716}, issn = {1875-5607}, abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.<br><br>METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.<br><br>RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.<br><br>DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.<br><br>CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid41510728, year = {2026}, author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M}, title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249397580251117044621}, pmid = {41510728}, issn = {1875-6166}, abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.}, }
@article {pmid41511175, year = {2026}, author = {Gomez Becerra, ML and Choi-Tucci, A and Albudoor, N and Bedore, LM and Peña, ED}, title = {Improving the Efficiency of the Bilingual Input-Output Survey-Home.}, journal = {American journal of speech-language pathology}, volume = {35}, number = {2}, pages = {448-460}, doi = {10.1044/2025_AJSLP-25-00169}, pmid = {41511175}, issn = {1558-9110}, mesh = {Humans ; *Multilingualism ; Child, Preschool ; Male ; Female ; *Speech-Language Pathology/methods ; *Child Language ; Surveys and Questionnaires ; Child ; Time Factors ; Reproducibility of Results ; }, abstract = {PURPOSE: The Bilingual Input-Output Survey (BIOS)-Home (Peña et al., 2018) is used to provide speech-language pathologists (SLPs) with an estimate of children's exposure to two languages. The current hour-by-hour approach of the BIOS can be time consuming to administer and calculate. The current study seeks to improve the efficiency of the BIOS-Home by replicating Calandruccio et al.'s (2021) finding that the BIOS can be shortened by time periods around children's routines and extending these findings by preliminarily exploring the relationship of the shortened BIOS with results of a bilingual screener.<br><br>METHOD: The current study includes 1,337 Spanish-English bilingual children from two data sets. Children's ages ranged from 49 to 71 months (M = 60.58, SD = 4.96). BIOS-Home data were collected by trained bilingual research assistants and SLPs who interviewed caregivers on their children's language input and output hour by hour. Principal components analysis (PCA) was conducted using caregiver-reported BIOS-Home data from both data sets to determine the smallest number of time chunks that could be used to measure language exposure. To explore the validity of the shortened BIOS-Home, bivariate correlation analyses were conducted to examine the relationship between children's semantics and morphosyntax scores and the original and shortened versions of the BIOS-Home.<br><br>RESULTS: PCAs using the two data sets identified three time periods (morning, afternoon, and late afternoon/evening) for weekday receptive language and three time periods (morning, afternoon, and evening) for weekend receptive language. Language test score correlations comparing the hour-by-hour and the shortened approaches are highly similar, supporting the validity of the shortened approach.<br><br>CONCLUSION: Consolidating the BIOS-Home questionnaire is a viable approach that can save time and elicit valid information about children's bilingual input and output.}, }
@article {pmid41511321, year = {2025}, author = {Borgheai, SB and Achorn, BE and Zisk, AH and Hosni, SM and Richter, KEG and Menniti, FS and Shahriari, Y}, title = {A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {15}, number = {1}, pages = {}, pmid = {41511321}, issn = {2073-4409}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; NSF-2006012//U.S. National Science Foundation/ ; P20GM103430//Institutional Development Award (IDeA) Network for Biomedical Research Excellence/ ; NSF-1913492//U.S. National Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics ; *Cognitive Dysfunction/physiopathology ; Brain/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS.}, }
@article {pmid41511639, year = {2026}, author = {Keerthipriya, MS and Kotambail, A and Deekshitha, M and Mahima, R and Ramyashree, MB and Rao, BM and Biswas, P and Baskar, D and Balaji, P and Mehta, M and Gray, O and Wasik, KA and Emde, AK and Polavarapu, K and Preethish-Kumar, V and Reddy, P and Thomas, PT and Nashi, S and Arunachal, G and Vengalil, S and Nalini, A}, title = {Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {72}, pmid = {41511639}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology ; Male ; India/epidemiology ; *Superoxide Dismutase-1/genetics ; Female ; Middle Aged ; Adult ; Cohort Studies ; Retrospective Studies ; Mutation/genetics ; Exome Sequencing ; Aged ; }, abstract = {Mutations in the superoxide dismutase 1 (SOD1) gene are a predominant, genetic cause of amyotrophic lateral sclerosis (ALS). Given the marked variability in SOD1 variant prevalence and clinical manifestations across global populations, this study aimed to characterize the genetic and clinical profile of SOD1-associated ALS (SOD1-ALS) in a large cohort of Indian patients. Whole-exome sequencing (WES) was performed for the retrospective cohort, along with comprehensive bioinformatic analyses and interpretation of genetic variants. Data were analyzed using descriptive statistics and Kaplan-Meier survival analysis to assess clinical and survival outcomes. Among 765 individuals who underwent WES, 37 probands (4.8%) from 33 families were identified with SOD1-ALS, representing a substantial 24.2% of familial ALS (fALS) cases. Patients showed a male preponderance (1.64:1) with a mean age at onset of 41.9 ± 13.1 years. Analysis revealed 23 distinct pathogenic/likely pathogenic SOD1 variants, including four novel variants. Remarkably, a high frequency of homozygous variants (6 patients) were observed in the cohort, which were associated with earlier disease onset. Most patients presented with a lower limb onset (67.6%) and a lower motor neuron phenotype. Survival was noted to be prolonged in carriers of H47R, V88M, and I152N variants, while those with juvenile onset showed reduced survival. In conclusion, this study provides the first comprehensive characterization of SOD1-ALS in the Indian population, revealing a distinct genetic profile with a unique spectrum of SOD1 variants and a higher prevalence of homozygous cases. These detailed genotype-phenotype correlations contribute significantly to the genetic etiology of ALS.}, }
@article {pmid41511908, year = {2026}, author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I}, title = {Utility of Simple Speech Measures in Amyotrophic Lateral Sclerosis Assessment: Focus on Alternating Motion Rate as a Screening Tool.}, journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)}, volume = {}, number = {}, pages = {1-16}, doi = {10.1159/000550424}, pmid = {41511908}, issn = {1421-9972}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. Early detection of bulbar symptoms is crucial for timely diagnosis and intervention; however, variability in symptom progression complicates clinical assessment.<br><br>METHODS: This retrospective observational study aimed to classify patients with ALS into three groups - spinal onset, spinal onset with bulbar involvement, and bulbar onset - and to identify speech evaluation metrics that effectively differentiate these groups. Data from 68 patients with ALS were retrospectively analyzed. Speech samples were collected and evaluated for alternating motion rate (AMR), maximum phonation time (MPT), nasality, maximum tongue pressure (MTP), speech rate, and speech intelligibility. Group comparisons and receiver operating characteristic (ROC) curve analyses were conducted to assess discriminatory ability.<br><br>RESULTS: AMR significantly differed among the three groups, with the spinal-onset group demonstrating the highest rates and the bulbar-onset group showing the lowest rates. ROC analysis indicated that AMR exhibited excellent discriminatory power, particularly in distinguishing spinal-from bulbar-onset ALS. Significant differences were also observed in MTP, nasality, speech rate, and speech intelligibility, although some metrics were less effective in differentiating the intermediate group. No significant group differences were found in MPT.<br><br>CONCLUSION: These findings suggest that the AMR is a sensitive and easily administered measure for detecting bulbar symptoms and distinguishing ALS subtypes. The intermediate characteristics observed in the spinal-onset with bulbar involvement group support this classification as a distinct clinical phenotype. Combining AMR with secondary measures such as MTP, nasality, speech rate, and speech intelligibility may enhance early detection of bulbar symptoms and improve clinical decision-making.}, }
@article {pmid41512036, year = {2026}, author = {Zhu, B and Liu, Z and Van, R and Wang, H and Kuang, S and Jia, Y and Leon, EC and Yang, F and Zhang, J and Yang, J and Hong, H and Lobo, F and Yu, A and Wang, J and Tanzi, RE and Zhang, C and Mao, X and Shao, Y and Ran, C}, title = {Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {2}, pages = {e2513311123}, pmid = {41512036}, issn = {1091-6490}, support = {R01 AG083759/AG/NIA NIH HHS/United States ; R01AG085562//HHS | NIH (NIH)/ ; R01AG055413//HHS | NIH (NIH)/ ; R21 AG080222/AG/NIA NIH HHS/United States ; R01AG083759//HHS | NIH (NIH)/ ; S10 OD028609/OD/NIH HHS/United States ; CSTB2024NSCQ-MSX0365//CSTC | Natural Science Foundation of Chongqing Municipality ()/ ; S10OD028609//HHS | NIH (NIH)/ ; R56AG059814//HHS | NIH (NIH)/ ; R21AG059134//HHS | NIH (NIH)/ ; 2025MSXM061//CQMHC | Science-Health Joint Medical Scientific Research Project of Chongqing ()/ ; R21 AG078749/AG/NIA NIH HHS/United States ; R21AG078749//HHS | NIH (NIH)/ ; R01 AG085562/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Protein Folding ; alpha-Synuclein/metabolism/chemistry/cerebrospinal fluid ; *Luminescent Measurements/methods ; Humans ; Disease Models, Animal ; *Neurodegenerative Diseases/metabolism/diagnostic imaging ; Parkinson Disease/metabolism ; *Proteostasis Deficiencies ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism ; Brain/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *Optical Imaging/methods ; Luminescence ; Mice, Transgenic ; }, abstract = {Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.}, }
@article {pmid41512823, year = {2026}, author = {Guo, L and Mann, JR and Mauna, JC and Copley, KE and Wang, H and Rubien, JD and Bergmann, CA and Carey, JL and Merjane, J and Ngo, M and Xu, J and Odeh, HM and Lin, J and Lee, BL and Ganser, L and Robinson, E and Kim, KM and Murthy, AC and Paul, T and Portz, B and Gleixner, AM and Diaz, Z and Smirnov, A and Padilla, G and Lavorando, E and Espy, C and Shang, Y and Huang, EJ and Chesi, A and Fawzi, NL and Myong, S and Donnelly, CJ and Shorter, J}, title = {Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.}, journal = {Molecular cell}, volume = {86}, number = {1}, pages = {114-134.e10}, pmid = {41512823}, issn = {1097-4164}, support = {R21 NS133676/NS/NINDS NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; T32 NS086749/NS/NINDS NIH HHS/United States ; F31 NS129101/NS/NINDS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; R21 AG064940/AG/NIA NIH HHS/United States ; UL1 TR001878/TR/NCATS NIH HHS/United States ; T32 GM007601/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; R01 GM147677/GM/NIGMS NIH HHS/United States ; RF1 AG090910/AG/NIA NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 NS116176/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; *Prions/genetics/metabolism/chemistry ; *Oligonucleotides/genetics/pharmacology ; Phase Transition ; Protein Domains ; Motor Neurons/metabolism/pathology ; *RNA/genetics ; RNA-Binding Proteins/metabolism/genetics ; Protein Aggregates ; Mice ; }, abstract = {RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs that prevent FUS fibrillization by promoting liquid phases and distinct short RNAs that prevent and reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. We define a short RNA that dissolves cytoplasmic FUS aggregates, restores nuclear FUS, and mitigates FUS toxicity in optogenetic models and ALS patient-derived motor neurons. Another short RNA dissolves cytoplasmic TDP-43 aggregates, restores nuclear TDP-43, and mitigates TDP-43 toxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have utility for ALS/FTD and related disorders.}, }
@article {pmid41512846, year = {2026}, author = {Zou, C and Li, P and Li, B and Sparwasser, T and Yuan, J}, title = {Next steps in regulatory T cells: Biology and clinical application.}, journal = {Cell}, volume = {189}, number = {1}, pages = {6-22}, doi = {10.1016/j.cell.2025.11.035}, pmid = {41512846}, issn = {1097-4172}, mesh = {Humans ; *T-Lymphocytes, Regulatory/immunology/cytology ; Animals ; Interleukin-2/therapeutic use ; Graft vs Host Disease/immunology/prevention &amp; control/therapy ; Immune Tolerance ; Amyotrophic Lateral Sclerosis/therapy/immunology ; }, abstract = {Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a "living drug" to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.}, }
@article {pmid41513843, year = {2026}, author = {Keritam, O and Kleinveld, VE and Klotz, S and Caliskan, H and Mayerhofer, M and Sener, M and Jäger, F and Weng, R and Bormann, D and Pugna, I and Gebert, J and Fedak, I and Renner, A and Antoniewicz, L and Rath, J and Zulehner, G and Krenn, M and Zimprich, F and Löscher, WN and Cetin, H}, title = {Demographic, clinical and genetic characteristics of patients with amyotrophic lateral sclerosis from two specialised centres in Austria.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {74}, pmid = {41513843}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/physiopathology/diagnosis ; Austria/epidemiology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Registries ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness and ultimately death from respiratory failure. Heterogeneity in disease trajectories and outcomes among patients with ALS (pwALS) is influenced by healthcare access, rehabilitation, and palliative care, but real-world data on demographic and clinical characteristics remain scarce in many countries, including Austria.<br><br>OBJECTIVES: To characterise the demographic, clinical, and genetic landscape of pwALS in Austria.<br><br>METHODS: In this retrospective cohort study, we included pwALS diagnosed according to the Gold Coast criteria and treated at two large tertiary referral centres. Demographic, clinical, and genetic data were extracted from the local ALS registries, and survival was determined via linkage with Statistik Austria, censored in December 2023.<br><br>RESULTS: A total of 341 patients with motor neuron disease were included (44.9% female), of whom 5% were diagnosed with primary lateral sclerosis and 2.9% with progressive muscular atrophy. Among pwALS (n&#x2009;=&#x2009;314), spinal onset was most common (67.2%), followed by bulbar onset (29.6%) and respiratory onset (2.5%). Median survival from symptom onset was 36.0&#xa0;months (IQR 20.0-74.0), with age at onset (HR 1.04, 95% CI 1.02-1.05; p&#x2009;<&#x2009;0.0001), diagnostic delay (HR 0.97, 95% CI 0.96-0.98; p&#x2009;<&#x2009;0.0001), and PEG tube placement (HR 0.72, 95% CI 0.50-1.00; p&#x2009;=&#x2009;0.0478) as the only independent predictors of survival. (Likely) pathogenic variants were identified in 5.5% of patients, including two in SOD1 and one each in C9orf72, OPTN, TARDBP, and FUS.<br><br>CONCLUSIONS: This study provides the first comprehensive description of the demographic, clinical, and genetic characteristics of pwALS in Austria, offering valuable real-world insight into disease presentation and genetic diversity.}, }
@article {pmid41513898, year = {2026}, author = {Roos, AK and Forsberg, S and Stenvall, E and Andersen, PM and Zetterström, P and Nordin, A and Forsberg, KME}, title = {Heterogeneous phenotype and cardiovascular comorbidities in Swedish patients with spinobulbar muscular atrophy.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {75}, pmid = {41513898}, issn = {1432-1459}, support = {FO 2022-0309//Hj&#xe4;rnfonden/ ; FO2023-0088//Hj&#xe4;rnfonden/ ; 2012-3167//Vetenskapsr&#xe5;det/ ; 2017-03100//Vetenskapsr&#xe5;det/ ; . JLL-980693//Region J&#xe4;mtland H&#xe4;rjedalen/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; F2021-0044//Neurof&#xf6;rbundet/ ; 2023.10//Ulla-Carin Lindquists stiftelse f&#xf6;r ALS-forskning/ ; 2023.16//Ulla-Carin Lindquists stiftelse f&#xf6;r ALS-forskning/ ; RV-993493//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; RV-996140//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; RV-939329//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; RV56103-7002829//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; RV-1014212//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; RV-996234//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; RV-941598//V&#xe4;sterbotten L&#xe4;ns Landsting/ ; }, mesh = {Humans ; Male ; Sweden/epidemiology ; Middle Aged ; Female ; Aged ; Comorbidity ; *Cardiovascular Diseases/epidemiology/genetics ; Adult ; Phenotype ; Cohort Studies ; Receptors, Androgen/genetics ; Bulbo-Spinal Atrophy, X-Linked/epidemiology ; }, abstract = {BACKGROUND: Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disorder characterized by adult-onset progressive muscle atrophy, flaccid paresis, and bulbar palsy. In addition, increasing evidence indicates that SBMA is a multisystem disorder with prominent non-motor symptoms, such as sensory neuropathy, androgen insensitivity, and glucose intolerance. This study aimed to further characterize the clinical manifestations and biomarker profile in a large Swedish SBMA cohort.<br><br>METHODS: 49 genetically confirmed SBMA patients were identified from a motor neuron disease database at Ume&#xe5; University Hospital, Sweden. CAG repeat length in the androgen receptor (AR) gene was assessed by RP-PCR. Blood samples were analyzed for cardiovascular and muscle biomarkers. Clinical data were collected from medical records and interviews, with autopsy findings reviewed in two cases.<br><br>RESULTS: The mean CAG repeat length was 43.1, with a mean age at motor symptom onset of 58.6&#xa0;years. Notably, 19% of patients initially presented with sensory symptoms. High prevalence of hypertonia (70%), diabetes mellitus (39%), and cardiac disease (38%) was observed. Elevated troponin levels were common, and pNfL (neurofilament light chain in plasma) was elevated in seven patients, likely reflecting combined cerebrovascular and cardiovascular comorbidity. Importantly, two of these seven patients exhibited rapid disease progression, and a concomitant diagnosis of ALS was confirmed histopathologically.<br><br>DISCUSSION: This cohort was characterized by a relatively low number of AR gene CAG repeats and a late onset of motor symptoms. Sensory symptoms frequently occurred before motor decline. Cardiovascular disease and diabetes were common comorbidities and, in some cases, preceded neurological symptoms. These findings underscore the need for improved clinical awareness of the heterogeneous presentation of SBMA and support routine cardiovascular monitoring to reduce diagnostic delays and prevent early mortality.}, }
@article {pmid41515048, year = {2025}, author = {Ramírez-May, AG and Rivera-Cruz, MDC and Mendoza-López, MR and Acosta-Pech, RG and Trujillo-Narcía, A and Bautista-Muñoz, C}, title = {The Use of Rhizospheric Microorganisms of Crotalaria for the Determination of Toxicity and Phytoremediation to Certain Petroleum Compounds.}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {41515048}, issn = {2223-7747}, abstract = {Microbial toxicity tests in the rhizosphere play an important role in the risk assessment and phytoremediation of chemical compounds in the environment. Tests for the inhibition of nodule number (NN), Rhizobia in the rhizosphere (RhR), Rhizobium in nodules (RhN) and arbuscular mycorrhizal fungi (AMFs) are important to evaluate the toxicity as well as the removal of total petroleum hydrocarbons (TPHs), 15 linear alkanes (LAs), and total linear alkanes (TLAs). The inhibition and removal was evaluated at 60 (vegetative stage, VS) and 154 days (reproductive stage, RS) of the life cycle of Crotalaria incana and Crotalaria pallida in soil with four doses of CRO (3, 15, 30, and 45 g/kg) plus a control (16 treatments). Results indicated that RhN and five structures of the AMFs present an index of toxicity (IT < 1), and the microbiological variable is inhibited by the CRO. RhR exhibits a hormesis index (IT > 1) that is stimulated by the CRO in the VS and RS for C. incana and C. pallida. The highest removal of TPHs (77%) was in the rhizosphere of C. incana in the RS with 45 g/kg of CRO. C. pallida removed the greatest amount of TLA (91%). There was a positive correlation between the RhR and the removal of TPHs, TLA, and LAs (higher molecular weight). It could be argued that symbiotic microorganisms are significant for use in toxicity testing, and the rhizosphere of C. incana and C. pallida can be used for the phytoremediation of HTPs and ALs in loamy-clay soil contaminated with CRO.}, }
@article {pmid41516158, year = {2025}, author = {Lee, BC and Wang, CC and Chen, SP and Tsai, HJ}, title = {Multilevel Screening Platform Utilizing Cellular and Zebrafish Models to Identify Short Peptides with High Improvement of Motor Neuron Growth.}, journal = {International journal of molecular sciences}, volume = {27}, number = {1}, pages = {}, pmid = {41516158}, issn = {1422-0067}, support = {NSTC-114-2313-B-030-001//National Science and Technology Council, Taiwan/ ; 9991F02-1120232 and A0113210//Fu Jen Catholic University, Taiwan/ ; CPL-202508003//Collaborative Research Project between Fu Jen Catholic University Hospital and Fu Jen Catholic University, Taiwan/ ; }, mesh = {Animals ; Zebrafish ; *Motor Neurons/drug effects/metabolism/cytology ; Disease Models, Animal ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Peptides/pharmacology ; Humans ; Drug Evaluation, Preclinical/methods ; Zebrafish Proteins/genetics/metabolism ; Neuronal Outgrowth/drug effects ; }, abstract = {Zebrafish is emerging as a model animal for phenotype-based drug screening. Drugs screened from the zebrafish platform have advanced into clinical trials, underscoring their translational potential. Amyotrophic lateral sclerosis is a progressive motor neurons (MN) degenerative disease with few approved drugs. Previously, supplementation with exogenous recombinant phosphoglycerate kinase 1 (Pgk1) was found to improve MN growth through its interaction with receptor Eno2. To bypass the high complexity and cost of full-length Pgk1 production, a short segment within Pgk1 (M08) was predicted as the key motif interacting with Eno2, and a zebrafish phenotypic screening platform was established to find the most neurotrophic compound(s) among M08 and its mutants. We first found that M08-injected zebrafish embryos significantly increased branched caudal primary MNs (CaPMNs). However, compared to M08 (59.20 ± 1.80%), M039, among 17 mutants further screened, showed even more improvement of branched CaPMNs, up to 74.54 ± 3.73%. Next, when we administered the M039 peptide to C9ORF72-knockdown ALS-like zebrafish embryos, it improved axonal growth and swimming ability. Then, we employed a cellular model as a secondary screen, and M039 exhibited improved neurite outgrowth of MN (NOMN) and reduced p-Cofilin in NSC34 neural cells grown in ALS-like condition. Therefore, by using a zebrafish MN phenotype as a primary screening platform, we identified a mutated short peptide M039 having the most pronounced positive effect on improving neurite growth among all 17 mutants in comparison to parental M08, demonstrating the feasibility of zebrafish screening as a cost-effective strategy for finding promising neuroprotective short peptides that serve as neurotherapeutic potentials.}, }
@article {pmid41517507, year = {2025}, author = {Koska, V and Teufel, S and Aytulun, A and Weise, M and Ringelstein, M and Guthoff, R and Meuth, SG and Albrecht, P}, title = {Evolution of Retinal Morphology Changes in Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41517507}, issn = {2077-0383}, abstract = {Background/Objectives: To compare changes in the thickness of retinal layers between patients with amyotrophic lateral sclerosis (ALS) and healthy controls using optical coherence tomography. Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motoneurons with a rapidly progressive course, but non-motor symptoms such as decreased ocular motility and reduced visual acuity have also been reported. Specific biomarkers or surrogate parameters assessing neurodegeneration in ALS are of interest. Methods: In a retrospective, longitudinal study using optic coherence tomography of the retinal layers, we compared changes in the thickness of the layers between patients with ALS and healthy controls. Correlations to clinical scores, such as the modified ranking scale, were analyzed. Results: In our cohort of patients with early ALS (disease duration 5.15 ± 21.4 months at baseline), we neither observed differences in retinal layer thickness at baseline nor did the thickness changes in any retinal layer differ in comparison to healthy controls at baseline. Moreover, we observed no significant thickness changes over the course of the observational period in our patients with ALS. However, a correlation analysis revealed a negative association of the thickness change rates in the complex of ganglion cell and inner plexiform layer and the inner nuclear layer with a higher modified Rankin scale at follow-up. Conclusions: This study adds to the notion that OCT may not be a suitable tool to monitor atrophy and disease progression in ALS. However, further longitudinal studies with longer follow-up times and larger cohorts are warranted.}, }
@article {pmid41517538, year = {2025}, author = {Dziadkowiak, E and Marschollek, K and Kwaśniak-Nowakowska, A and Zimny, A and Rałowska-Gmoch, W and Boroń, M and Koszewicz, M}, title = {Establishing Diagnostic and Differential Diagnostic Criteria for Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41517538}, issn = {2077-0383}, abstract = {Motor neuron disease (MND) represents a broad and heterogeneous group of disorders involving the upper or lower motor neurons, represented mainly by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Rare atypical variants of MND-ALS include flail arm syndrome (FA), flail leg syndrome (FL), facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) and long-standing and juvenile MND-ALS. In this article, we present a review of diagnostic criteria and the differential diagnosis for MND, focusing on ALS.}, }
@article {pmid41517697, year = {2026}, author = {Wang, Z and Yao, L and Tu, M}, title = {Evaluating the causal connections between sleep duration and disease prevalence: A comprehensive systematic review and meta-analysis of Mendelian randomization studies.}, journal = {Medicine}, volume = {105}, number = {2}, pages = {e45225}, pmid = {41517697}, issn = {1536-5964}, mesh = {Humans ; Mendelian Randomization Analysis ; *Sleep/genetics/physiology ; Prevalence ; Genetic Predisposition to Disease ; Sleep Duration ; }, abstract = {BACKGROUND: The causal link between sleep duration and diverse health conditions remains unconfirmed. This meta-analysis aimed to clarify these relationships by synthesizing Mendelian randomization (MR) study evidence.<br><br>METHODS: PubMed was systematically searched up to February 15, 2024, for MR studies exploring genetic predispositions to sleep duration/insomnia (short/long/overall sleep duration, insomnia) and associations with circulatory, digestive, neurodegenerative, metabolic diseases, and cancers. Eligible effect estimates were meta-analyzed.<br><br>RESULTS: Fifty-one MR studies were included. Genetic variations in sleep traits were strongly linked to elevated risk of 12 cardiovascular diseases, obesity-related metrics (Type 2 diabetes, fasting glucose/insulin, HbA1c), neurological disorders (Alzheimer, amyotrophic lateral sclerosis, Parkinson disease), mental health conditions (attention-deficit/hyperactivity disorder, autism, bipolar disorder, major depressive disorder, schizophrenia), inflammatory bowel disease, and lung cancer.<br><br>CONCLUSION: Genetic evidence confirms causal associations between sleep characteristics and multiple diseases, emphasizing sleep's key role in health promotion and supporting personalized sleep management to reduce disease risk.}, }
@article {pmid41517814, year = {2026}, author = {Jacob, SM and Son, B and Bagheri, S and Lee, S and Leckie, J and Chohan, B and Belway, C and Mascarenhas, J and Mobach, T and Korngut, LW and Sharkey, KA and Park, J and Nguyen, MD and Kim, SH and Pfeffer, G}, title = {The Oral Microbiome in Amyotrophic Lateral Sclerosis Shows Differentially Abundant Organisms in Limb Versus Bulbar Onset Disease: A Binational Study.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {1}, pages = {66-75}, pmid = {41517814}, issn = {1738-6586}, support = {//ALS Canada Discovery Grant/Canada ; //Barry Barrett Foundation/Canada ; /CAPMC/CIHR/Canada ; //International Development Research Council/Canada ; //Rose Family Foundation/Canada ; //Fondation Brain Canada/Canada ; /MOHW/Ministry of Health and Welfare/Korea ; RS-2024-00348451/MSIT/Ministry of Science and ICT, South Korea/Korea ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons leading to progressive disability and death. Approximately 10% of cases are caused by single-gene disorders with the remaining 90% of cases presumed to be caused by a combination of environmental and genetic factors. The microbiome (the ensemble of microorganisms that colonize body surfaces and organs) was recently identified for its importance in the pathogenesis of ALS.<br><br>METHODS: In this study, we recruited 100 participants from two ethnically and geographically distinct sites (71 from Calgary, Canada, and 29 from Seoul, Republic of Korea) which included 59 ALS participants and 41 controls. All participants provided saliva samples for oral microbial analysis using 16S rRNA sequencing. Basic demographic information was collected from all participants, and ALS participants provided additional clinical information including site of disease onset, disease duration, and ALS Functional Rating Scale - Revised score.<br><br>RESULTS: Significant differences in beta diversity of the oral microbiomes were seen between limb- and bulbar-onset ALS participants. Two bacterial genera were differentially abundant between these groups, Bifidobacteriaceae Bifidobacterium was enriched in bulbar-onset cases, while Pasteurellaceae Haemophilus was enriched in limb-onset cases. No significant differences were found between ALS participants and controls, but there were significant differences when comparing participants from different sites of recruitment. Amongst household pairs (n=35 pairs), ALS participants differed from control participants at the Seoul site.<br><br>CONCLUSIONS: Despite the cohort and household effects, our study identified differentially abundant organisms that may be important to the phenotypic variability of ALS and should be considered for future study. Our study provides novel insights into design for future multi-site microbiome research in ALS.}, }
@article {pmid41517820, year = {2026}, author = {Choi, SJ and Park, H and Sung, JJ}, title = {First Korean Case of C9orf72-Related Amyotrophic Lateral Sclerosis With Progressive Supranuclear Palsy-Like Features.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {1}, pages = {125-127}, pmid = {41517820}, issn = {1738-6586}, }
@article {pmid41517981, year = {2026}, author = {Xu, X and Xu, J and Zhao, B and Guo, B and Wei, S and Li, B and Qi, Z and Chen, S and Wang, G and Liu, X}, title = {Target-site mutations and non-target-site detoxification confer ALS-inhibitor resistance in Bromus japonicus populations in China.}, journal = {Pest management science}, volume = {82}, number = {4}, pages = {3874-3883}, doi = {10.1002/ps.70510}, pmid = {41517981}, issn = {1526-4998}, support = {//the HAAFS Science and Technology Innovation Special Project (2022KJCXZX-LYS-13)/ ; //the Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences (2024060203)/ ; //the HAAFS Youth Innovation Fund Project (2023LYS03)/ ; }, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics/antagonists &amp; inhibitors/metabolism ; *Herbicides/pharmacology ; China ; Mutation ; *Plant Proteins/genetics/metabolism/antagonists &amp; inhibitors ; Inactivation, Metabolic ; }, abstract = {BACKGROUND: The emergence of herbicide-resistant Japanese brome (Bromus japonicus) populations has been increasingly documented throughout China. Two such populations, DZ-R and XL-R, exhibit resistance to acetolactate synthase (ALS)-inhibiting herbicides, yet their resistance level and mechanism remain undetermined. This study sought to: (i) quantify resistance levels to flucarbazone-sodium, mesosulfuron-methyl, and pyroxsulam; (ii) screen for ALS mutations conferring target-site resistance (TSR); and (iii) characterize non-target-site resistance (NTSR) mechanisms using a multi-omics approach.<br><br>RESULTS: Whole-plant bioassay results indicated that the resistance indices of DZ-R and XL-R populations were 111.3 and 90.5 to flucarbazone-sodium, 36 and 206.4 to mesosulfuron-methyl, and 109.8 and 429.5 to pyroxsulam. The TSR mechanism was mediated by distinct ALS gene mutations: a Pro197-Ser substitution in DZ-R and a Pro197-Thr substitution in XL-R. Integrated transcriptomic, metabolomics and malathion-inhibited bioassay analyses revealed the NTSR mechanism, identifying two ABCB4, ABCG48, ABCB11 genes, two unnamed ABC, POD 35, POD P7-like, GST1, GSTU17, 2 GSTU6, IN2-1-like isoform X3 genes, three unnamed GST, GT 73C6-like, ZWY2020_001091, cis-zeatin O-GT, CYP74A15, noroxomaritidine synthase 2-like, indole-2-monooxygenase-like genes and four unnamed CYP450 genes as candidate genes. These genes participated in ATP-binding cassette transporters, phenylpropanoid biosynthesis, glutathione metabolism and zeatin biosynthesis metabolic pathways that synergistically mediate herbicide detoxification. Notably, two putative flucarbazone-sodium degradation pathways were deduced in the resistant populations.<br><br>CONCLUSION: Collectively, these findings demonstrated that both TSR and NTSR mechanisms contributed to herbicide resistance in the DZ-R and XL-R populations. Future research should prioritize functional validation of the identified candidate genes to elucidate their specific roles in herbicide metabolism. &#xa9; 2026 Society of Chemical Industry.}, }
@article {pmid41518572, year = {2026}, author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P}, title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {1}, pages = {11}, pmid = {41518572}, issn = {1573-675X}, support = {82171363//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; }, abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.}, }
@article {pmid41518628, year = {2026}, author = {Chevet, ML and Garnier, M and Fadel, M and Scherer, C and Cassereau, J and Levaillant, M and Codron, P}, title = {Epidemiology of Amyotrophic Lateral Sclerosis in the Pays de la Loire, France: A 20-Year Study from a Centralized Diagnostic Center.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-8}, pmid = {41518628}, issn = {1423-0208}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neurons disease with multifactorial etiology. The epidemiology of ALS in France is mainly documented through the Limousin regional registry (FRALim). We aimed to determine the incidence and clinical characteristics of ALS cases over a 20-year period in another French region, the Pays de la Loire, served by a single centralized diagnostic center.<br><br>METHODS: All patients diagnosed with ALS at the Angers University Hospital reference center between 2003 and 2023 were retrospectively included. Demographic and clinical data were extracted from medical records, and incidence rates were calculated using annual population estimates from the National Institute of Statistics and Economic Studies. Spatial analyses were performed to identify over-incidence areas and potential environmental or occupational determinants.<br><br>RESULTS: A total of 1,316 patients were diagnosed with ALS during the study period, corresponding to a crude incidence rate of 1.88 cases per 100,000 person-years (95% CI: 1.78-1.98), with no significant variation over time. The standardized incidence rate was 1.73 (95% CI: 1.63-1.83). The mean age at symptom onset was 63.6 &#xb1; 11.2 years, 58.7% of patients were male. The mean disease duration was 3.7 &#xb1; 3.5 years. ALS onset was spinal in 70.3%, bulbar in 27.9%, and respiratory in 1.7% of cases. Familial or genetic forms accounted for 6% of patients. Four geographical over-incidence areas were identified, with no correlation found with pesticide use, air pollution, or other environmental indicators. One occupational cluster was observed among farmers in a specific commune, prompting a dedicated investigation.<br><br>CONCLUSION: This 20-year retrospective study provides the first epidemiological data on ALS in western France. The incidence and clinical features are consistent with national and European data. The identification of spatial and occupational clusters underlines the importance of continued regional surveillance and of prospective, registry-based studies to clarify environmental and occupational risk factors for ALS.}, }
@article {pmid41518742, year = {2026}, author = {Milella, G and Carlone, S and Luisi, F and Velucci, V and Defazio, G}, title = {Facial-onset SOD1 amyotrophic lateral sclerosis: A case report and systematic review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {145}, number = {}, pages = {111856}, doi = {10.1016/j.jocn.2026.111856}, pmid = {41518742}, issn = {1532-2653}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Facial Paralysis/genetics/etiology ; *Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Facial-onset weakness is an exceptionally rare presentation of SOD1-associated amyotrophic lateral sclerosis (ALS), and its natural history, anatomical spread, and prognostic implications remain unclear.<br><br>METHODS: We report a woman carrying a heterozygous SOD1 A5T variant who presented with isolated, rapidly progressive bilateral facial palsy, and we performed a PRISMA-compliant systematic review of MEDLINE, Scopus, and Web of Science to identify genetically confirmed SOD1-positive ALS with facial-onset weakness. Case-level demographic, genetic, clinical, neurophysiological, and outcome data were extracted and synthesised descriptively.<br><br>RESULTS: Eleven patients were included (7 men, 4 women; mean age at onset 52.3&#xa0;years). Seven SOD1 variants were represented, predominantly associated with short survival (e.g. A5V, C7G, A5T). Facial weakness was initially confined to the lower face in 5/11 patients, while 6/11 had combined upper and lower facial involvement. Disease spread followed a stereotyped pattern: early contralateral facial recruitment (mean 3.6&#xa0;months), rapid bulbar involvement (4.2&#xa0;months), and later extension to the upper limbs (9.2&#xa0;months), frequently with side-concordance between facial and arm involvement. Lower motor neuron (LMN) signs predominated in the early phases of the disease. Survival was short (median 16&#xa0;months), lower than reported for unselected SOD1-ALS cohorts with the same genotypes. Three patients received tofersen, with heterogeneous outcomes.<br><br>CONCLUSIONS: Facial-onset SOD1 ALS defines a distinctive phenotype characterised by LMN-predominant facial palsy in early phases, near-neighbour spread, and an aggressive course exceeding genotype-based expectations. Prompt recognition and genetic testing in progressive facial palsy unresponsive to immunotherapy are essential to ensure access to gene-targeted treatments.}, }
@article {pmid41519115, year = {2026}, author = {Chen, MH and Bai, YM and Tsai, SJ}, title = {Depression, cognition, and GLP-1 receptors: Heterogeneity and therapeutic prospects.}, journal = {Med (New York, N.Y.)}, volume = {7}, number = {1}, pages = {100954}, doi = {10.1016/j.medj.2025.100954}, pmid = {41519115}, issn = {2666-6340}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Depression/drug therapy ; Glucagon-Like Peptide-1 Receptor ; Glucagon-Like Peptides/therapeutic use/pharmacology ; *Cognition/drug effects ; Quality of Life ; *Cognitive Dysfunction/drug therapy ; Glucagon-Like Peptide 1 ; Semaglutide ; }, abstract = {Cognitive impairments in depression, driven by both the illness per se and low-grade systemic inflammation, markedly reduce functional capacity and quality of life among patients who suffer. Findings from Badulescu et al.'s placebo-controlled trial reported that semaglutide, a GLP-1 receptor agonist, may improve attention and memory, although there was no significant improvement in overall depressive symptoms.}, }
@article {pmid41520601, year = {2026}, author = {Squintani, G and Muzio, MD and Rasera, A and Paio, F and Borin, GU and Humaidan, K and Orlando, D and Refatti, N and Romito, S and Tinazzi, M and Bonetti, B and Ermani, M}, title = {Sensory and motor cortical hyperexcitability in patients with amyotrophic lateral sclerosis: are they related? a prospective pilot study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {183}, number = {}, pages = {2111485}, doi = {10.1016/j.clinph.2025.2111485}, pmid = {41520601}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Motor Cortex/physiopathology ; Pilot Projects ; *Evoked Potentials, Somatosensory/physiology ; Aged ; *Somatosensory Cortex/physiopathology ; *Evoked Potentials, Motor/physiology ; Transcranial Magnetic Stimulation/methods ; Prospective Studies ; Adult ; }, abstract = {OBJECTIVE: Our study evaluates sensory and motor cortical hyperexcitability as diagnostic biomarkers in ALS patients and investigates their relationship, identifying distinct or interconnected pathophysiological mechanisms in different sub-groups.<br><br>METHODS: We examined 26 ALS patients and 18 healthy controls. Motor cortex excitability was assessed using transcranial magnetic stimulation to measure the motor evoked potential (MEP) suppression ratio. Somatosensory cortex excitability was evaluated through upper-limb somatosensory evoked potentials (SEPs) with conventional and paired-pulse techniques. Statistical analyses included parametric/non-parametric tests, correlation analyses, and &#x3c7;[2] tests. ROC analysis was used to assess diagnostic performance. Significance threshold was p&#xa0;<&#xa0;0.05.<br><br>RESULTS: ALS patients showed a significantly reduced MEP suppression ratio (p&#xa0;<&#xa0;0.001) with excellent discriminative power (100&#xa0;% accuracy). SEP suppression ratio was significantly lower in ALS (p&#xa0;<&#xa0;0.001), with sensitivity 76.3&#xa0;%, specificity 91.7&#xa0;%, and accuracy 84&#xa0;%. In patients with giant SEPs, a strong inverse correlation was observed between MEP and SEP suppression ratios (r&#xa0;=&#xa0;&#xa0;-&#xa0;0.70, p&#xa0;<&#xa0;0.001).<br><br>CONCLUSIONS: MEP and SEP suppression ratio are robust biomarkers of motor cortical dysfunction in ALS patients with a highlighting cortical heterogeneity between sub-groups, suggesting cortical interconnection.<br><br>SIGNIFICANCE: Alongside confirming motor and sensory cortical hyperexcitability as ALS hallmarks, this study reveals subgroup-specific patterns suggesting a compensatory interplay between sensory and motor cortex.}, }
@article {pmid41520654, year = {2026}, author = {Mehdiyoun, NF and Wright, J and Robinson, RL and Brandt, AU and Hoyt, M and Guo, J and Ball, N and Iqbal, H and Ringland, C and Milligan, G and Curtis, SE}, title = {Evaluating ALSFRS-R as an indicator of disease milestones and functional independence: An observational study of US neurologists and their patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {481}, number = {}, pages = {125732}, doi = {10.1016/j.jns.2026.125732}, pmid = {41520654}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Activities of Daily Living ; Cross-Sectional Studies ; Aged ; *Neurologists ; *Disease Progression ; United States/epidemiology ; Severity of Illness Index ; Adult ; }, abstract = {BACKGROUND: The Revised Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS-R) is a clinician-reported outcome measure monitoring disease progression in people living with ALS (pALS). This study examined the relationship of ALSFRS-R scores with disease progression and independence levels for activities of daily living (ADLs) among pALS.<br><br>METHODS: Real-world data, including the ALSFRS-R, were drawn from a cross-sectional survey of US neurologists treating pALS (Adelphi ALS Disease Specific Programme&#x2122;), conducted between July 2020 and March 2021. ALSFRS-R scores were modeled against 11 pre-defined disease milestones. The relationship between ALSFRS-R scores and levels of independence in 24 ADLs was examined using ordered logistic regression.<br><br>RESULTS: Fifty-nine neurologists provided data for 379 pALS (mean age: 59.5&#xa0;years; mean disease duration: 16.1&#xa0;months). Estimated mean ALSFRS-R total score decreased (worsened) from 46.1 at first consultation regarding ALS symptoms to 25.1 upon receipt of a feeding tube. In general, pALS were likely to be completely dependent in most ADLs when their ALSFRS-R total scores were&#xa0;&#x2264;&#xa0;25. A 1-point decrease in ALSFRS-R total score was associated with increased risks of losing independence across all ADLs. For each ADL, a 1-point decrease in domain score was associated with varying risks of losing independence across different domains.<br><br>CONCLUSIONS: There is a correlation between ALSFRS-R scores and levels of independence in ADLs among pALS, facilitating score interpretation for monitoring disease and function status. Yet, the relevance of the ALSFRS-R total score diminishes in advanced stages of ALS, indicating a need for additional measures to provide comprehensive evaluation.}, }
@article {pmid41521074, year = {2026}, author = {Ham, HJ and Lee, JA}, title = {Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.}, journal = {BMB reports}, volume = {59}, number = {2}, pages = {85-100}, pmid = {41521074}, issn = {1976-670X}, mesh = {Humans ; *Aging/metabolism/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Stress Granules/metabolism/physiology ; Animals ; *Organelles/metabolism ; Mitochondria/metabolism ; Neurons/metabolism ; Cytoplasmic Granules/metabolism ; Autophagy ; Stress, Physiological ; }, abstract = {Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics-with an increased propensity to form SGs while displaying reduced efficiency in their clearance-resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging. [BMB Reports 2026; 59(2): 85-100].}, }
@article {pmid41521076, year = {2025}, author = {Lee, SP and Choi, J and Park, JH and Lee, KN and Lee, HL and Sung, W}, title = {Predictors of Percutaneous Endoscopic Gastrostomy-Related Complications in Amyotrophic Lateral Sclerosis: A 19-Year Retrospective Study From a Tertiary Center.}, journal = {Journal of digestive diseases}, volume = {26}, number = {11-12}, pages = {492-508}, doi = {10.1111/1751-2980.70025}, pmid = {41521076}, issn = {1751-2980}, mesh = {Humans ; *Gastrostomy/adverse effects/methods ; Male ; Retrospective Studies ; Female ; *Amyotrophic Lateral Sclerosis/complications ; Middle Aged ; Aged ; Risk Factors ; Tertiary Care Centers ; *Postoperative Complications/etiology/epidemiology ; *Deglutition Disorders/etiology/therapy/surgery ; Adult ; *Gastroscopy/adverse effects ; Enteral Nutrition/adverse effects/methods ; Ileus/complications ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that inevitably leads to swallowing difficulties as the disease progresses. Percutaneous endoscopic gastrostomy (PEG) is recommended for optimal supportive management of dysphagia among these patients. We aimed to investigate PEG-related complications and risk factors in patients with ALS.<br><br>METHODS: Medical records of the ALS patients who underwent PEG from March 2006 to February 2025 in a single tertiary care center were retrospectively reviewed. PEG-related complications and risk factors were assessed through chart review, endoscopic reports and images, radiological findings, and follow-up data.<br><br>RESULTS: Altogether 501 ALS patients (262 men) underwent PEG, of whom 60 developed early complications and 82 developed late complications, including 11 patients who developed both. Pneumoperitoneum was more common in underweight patients (p&#x2009;=&#x2009;0.004), and wound infection was more common in patients with pre-PEG ileus (p&#x2009;=&#x2009;0.044). Multivariate analysis revealed that low albumin level, long procedure time, and ileus were significantly associated with early complications. Obesity and ileus were independent risk factors for buried bumper syndrome. Those with an internal bolster at the upper body of the stomach and with an external bolster in the midline of the abdomen were at significant risk of inadvertent PEG removal.<br><br>CONCLUSIONS: Albumin and body mass index extremes are predictors of complications, and care is needed when PEG is performed on patients with pre-PEG ileus. To reduce such&#xa0;risks, the PEG tube should not be inserted into the upper body of the stomach or the midline of the abdomen.}, }
@article {pmid41523053, year = {2025}, author = {Nagmode, P and Deshmukh, V and Abraham, S and Lokhande, N and Diggikar, K and Chavhan, G}, title = {Comparative Evaluation of Effectiveness of 35% and 20% Concentration of Hydrogen Peroxide Alone and in Combination with Pomegranate Extract on Human Enamel Used for Tooth Bleaching - An Invitro Study.}, journal = {Journal of pharmacy &amp; bioallied sciences}, volume = {17}, number = {Suppl 4}, pages = {S3322-S3324}, pmid = {41523053}, issn = {0976-4879}, abstract = {AIM: To evaluate the color change in human enamel bleached with two concentrations of hydrogen peroxide (35% and 20%) alone and in combination with pomegranate extract using a reflectance spectrophotometer.<br><br>MATERIALS AND METHODS: Forty extracted permanent maxillary incisors were randomly divided into four groups: Group 1a: 35% hydrogen peroxide alone, Group 1b: 35% hydrogen peroxide + pomegranate extract, Group 2a: 20% hydrogen peroxide alone, Group 2b: 20% hydrogen peroxide + pomegranate extract. Pomegranate extract was prepared from 1500 g of peeled white pomegranate blended with 25 ml distilled water and centrifuged at 2000 rpm for 2 minutes at 4&#xb0;C. Teeth were artificially stained following Sulieman et al.'s protocol and immersed in respective bleaching agents for 20 minutes. Color change (&#x394;E) was measured using a reflectance spectrophotometer.<br><br>RESULTS: Groups using pomegranate extract with hydrogen peroxide exhibited significantly greater &#x394;E values, indicating enhanced bleaching efficacy compared to hydrogen peroxide alone.<br><br>CONCLUSION: Hydrogen peroxide combined with pomegranate extract significantly improves tooth color change compared to hydrogen peroxide alone.}, }
@article {pmid41523190, year = {2026}, author = {Jiang, Y and Fu, Y and Song, X and Wang, X and Li, J and Cheng, L and Chen, Y and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L}, title = {Microstructure and gene expression influence gyrification in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {1}, pages = {fcaf491}, pmid = {41523190}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Beyond well-established grey and white matter pathology, alterations in cortical gyrification have recently been observed, yet their clinical relevance and molecular underpinnings remain to be understood. Here, we investigated this premise by examining its microstructural and transcriptional basis in 60 patients with amyotrophic lateral sclerosis (median age = 55, range = 25-72 years) and 60 matched controls (median age = 56, range = 27-72 years) using structural and diffusion MRI. Patients exhibited a significant reduction in local gyrification index within bilateral precentral and postcentral gyri, left middle frontal gyrus and left superior parietal lobule. This was accompanied by reduced fractional anisotropy in the white matter tracts, primarily involving the corticospinal tract and corpus callosum. Higher local gyrification index and fractional anisotropy values were associated with better motor function as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, and local gyrification index also showed positive associations with global cognitive status. A mediation analysis indicated that fractional anisotropy partially accounted for the relationship between local gyrification index and functional disability, suggesting that disrupted white matter pathways contribute to the clinical impact of gyrification changes. To explore underlying mechanisms, we integrated neuroimaging findings with transcriptomic data from the Allen Human Brain Atlas. Regions of reduced local gyrification index showed spatial convergence with cortical expression of amyotrophic lateral sclerosis-related genes such as TARDBP and C9orf72, enriched for biological processes related to protein aggregation, axon guidance and synaptic signalling. Together, these findings suggest that cortical gyrification abnormalities in amyotrophic lateral sclerosis are closely linked to white matter degeneration, functional impairment and genetic vulnerability, thereby offering an integrative window into the multiscale pathology of amyotrophic lateral sclerosis.}, }
@article {pmid41524979, year = {2026}, author = {Sun, Y and Huang, C and Pan, Y and Zhang, H and He, X}, title = {Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {357}, pmid = {41524979}, issn = {1559-1182}, support = {2021KY727//Health Commission of Zhejiang Province, Medical and health project/ ; A20210510//Hangzhou Municipal Health Commission, Medical and health science project/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications ; Fibrosis ; *Muscle, Skeletal/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily characterized by the degeneration of motor neurons. However, the pathological process of ALS extends beyond the central nervous system, with dynamic changes in skeletal muscle playing a crucial role in the progression of the disease. Recent research has shown that muscle fibrosis, marked by the abnormal accumulation of extracellular matrix (ECM), leads to reduced muscle elasticity, compromised contractile function, and impaired regeneration of neuromuscular junctions (NMJs). This condition represents not only the final stage of muscle atrophy in ALS but also a significant factor accelerating disease progression through "neuromuscular interactions." We conducted a systematic review of the molecular mechanisms of muscle fibrosis in ALS. This included examining the dysregulation of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF/CCN2), and the Wnt/β-catenin signaling pathways. We also considered key cellular contributors, such as fibro-adipogenic precursor cells and macrophages. The review also covers the use of non-invasive imaging techniques, such as MRI and muscle ultrasound, for early detection and monitoring. We also evaluate potential therapeutic approaches, ranging from anti-fibrotic drugs and gene therapy to physical interventions. In summary, muscle fibrosis is a promising therapeutic target that could complement strategies focused on motor neurons, ultimately improving functional outcomes in patients with amyotrophic lateral sclerosis.}, }
@article {pmid41525811, year = {2026}, author = {Pradhan, LK and Das, SK}, title = {Zebrafish neural regeneration: mechanistic insights into human nervous system repair.}, journal = {Neuroscience}, volume = {596}, number = {}, pages = {1-15}, doi = {10.1016/j.neuroscience.2026.01.009}, pmid = {41525811}, issn = {1873-7544}, mesh = {Animals ; Zebrafish/physiology ; *Nerve Regeneration/physiology ; Humans ; Disease Models, Animal ; Neurogenesis/physiology ; }, abstract = {The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke, epilepsy, autism spectrum disorders, and CNS injuries. Unlike mammals, they restore damaged axons and recover function through a permissive extracellular matrix, transient inflammation, and glial plasticity. In the retina, Müller glia reprograms after injury to generate progenitors that replace lost neurons, regulated by Wnt/β-catenin, Shh, EGF, Hippo/YAP, and ROCK signaling. In the spinal cord, ependymo-radial glia forms a laminin- and fibronectin-rich "glial bridge," guided by FGF and CTGF signaling, supporting axon regrowth. In the brain, GFAP- and Olig2-positive radial glia drive neurogenesis within ventricular niches, integrating new neurons while maintaining circuit integrity. Regeneration involves transient Notch suppression, context-specific Wnt and FGF activation, and immune modulation without fibrosis. Advances in single-cell RNA sequencing, CRISPR-Cas9, lineage tracing, and multi-omics have identified injury-induced progenitor states, regulators (ascl1a, lin28, sox2, stat3), and epigenetic programs enabling regeneration. Emerging research on bioelectric signaling, microbiota-brain interactions, and lipid mediators further expands systemic understanding. Overall, zebrafish provide a unified model for decoding vertebrate CNS regeneration and guiding therapeutic strategies to restore neural repair in humans.}, }
@article {pmid41525886, year = {2026}, author = {Zimyanin, V and Dash, BP and Simolka, T and Glaß, H and Pal, A and Haidle, F and Zarnack, K and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Müller-McNicoll, M and Redemann, S and Hermann, A}, title = {Compartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107268}, doi = {10.1016/j.nbd.2026.107268}, pmid = {41525886}, issn = {1095-953X}, mesh = {*Motor Neurons/metabolism/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Transcriptome ; *Extracellular Matrix/metabolism ; Humans ; *Cell Cycle Proteins/metabolism/genetics ; Animals ; Signal Transduction/physiology ; Axons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Mutations in FUSED IN SARCOMA (FUS) cause juvenile-onset amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS-ALS involves impaired transcription and splicing, DNA damage response, and axonal degeneration. However, the molecular pathophysiology and the link between somatic and axonal phenotypes are still poorly understood. We evaluated whether compartment-specific transcriptome differences could distinguish and drive early axonal degeneration. We used iPSC-derived motor neurons (MNs) coupled with microfluidic approaches to generate RNA-sequencing profiles from axonal and somatodendritic compartments. We demonstrate that the axonal transcriptome is unique and distinct, with RNA metabolism, extracellular secretion, and matrix disassembly pathways particularly enriched in distal axonal compartments. FUS mutation leads to changes in distinct pathways that were clustered in only a few distinct protein-protein interaction (PPI) networks. Somatodendritic changes upon FUS mutation include WNT signaling, mitochondrial, extracellular matrix (ECM)-, and synapse-related functions. In contrast, analysis of the axonal transcriptome in mutant MNs centers on the PLK1 pathway, mitochondrial gene expression, and regulation of inflammation. Comparison to CLIP-seq data revealed a significant enrichment for PLK1 and DNA replication pathways in axons. PLK1 upregulation did not activate cell-cycle re-entry but contributed to mutant MNs survival, and its inhibition increased neuronal cell death. We propose that upregulation of PLK1 represents an early event in the pathogenesis of ALS and could act in response to DNA damage, mitochondrial damage, and immune response activation in the affected cells. Additionally, downregulation of ECM pathways in the somatodendritic compartment and axons could explain strongly compromised dynamics of axonal outgrowth. Overall, we provide a novel valuable resource of the potential targets and affected processes changed in the specific compartments of FUS-ALS motor neurons.}, }
@article {pmid41525888, year = {2026}, author = {Tessitore, S and Torazza, C and Bonifacino, T and Bacchetti, F and Roselli, F and Raiteri, L and Milanese, M and Bonanno, G}, title = {Focus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107272}, doi = {10.1016/j.nbd.2026.107272}, pmid = {41525888}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/metabolism/drug therapy ; Humans ; *Synaptic Transmission/physiology ; Animals ; Motor Neurons/metabolism/physiology ; Glutamic Acid/metabolism ; *Neural Inhibition/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. Evidence indicates that ALS is a "multifactorial" and "multicellular" disease; however, the causes of ALS remain elusive, as the mechanisms underlying the disease have not yet been completely clarified. One major proposed mechanism, first described in 1990, is the glutamate excitotoxicity theory. This theory suggests that excessive glutamatergic neurotransmission, combined with impaired glutamate clearance, significantly contributes to motor neuron degeneration. Aberrant glutamate neurotransmission may lead to precocious motor neuron hyperexcitability in the brain cortex and spinal cord, which can be later followed by hypoexcitability phases. Accumulating evidence suggests that impairment in inhibitory neurotransmission is relevant for excitation/inhibition imbalance, leading to excitotoxicity, a critical feature of ALS. Gamma-aminobutyric acid (GABA) and glycine are the primary inhibitory neurotransmitters that modulate neuronal excitability, including that of motor neurons. In ALS, dysfunction of inhibitory processes and loss of cortical and spinal inhibitory interneurons are observed. Renshaw cells, which mediate recurrent inhibition in the spinal cord, seem particularly vulnerable. The interactions among neurotransmitters, including glutamate, GABA, and glycine, play pivotal roles in regulating the excitation/inhibition balance. Auto- or hetero-receptor-mediated interactions are crucial, but auto- or hetero-transporter-mediated neurotransmission control, as well as other molecular mechanisms that regulate neuronal interplay, are also relevant, as they can be altered in pathological conditions such as ALS. To facilitate the search for new effective therapies for ALS, attention toward the impairment of inhibitory neurotransmission is essential to determine the role of excitation/inhibition imbalance on excitotoxicity. Different pharmacological agents are being used to treat other pathologies in which the excitation/inhibition ratio is impaired. Among these, we highlighted the potential of novel glycine and GABA receptor ligands and transporter inhibitors, as stand-alone interventions or in combination with other treatments. The present review aims to elucidate the complex interplay between excitatory and inhibitory neurotransmission in ALS, exploring the potential to target this imbalance for therapeutic purposes.}, }
@article {pmid41527739, year = {2026}, author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W}, title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {5-25}, doi = {10.1177/13872877251411546}, pmid = {41527739}, issn = {1875-8908}, mesh = {Humans ; Biomarkers/metabolism ; *Phosphoproteins/metabolism ; *Proteomics/methods ; *Brain Diseases/metabolism/diagnosis ; Phosphorylation ; Animals ; }, abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.}, }
@article {pmid41530082, year = {2026}, author = {Cooper, P and Lu, M and Chan, M and Wilman, A and Kalra, S and Ghavanini, AA}, title = {Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-6}, doi = {10.1017/cjn.2026.10527}, pmid = {41530082}, issn = {0317-1671}, abstract = {OBJECTIVES: Early diagnosis of amyotrophic lateral sclerosis (ALS) is essential for treatment initiation and symptom management, yet it remains challenging due to nonspecific symptoms and the lack of reliable diagnostic biomarkers. Although conventional MRI sequences such as T2* weighted and fluid-attenuated inversion recovery (FLAIR) have shown potential in identifying upper motor neuron abnormalities, their diagnostic utility in ALS is not well established. This study aimed to evaluate the sensitivity and specificity of brain T2* weighted and FLAIR MRI sequences in diagnosing ALS using prospectively collected data and to assess associations with disease severity.<br><br>METHODS: Data were analyzed from 20 patients with ALS and 20 healthy controls enrolled at the Edmonton site of the Canadian ALS Neuroimaging Consortium 1 (CALSNIC-1) study. Single-slice 2D axial susceptibility-weighted echo planar imaging (SWEPI) and FLAIR images were independently rated by a blinded neurologist and radiologist for signs of corticospinal tract and motor cortex abnormalities. Sensitivity and specificity were calculated, and linear regression was used to examine associations with ALS Functional Rating Scale-Revised (ALSFRS-R) scores.<br><br>RESULTS: T2* weighted and FLAIR MRI sequences showed high specificity (0.95 and 0.85, respectively) but low sensitivity (both 0.25) for ALS diagnosis. No significant correlation was found between imaging abnormalities and ALSFRS-R scores. Inter-rater reliability was poor (&#x3ba; = 0.25 for SWEPI; &#x3ba; = 0.14 for FLAIR).<br><br>CONCLUSION: While T2* weighted and FLAIR MRI sequences may have some specificity for ALS, our study suggests they are not sufficiently sensitive to be used as reliable diagnostic tools for ALS.}, }
@article {pmid41530593, year = {2026}, author = {Muneer, MA and Tariq, I and Zulfiqar, E and Saaki, SS and Gupta, I and Bokhari, SMNA and Verma, A and Mehta, R and Sah, R and Ahmed, SI}, title = {Efficacy and safety of dextromethorphan/quinidine in treating pseudobulbar affect in neurological disorders: A systematic review and dose-classified network meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {159}, pmid = {41530593}, issn = {1590-3478}, mesh = {Humans ; *Dextromethorphan/administration &amp; dosage/adverse effects/pharmacology/therapeutic use ; Drug Combinations ; *Nervous System Diseases/drug therapy/complications ; *Pseudobulbar Palsy/drug therapy ; *Quinidine/administration &amp; dosage/adverse effects/pharmacology/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Pseudobulbar affect (PBA) is a disabling neuropsychiatric condition characterized by sudden, involuntary episodes of crying or laughing incongruent with mood. It occurs in several neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury (TBI). Dextromethorphan/quinidine (DM/Q) is the only Food and Drug Administration (FDA)-approved therapy for PBA, but optimal dosing and safety profiles remain uncertain.<br><br>OBJECTIVE: To evaluate the efficacy and safety of different DM/Q dosing regimens for treating PBA through a systematic review and network meta-analysis.<br><br>METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through March 2025. Randomized controlled trials reporting outcomes on the Center for Neurologic Study-Lability Scale (CNS-LS), Visual Analog Scale-Quality of Life (VAS-QOL), Visual Analog Scale-Quality of Recovery (VAS-QOR), and adverse events were included. Analyses were performed using R (netmeta package), and bias was assessed with the Cochrane RoB 2.0 tool.<br><br>RESULTS: Five randomized controlled trials comprising 605 participants were analyzed. DM/Q 20/10&#xa0;mg and 30/10&#xa0;mg significantly improved CNS-LS scores (mean difference [MD] -&#x2009;2.52 and -&#x2009;2.45, respectively), while DM/Q 30/30&#xa0;mg produced greater gains in VAS-QOL (MD 17.20) and VAS-QOR (MD 14.90). Dizziness was the only statistically significant, dose-related adverse event.<br><br>CONCLUSION: DM/Q combination therapy provides effective symptom control for PBA, with favorable tolerability. Both 20/10&#xa0;mg and 30/10&#xa0;mg doses improve emotional lability, while 30/30&#xa0;mg yields additional quality-of-life benefits. Further studies should assess long-term safety and disorder-specific dosing optimization.}, }
@article {pmid41531269, year = {2026}, author = {Elmaleh, B and Faust, O and Rosenzweig, R}, title = {The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70395}, pmid = {41531269}, issn = {1742-4658}, support = {1093/22//Israel Science Foundation/ ; //Minerva Foundation/ ; ERC-CoG-2024 101169856//H2020 European Research Council/ ; }, abstract = {DNAJC7, a member of the J-domain protein (JDP/Hsp40) family, plays a key role in protein homeostasis by regulating Hsp70 activity and preventing protein aggregation. Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis (ALS); yet, the molecular mechanisms by which these variants impair chaperone function remain poorly understood. DNAJC7 is a conserved chaperone featuring both a canonical J-domain, essential for Hsp70 activation, and three TPR domains, which serve as protein-protein binding interfaces. Here, we investigate the structural and functional consequences of the ALS-associated E425K mutation located within the conserved J-domain. Using NMR spectroscopy, we show that although the E425K mutation does not alter the structure of the protein, it significantly disrupts the conserved J-domain-Hsp70 interaction. We further identify a second Hsp70-binding interface within the TPR domains, which interacts with the C-terminal EEVD motif of Hsp70. This TPR-EEVD interaction is preserved in the E425K mutant but cannot compensate for the loss of J-domain binding or restore DNAJC7-dependent Hsp70 activation. Functionally, we show that the TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation and that this holdase activity is retained in the E425K mutant. However, the mutant fails to support client transfer to Hsp70 and the subsequent Hsp70-mediated substrate refolding. Together, these findings demonstrate that DNAJC7 requires coordinated action of both J-domain and TPRs to regulate Hsp70 function and that disruption of J-domain-mediated activation uncouples DNAJC7 from the Hsp70 cycle, providing a mechanistic basis for its dysfunction in ALS.}, }
@article {pmid41531792, year = {2026}, author = {Yang, X and Huang, S and Wang, Y and Yuan, J and Yao, X}, title = {Identification of Comprehensive Landscape of Peripheral Immunity and Chemokine-Related Genes in Amyotrophic Lateral Sclerosis.}, journal = {ImmunoTargets and therapy}, volume = {15}, number = {}, pages = {1-15}, pmid = {41531792}, issn = {2253-1556}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive loss of motor neuron function and disruption of the blood-brain barrier are key features of ALS. Under the influence of chemokines, peripheral immune cells migrate into the central nervous system, thereby affecting the neuronal microenvironment. The aim of this study is to classify ALS based on the immune characteristics of peripheral blood in patients with the disease, and to construct prognostic models.<br><br>PATIENTS AND METHODS: A total of 397 ALS patients and 645 healthy controls (GSE112676 and GSE112680) were included. ALS chemotactic subtypes were constructed based on differentially expressed genes of chemokine and chemokine receptors (CCRs). The Cibersort algorithm was used to investigate the abundance of immune cells in peripheral blood. Univariate Cox regression analysis was performed to screen for CCRs genes, clinical characteristics, and immune cells associated with prognosis. Prognostic models were constructed based on these variables. Finally, external validation was conducted using samples from ALS patients diagnosed at the First Affiliated Hospital of Sun Yat-sen University.<br><br>RESULTS: There were significant differences in the abundance of peripheral immune cells between ALS patients and healthy controls. 17 CCRs genes were identified as differentially expressed. CCL23, CCR8, CXCR4, site of onset, age of onset, and "CD4 naive T cells" were demonstrated to be significantly correlated with survival time. Two chemotactic subtypes were established. Eight prognostic models could distinguish between high-risk and low-risk ALS patients. At year five, the areas under the receiver operating characteristic curves for the PlsRcox, Coxboost, and Xgboost algorithms were 0.747, 0.733, and 0.728, respectively. External test sets successfully validated these results.<br><br>CONCLUSION: ALS patients exhibit peripheral immune abnormalities. Peripheral immune status could be used to distinguish ALS subtypes and construct prognostic models. Understanding peripheral immune changes in ALS patients may inform potential immunotherapies.}, }
@article {pmid41531877, year = {2025}, author = {Finsterer, J}, title = {There is currently no evidence that long-COVID-19 leads to neurodegenerative diseases such as SDAT, amyotrophic lateral sclerosis, or Parkinson's disease.}, journal = {Brain circulation}, volume = {11}, number = {4}, pages = {354-355}, pmid = {41531877}, issn = {2455-4626}, }
@article {pmid41532955, year = {2026}, author = {Bernal-Vicente, BN and Ponce, I and Ríos-Castro, E and Moreno-Castilla, P and Tovar-Y-Romo, LB}, title = {Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.}, journal = {Journal of neurochemistry}, volume = {170}, number = {1}, pages = {e70350}, pmid = {41532955}, issn = {1471-4159}, support = {IN214723//Direcci&#xf3;n General de Asuntos del Personal Acad&#xe9;mico, Universidad Nacional Aut&#xf3;noma de M&#xe9;xico/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroprotection/physiology ; Biomarkers/metabolism ; }, abstract = {Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and α-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.}, }
@article {pmid41533211, year = {2026}, author = {Shu, X and Zeng, J and Zhang, K}, title = {TREM2-mediated Crosstalk in ALS: Microglial Fate Transition, Protein Aggregate Clearance, and Peripheral Nerve Repair.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {41533211}, issn = {1995-8218}, }
@article {pmid41534282, year = {2026}, author = {Hosseinpour Moghaddam, M and Karimian, N and Johnston, SG and Choppala, G and Rastegari, M and Burton, ED}, title = {Goethite as an antimony host-phase: Atomic-scale retention mechanisms and the selectivity of commonly-applied extraction schemes.}, journal = {Journal of hazardous materials}, volume = {503}, number = {}, pages = {141097}, doi = {10.1016/j.jhazmat.2026.141097}, pmid = {41534282}, issn = {1873-3336}, abstract = {Goethite (α-FeOOH) is one of the most important host-phases for Sb(V) in soils, sediments and geogenic wastes. This study examines, for the first time, how variability in the atomic-scale mechanisms of Sb(V) retention by goethite impacts the selectivity of commonly-applied Sb extraction schemes. EXAFS spectroscopy shows that Sb(V) retention via coprecipitation involves Sb(V) incorporation into goethite's structure through Sb(V)-for-Fe(III) substitution. In contrast, Sb(V) retention via sorption involves edge and double-corner sharing between SbO6 and FeO6 octahedra at the goethite surface. Incorporation of Sb(V) into goethite's structure causes Sb(V) to be largely inaccessible to 1 M HCl, steps 1, 2 and 3 of Wenzel et al.'s sequential extraction scheme and all 3 steps of the BCR extraction scheme. In contrast, Sb(V) sorption to goethite's surface facilitates more substantial Sb(V) extractability, which varies with the relative abundance of SbO6-FeO6 linkages. Importantly, Sb(V) sorption to the goethite surface is underestimated by both the Wenzel et al. and BCR schemes. In addition, the BCR scheme misidentifies a significant portion of goethite-sorbed Sb(V) as oxidisable phases (e.g. sulfides or organic matter). Hence, in soils, sediments or geogenic wastes where Sb(V) is sorbed to goethite, the BCR scheme is not appropriate for quantifying Sb(V) fractionation. Overall, our results demonstrate that variability in the atomic-scale mechanisms by which goethite retains Sb(V) translate to substantial complexity in Sb(V) extractability.}, }
@article {pmid41534442, year = {2026}, author = {Nomura, E and Morihara, R and Osakada, Y and Yunoki, T and Takemoto, M and Yamashita, T and Ishiura, H}, title = {The utility of Gold Coast criteria for amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {481}, number = {}, pages = {125733}, doi = {10.1016/j.jns.2026.125733}, pmid = {41534442}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Male ; Middle Aged ; Female ; Retrospective Studies ; Aged ; Sensitivity and Specificity ; Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Current diagnostic criteria, including the revised El Escorial (rEE) and Awaji (AW) criteria, have limitations in sensitivity. The Gold Coast (GC) criteria were proposed to simplify diagnosis and improve early detection, but their real-world performance remains unclear.<br><br>METHODS: We retrospectively analyzed 260 patients suspected of ALS who were admitted to our department between 2013 and 2022. The GC, AW, and rEE criteria were applied to data from initial hospitalization. Final diagnoses were based on follow-up data, and sensitivity/specificity were compared using McNemar's test.<br><br>RESULTS: The GC criteria showed equivalent sensitivity (91.6&#xa0;%), but higher specificity (75.9&#xa0;%) compared to all combined AW and rEE categories. GC sensitivity was significantly higher than that of AW/rEE definite/probable categories. False negatives of GC criteria were often due to insufficient LMN signs, particularly in bulbar-onset cases. Subgroup analysis showed consistent trends.<br><br>CONCLUSION: The GC criteria demonstrated high sensitivity and moderate specificity, supporting their clinical utility in early ALS diagnosis. However, variability in clinical presentation and retrospective limitations suggest the need for further prospective validation.}, }
@article {pmid41534462, year = {2026}, author = {Mortensen, CK and Jokinen, CLV and Sørensen, CLH and Løkkegaard, SS}, title = {Beyond the birthing body: Towards a relational and inclusive understanding of birth trauma. A commentary on Donegan et al. (2025).}, journal = {Midwifery}, volume = {154}, number = {}, pages = {104705}, doi = {10.1016/j.midw.2026.104705}, pmid = {41534462}, issn = {1532-3099}, mesh = {Humans ; Female ; Pregnancy ; Qualitative Research ; Adult ; *Parturition/psychology ; Denmark ; }, abstract = {In their recent scoping review, Donegan, Zhao, and Mansu (2025) provide a valuable synthesis of international best practice guidelines on birth trauma support for birthing women. While several reviews have explored fathers' experiences of traumatic or complicated births and proposed recommendations for improved care, systematic implementation and empirical evaluation remain limited. In this commentary, we broaden Donegan et al.'s focus on birthing women by extending the scope of trauma-informed perinatal care to also include non-birthing parents. Drawing on findings from a Danish qualitative study conducted in spring 2025, as well as existing research and theoretical perspectives, we explore how non-birthing parents can be profoundly affected by traumatic births - often without recognition or adequate support. We conclude by offering six recommendations for practice and future research aimed at broadening the scope of trauma-informed perinatal care to meaningfully include non-birthing parents and thereby reduce the triadic impact of birth trauma and support individual and family functioning.}, }
@article {pmid41534629, year = {2026}, author = {Ortega Douville, C}, title = {First evidence supporting the theory of the sensorimotor paradox on the origins of mind and language.}, journal = {Bio Systems}, volume = {262}, number = {}, pages = {105691}, doi = {10.1016/j.biosystems.2026.105691}, pmid = {41534629}, issn = {1872-8324}, mesh = {Humans ; *Language ; *Feedback, Sensory/physiology ; Electroencephalography ; *Biological Evolution ; Movement/physiology ; Brain/physiology ; }, abstract = {For now 15 years, I have been developing a hypothesis on the origins of mind and language during our evolution, called theory of the sensorimotor paradox. The core neuroimaging part of the hypothesis is that the switch in our relation to our hands, coming with bipedal stance, would have allowed us to disrupt the function of sensory prediction to resolve into motor action and sensory feedback: we can't take our hand as an object of interaction and have it grasp itself at the same time. This would later on be autonomised as mental representation. From there, non-resolution of prediction into motor action would prevent a system from liberating tension in order to be available again and collect feedback (meta-prediction). Using Schalk, G. et al.'s extensive dataset of EEG recordings on motor movement and imagery (2009), I am now able to support some of the theory's claims. Notably, meta-analysis of movement and imagery recordings tends to stress a higher variability of frequency activation amongst motor signals than imagery's. This would indicate a greater difficulty for a system to release tension in an effort to produce and maintain mental representation. Similar short oscillatory predictive change, but greater uncoupling of frontal and prefrontal regions suggests sensory suppression of efference-copy and greater instability toward the eventuality of collecting feedback when motor action is triggered, relying on somatosensory support. Event-related time-frequency analysis on proprioceptive areas shows delay of neural signal to mental representation compared to motor action, which could be a strong evidence of dissociation.}, }
@article {pmid41534661, year = {2026}, author = {Costa, I and Barbosa, DJ and Remião, F and Sousa, ME and Silva, R}, title = {A dive into the untapped potential of marine compounds in counteracting neurodegeneration.}, journal = {Pharmacology &amp; therapeutics}, volume = {279}, number = {}, pages = {108982}, doi = {10.1016/j.pharmthera.2026.108982}, pmid = {41534661}, issn = {1879-016X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Animals ; *Aquatic Organisms/chemistry ; *Biological Products/pharmacology/therapeutic use/isolation &amp; purification ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation &amp; purification ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms - including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.}, }
@article {pmid41534682, year = {2026}, author = {Sangari, S and Lackmy-Vallée, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V}, title = {Afferent-driven modulation of spinal interneuron circuits across disease stages in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107270}, doi = {10.1016/j.nbd.2026.107270}, pmid = {41534682}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; *Interneurons/physiology ; Humans ; Female ; Male ; Middle Aged ; Aged ; *Spinal Cord/physiopathology ; Motor Neurons/physiology ; *Afferent Pathways/physiopathology ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively disrupts voluntary motor command through combined cortical and spinal motor neuron degeneration. However, how spinal circuits reorganize during the disease remains poorly understood, particularly in humans. This study examined the function of excitatory and inhibitory spinal interneuron circuits that control upper and lower limb movements, using non-invasive electrophysiological techniques targeting specific afferent-motoneuron pathways at cervical and lumbar levels. These segments are clinically relevant, as spinal-onset forms constitute the predominant clinical presentation of ALS. We compared patients with ALS at different stages of functional impairment to healthy individuals. Spinal circuits predominantly driven by muscle spindle afferents (group Ia and II) showed, at the group level, a marked reduction in inhibition together with enhanced propriospinal excitation. In contrast, pathways mediated by tendon afferents (group Ib) and cutaneous inputs appeared preserved in unstratified analyses. However, when accounting for disease stage, inhibitory dysfunction emerged as an early feature, whereas excitation increased progressively with functional impairment, and modulations also became detectable in Ib- and cutaneous-driven responses. These findings reveal an afferent- and stage-dependent hierarchy of spinal dysfunction, following a reproducible sequence from early disinhibition to maladaptive excitation. This dynamic pattern mirrors the organization observed in preclinical spinal models and aligns with cortical pathophysiology, where widespread loss of inhibition precedes selective increases in excitation. Together, these results refine the mechanistic understanding of motor network disorganization in ALS and identify inhibitory interneurons as potential therapeutic targets to stabilize spinal network function.}, }
@article {pmid41535729, year = {2026}, author = {Tong, SC and Zhang, J and Diao, CJ and Zhao, L and Lu, ZY}, title = {Tuning the Liquid-Liquid Phase Separation of FUS by Phosphorylation: A Role of Domain-Specific Compensation.}, journal = {The journal of physical chemistry. B}, volume = {130}, number = {4}, pages = {1437-1446}, doi = {10.1021/acs.jpcb.5c07950}, pmid = {41535729}, issn = {1520-5207}, mesh = {Phosphorylation ; *RNA-Binding Protein FUS/chemistry/metabolism ; Molecular Dynamics Simulation ; Protein Domains ; Humans ; Biomolecular Condensates/chemistry ; Phase Separation ; }, abstract = {Biomolecular condensates, a type of subcellular or membraneless organelle, form through liquid-liquid phase separation (LLPS) driven by multivalent interactions. As an RNA-binding protein, FUS participates in biological processes by forming dynamic liquid condensates via LLPS, with its abnormal fibrous aggregation associated with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Experiments show that phosphorylation inhibits LLPS of the FUS low-complexity domain (LCD) under low salt conditions, whereas for full-length FUS, phosphorylation does not block initial LLPS but inhibits the conversion of liquid droplets to toxic aggregates. The molecular mechanism underlying the difference between the two remains unknown. In this molecular dynamics simulation study, we examined condensate structural characteristics and compared wild-type (WT) versus phosphorylated condensates, revealing the molecular details of how full-length FUS avoids LLPS impairment through synergistic compensatory regulation among various domains. As for the FUS-LCD system, the extent to which their LLPS is reduced by phosphorylation is associated with the number of phosphorylation sites. Moreover, we have developed a model for analyzing the viscoelasticity of the condensates, which revealed that altered interaction patterns impact condensate viscoelasticity. This study characterizes the postphosphorylation architecture of FUS condensates and elucidates the molecular mechanisms by which phosphorylation regulates condensate formation and properties.}, }
@article {pmid41535829, year = {2026}, author = {Fang, C and Jin, J and Shi, W and Xu, X and Li, H and Duan, Q and Yu, X and Wu, S and Lu, T and Hu, F and Qin, X and Huang, J and Sun, D and Zhang, M and He, S and Dang, J and He, Q and Zhang, Q and Gan, S}, title = {Accelerated brain aging in amyotrophic lateral sclerosis and its prognostic associations: a cohort study.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {86}, pmid = {41535829}, issn = {1741-7015}, support = {2020SF-098//Key Research and Development Projects of Shaanxi Province/ ; 32400880//National Natural Science Foundation of China/ ; 32400926//National Natural Science Foundation of China/ ; 2022JQ-964//Natural Science Basic Research Program of Shaanxi Province/ ; 2408085MC081//Anhui Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/mortality ; Male ; Female ; Middle Aged ; *Brain/pathology/diagnostic imaging ; Prognosis ; Aged ; *Aging/pathology ; Magnetic Resonance Imaging ; Cohort Studies ; Neuropsychological Tests ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, appearing to be associated with accelerated brain aging. Although increased brain age has been associated with mortality risk in older adults, it remains unclear how the brain aging process is accelerated in ALS and how this acceleration relates to patient prognosis.<br><br>METHODS: One hundred seventy sporadic ALS patients and 84 age- and sex-matched HCs were recruited and underwent neuropsychological tests and T1-weighted magnetic resonance imaging (MRI) scans. A brain-age prediction model was developed using a 3D-Conformer deep learning framework trained on 4310 healthy T1-weighted MRI data from public datasets. Brain age was predicted in HCs and ALS patients, and then the predicted-age difference (PAD&#x2009;=&#x2009;brain age-chronological age) was calculated. In the ALS cohort, the neuroanatomical association of PAD was examined, and cell-specific gene expression of PAD-related volume loss was analyzed using transcriptomic data from the Allen Human Brain Atlas. Associations between PAD, neuropsychological performance, clinical characteristics, and survival outcomes were further evaluated in ALS patients.<br><br>RESULTS: The brain aging process was accelerated in ALS by an average PAD of 1.77&#xa0;years, which was predominantly associated with a widespread loss of gray matter volume. Cell-specific gene expression analyses showed microglia, inhibitory neurons, endothelial cells, and pericytes as significant contributors to the accelerated brain aging in ALS, with endothelial cells and pericytes being essential for constructing the blood-brain barrier (BBB) and microglia being involved in neuroinflammation. The acceleration in brain aging was more prominent in older patients and was associated with cognitive impairments. Notably, older brain age at initial diagnosis was an independent risk factor for death (hazard ratio, 1.026; 95% CI [1.008, 1.045]) and was associated with shorter survival and more rapid disease progression.<br><br>CONCLUSIONS: Accelerated brain aging is common in ALS; this could be hypothesized to be associated with the interplay between BBB breakdown and neuroinflammation, leading to gray matter degeneration. Furthermore, older brain age at initial diagnosis is associated with worse clinical outcomes. These findings suggest that therapeutic strategies targeting neuroinflammation and BBB integrity may help attenuate accelerated brain aging and improve prognosis.}, }
@article {pmid41536515, year = {2026}, author = {Voldřich, R and Svoboda, N and Kachlířová, Z and Bartáková, L and Charvát, F and Netuka, D}, title = {Urodynamic outcomes and prognostic determinants following endovascular treatment of spinal dural arteriovenous fistulas.}, journal = {Brain &amp; spine}, volume = {6}, number = {}, pages = {105913}, pmid = {41536515}, issn = {2772-5294}, abstract = {INTRODUCTION: The prognosis of untreated spinal dural arteriovenous fistulas (SDAVFs) is unfavorable. Current outcome scales used to assess the effect of surgery or endovascular treatment (EVT) rely largely on patient-reported symptoms and may underestimate actual impairment. Moreover, prognostic factors remain debated and conclusions in the literature are inconsistent.<br><br>RESEARCH QUESTION: The aim was to quantify urological outcomes after SDAVF embolization using specialized urodynamic testing, compare these objective findings with subjective outcomes derived from traditional scales, and identify prognostic factors associated with unfavorable clinical results.<br><br>METHODS: In this single-center retrospective study, all patients underwent EVT as first-line therapy. Clinical status was assessed using Aminoff-Logue scale (ALS), compared with preoperative data, and correlated with angiographic findings. Urodynamic testing was performed to objectively evaluate bladder function.<br><br>RESULTS: Twent-four patients met the inclusion criteria. Urodynamic testing was performed in 14 (58&#xa0;%) patients. The most frequent abnormal finding was bladder hyposensitivity (79&#xa0;%), followed by pathological post-void residual volume (64&#xa0;%) and elevated bladder capacity (50&#xa0;%). Six (43&#xa0;%) patients reported no subjective urological symptoms (ALS&#xa0;=&#xa0;0); urodynamic testing revealed two or more pathological parameters in all of them. EVT failure and subsequent surgery predicted gait deterioration (p&#xa0;=&#xa0;0.011) as well as detrusor overactivity (p&#xa0;=&#xa0;0.001). Symptom duration over one year (p&#xa0;=&#xa0;0.038) and fistula location above the T9 level (p&#xa0;=&#xa0;0.021) were negative prognostic factors for bladder function.<br><br>CONCLUSION: The results suggest a potential underestimation of urological impairment when relying on subjective scales and highlight the need for standardized urodynamic testing. They also emphasize the importance of early treatment of SDAVF.}, }
@article {pmid41536906, year = {2025}, author = {Yang, X and Zheng, J and Wang, X and Cai, H and Yu, J}, title = {Pathogenic mechanisms of amyotrophic lateral sclerosis-linked VAPB P56S mutation in the degeneration of corticospinal motor neurons.}, journal = {Ageing and neurodegenerative diseases}, volume = {5}, number = {3}, pages = {}, pmid = {41536906}, issn = {2769-5301}, support = {Z01 AG000959/ImNIH/Intramural NIH HHS/United States ; ZIA AG000946/ImNIH/Intramural NIH HHS/United States ; }, abstract = {AIM: The endoplasmic reticulum (ER)-localized vesicle-associated membrane protein-associated protein B (VAPB) is implicated in many cellular processes, such as ER-organelle tethering, calcium homeostasis, and unfolded protein response. The P56S missense mutation in VAPB has been associated with familial forms of motor neuron diseases such as typical amyotrophic lateral sclerosis (ALS), atypical ALS, and spinal muscular atrophy. However, it has not been determined how the VAPB P56S mutation induces the degeneration of corticospinal motor neurons (CSMNs) in ALS.<br><br>METHODS: Using homozygous knock-in (KI) mice expressing P56S VAPB, we investigated the mutation's pathogenic impacts and underlying mechanisms on the survival and function of CSMNs. We performed a wide variety of assays to examine the behavioral, histological, cellular, and molecular abnormalities of KI mice.<br><br>RESULTS: Compared with wild-type controls, KI mice showed the downregulated protein level of mutant VAPB, proteinase K-resistant cytoplasmic inclusions of mutant VAPB in CSMNs, abnormal hyperactivity, impaired motor coordination, neuronal loss of CSMNs, and axonal degeneration of pyramidal and corticospinal tracts. Mechanistic studies revealed that the VAPB P56S mutation rendered the mutant protein destabilized and inclusion-prone in cortical neurons, and the proteasomal degradation played a critical role in modulating mutant VAPB's protein level and inclusion formation. In addition, the VAPB P56S mutation disrupted ER-mitochondria contacts, impaired VAPB-PTPIP51 interaction and IP3R-VDAC interaction, elevated cytosolic Ca[2+], activated CaMKII, and increased CRMP2 phosphorylation. Moreover, the VAPB P56S mutation activated the IRE1-XBP1/p38 mitogen-activated protein kinase (MAPK)/ c-Jun N-terminal kinase (JNK) pathway, increased tau hyperphosphorylation, and upregulated p53 expression and phosphorylation.<br><br>CONCLUSION: These findings demonstrate the progressive degeneration of CSMNs induced by VAPB P56S mutation and indicate the involvement of the Ca[2+]-CaMKII-CRMP2 and IRE1-p38 MAPK/JNK-tau/p53 pathways in the pathogenic process.}, }
@article {pmid41538404, year = {2026}, author = {Zhao, Y and Liu, Y and Yuan, B and Yu, W and Li, T and Zhang, J and Ye, F and Fu, Y}, title = {Pharmacophore Reorganization-Based Design, Synthesis, and Safener Activity of Novel Isoxazole-Piperazinone Derivatives.}, journal = {Journal of agricultural and food chemistry}, volume = {74}, number = {3}, pages = {2737-2748}, doi = {10.1021/acs.jafc.5c15324}, pmid = {41538404}, issn = {1520-5118}, mesh = {*Herbicides/chemistry/pharmacology/chemical synthesis ; Acetolactate Synthase/antagonists &amp; inhibitors/chemistry/metabolism ; Oryza/drug effects/growth &amp; development/enzymology ; Drug Design ; *Isoxazoles/chemistry/pharmacology ; *Piperazines/chemistry/pharmacology/chemical synthesis ; Plant Proteins/chemistry/metabolism/antagonists &amp; inhibitors/genetics ; Structure-Activity Relationship ; Molecular Structure ; Plant Weeds/drug effects/enzymology/growth &amp; development ; Molecular Docking Simulation ; Sulfonylurea Compounds/chemistry ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Pharmacophore ; }, abstract = {Bensulfuron, an acetolactate synthase (ALS)-inhibiting herbicide, is widely used in rice cultivation for the effective control of sedge and broadleaf weeds. However, japonica varieties are highly sensitive to this herbicide and can develop phytotoxicity when it is improperly applied. Herbicide safeners enhance crop tolerance to herbicides without reducing their weed control efficacy, offering a significant strategy for the safe use of herbicides. To alleviate bensulfuron-induced phytotoxicity in rice, a series of novel isoxazole-piperazinone derivatives were designed through pharmacophore recombination. The structures of the target compounds were confirmed by infrared spectroscopy, [1]H and [13]C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The spatial configuration of compound II-1 was further determined by single-crystal X-ray diffraction. Bioactivity assays demonstrated that most target compounds effectively reduced bensulfuron-induced phytotoxicity in rice. Evaluation of key physiological parameters, including plant growth indices, ALS enzyme activity, and detoxification enzyme activity, revealed that compounds II-10 and II-40 exhibited superior safener activity compared to isoxadifen-ethyl. Molecular structure analysis and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated that compound II-10 possesses good pharmacokinetic properties comparable to those of isoxadifen-ethyl. Molecular docking analysis revealed that compound II-10 exerts its protective effect by competitively binding to the ALS active site with bensulfuron. Furthermore, ecological risk predictions suggested that compound II-10 poses low or negligible toxicity risks to nontarget organisms such as mammals, birds, and algae. Overall, these results highlight compound II-10 as a promising structure for the development of novel herbicide safeners.}, }
@article {pmid41538578, year = {2026}, author = {Khan, M and Saeed, U and Piracha, ZZ and Ozsahin, I and Shao-Chun, C}, title = {Innovative public-health strategies for neurodegenerative disease: leveraging diversified ultraviolet irradiation as a next-generation therapy.}, journal = {Brazilian journal of biology = Revista brasleira de biologia}, volume = {85}, number = {}, pages = {e297765}, doi = {10.1590/1519-6984.297765}, pmid = {41538578}, issn = {1678-4375}, mesh = {Humans ; *Neurodegenerative Diseases/radiotherapy/therapy ; *Ultraviolet Therapy/methods ; *Ultraviolet Rays ; *Public Health ; Oxidative Stress/radiation effects ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis are escalating worldwide, straining healthcare systems and leaving patients with therapies that are largely palliative. Emerging evidence positions diversified ultraviolet (UV) irradiation as a groundbreaking, non-invasive strategy to counter these disorders. Beyond its traditional use in sterilization, specific UV spectra, UV-B (280-320 nm), UV-C (200-280 nm), and far-UV (207-222 nm), are now recognized for modulating oxidative stress, restoring mitochondrial function, correcting apoptotic dysregulation, and enhancing DNA repair. Innovative approaches such as riboflavin-mediated phototherapy and photobiomodulation (PBM) show the capacity to disaggregate toxic protein aggregates like β-amyloid and α-synuclein, boost antioxidant defenses, stimulate neurotrophic factors, and quell neuroinflammation. Preclinical models and early clinical trials reveal preserved cognition, enhanced neurogenesis, and reduced disease biomarkers, suggesting real translational promise. From a public-health perspective, UV-based interventions offer a cost-effective, scalable option for aging populations and resource-limited settings, especially when integrated with community-level health technologies and remote delivery platforms. Continued investigation of optimal dosing, long-term safety, and mechanistic pathways will be pivotal to unlock the full therapeutic and population-wide impact of this novel modality.}, }
@article {pmid41539219, year = {2026}, author = {Gawronski, B and Rokosz, M and Stefanczyk, MM and Białek, M}, title = {Many heads are more utilitarian than one, but are they also less deontological? Reply to Baron and Skovgaard-Olsen (2026).}, journal = {Cognition}, volume = {271}, number = {}, pages = {106441}, doi = {10.1016/j.cognition.2026.106441}, pmid = {41539219}, issn = {1873-7838}, mesh = {Humans ; *Morals ; *Judgment ; *Ethical Theory ; }, abstract = {Using the CNI model to quantify three factors underlying moral-dilemma judgments, Rokosz et al. (2025) found that groups show greater concerns about outcomes than individuals, but do not differ in terms of norm adherence and general action tendencies. In a commentary on this work, Baron and Skovgaard-Olsen (2026) argue that (a) groups show less "nonsensical" judgments and (b) analyses controlling for this difference reveal that groups additionally show weaker concerns about moral norms. The current reply identifies conceptual and empirical problems with Baron and Skovgaard-Olsen's (2026) arguments. Expanding on this discussion, we present an alternative reanalysis of Rokosz et al.'s (2025) data to gauge the robustness of their findings against model specifications. Our reanalysis revealed (a) robust evidence that groups are more concerned about outcomes than individuals and (b) some evidence for differential concerns about moral norms, but this evidence is less reliable in that it depends on data-analytic choices.}, }
@article {pmid41540277, year = {2026}, author = {Hutchinson, DR and Little, DR and Osth, AF}, title = {Recency is sufficient for reconciling categorisation and memory: Commentary on Devraj et al. (2024).}, journal = {Psychonomic bulletin &amp; review}, volume = {33}, number = {1}, pages = {48}, pmid = {41540277}, issn = {1531-5320}, mesh = {Humans ; *Memory/physiology ; *Mental Recall/physiology ; }, abstract = {Devraj et al. (Psychonomic Bulletin and Review. https://doi.org/10.3758/s13423-023-02448-2 , 2024) argued that findings which suggest that memories for items become less accessible over time conflict with categorisation findings where exemplar performance improves across training. To reconcile this, they highlighted that under real-world conditions items tend to reappear less frequently over time, thus preferentially maintaining new items can improve performance. Typical categorisation experiments instead distribute exemplars uniformly across trials. However, under a power-law stimulus distribution, Devraj et al. showed worsening fit for exemplar classification models across trials. They used this as evidence that forgetting behaviour adapted to task demands, reducing exemplar accessibility and encouraging prototype use for classification decisions. By re-analysing the same data, we argue instead that this pattern can be produced with exemplar-forgetting in both conditions. By systematically increasing in the delays across which stimuli were tested, their Experimental condition exaggerated the effects of forgetting on performance in later trials compared to the Control condition. This resulted in a reversal of performance growth across trials - instead leading to a steady decline in performance. As exemplar model-fit advantage is expected to vary with performance, we suggest that trends in this advantage are not diagnostic of a shift in classification strategy. We found that a forgetting-function improved exemplar model fit to Devraj et al.'s data, and under reasonable parameters could predict the observed patterns of performance and model-fit a priori. Compared with a strategy-shifting mixture model, exemplar-forgetting provided equivalent fits despite being more theoretically parsimonious. We suggest power-law memory decay does not produce a tension between categorisation and memory findings, as increased forgetting is found across longer retention intervals, whereas the delay between exemplar learning and classification remains constant across typical categorisation experiments.}, }
@article {pmid41540870, year = {2026}, author = {Ghika, N and Accolla, E and Girardin, F and Theaudin, M}, title = {[Pharmacotherapy of neuromuscular diseases : what's new in 2025].}, journal = {Revue medicale suisse}, volume = {22}, number = {945}, pages = {66-70}, doi = {10.53738/REVMED.2026.22.945.48049}, pmid = {41540870}, issn = {1660-9379}, mesh = {Humans ; *Neuromuscular Diseases/drug therapy ; Oligonucleotides, Antisense/therapeutic use/pharmacology ; *Oligonucleotides/therapeutic use/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Switzerland ; Friedreich Ataxia/drug therapy ; Oxidative Stress/drug effects ; Superoxide Dismutase-1/genetics ; }, abstract = {Two new drugs have recently become available for treating neuromuscular diseases: omaveloxolone and tofersen. Omaveloxone, which is available in Switzerland, mitigates mitochondrial oxidative stress and has been shown to slow the clinical progression of Friedreich's ataxia. Tofersen is an antisense oligonucleotide that induces posttranscriptional silencing of the SOD1 (superoxide dismutase 1) gene, which is involved in familial forms of amyotrophic lateral sclerosis. Although its efficacy has so far only been indirectly demonstrated through its ability to reduce serum neurofilament levels, it is available on a compassionate use basis in Switzerland.}, }
@article {pmid41542389, year = {2026}, author = {Bolger, I and Shaw, R and Tam, OH and Roque, CG and Jackson, CA and O'Neill, K and ,  and Smith, C and Phatnani, H and Natarajan, K and Hammell, MG}, title = {TDP-43 dysfunction leads to the accumulation of cryptic transposable element-derived exons, crypTEs, in iPSC derived neurons and ALS/FTD patient tissues.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41542389}, issn = {2692-8205}, support = {P30 CA016087/CA/NCI NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 is an RNA and DNA binding protein that plays major roles in regulating RNA processing. In particular, TDP-43 dysfunction leads to the accumulation of cryptic splice isoforms that result from improperly spliced mRNAs. In addition to its role in regulating splicing, TDP-43 is also known to regulate the expression of transposable elements (TEs). TEs are mobile genetic elements which comprise a significant proportion of the human genome, but are normally silenced in healthy somatic cells. TEs are interspersed throughout the genome, both in gene-depleted regions and within gene introns and gene regulatory sequences. We used optimized long-read RNA sequencing assays to generate catalogs of mis-spliced and mis-expressed genes and TEs in human neurons depleted for TDP-43. In addition to known TDP-43 driven cryptic isoforms, we identified hundreds of TDP-43 dependent spliced RNAs that form cryptic gene-TE fusion events as a result of mis-splicing of TE sequences into gene transcripts. Among these TDP-43 dependent cryptic gene-TE transcripts (crypTEs), we found: TEs that provide alternate gene promoters/5'UTRs, TEs that act as cassette exons inside host gene mRNAs, as well as TEs that provide alternate transcript 3' ends. These cryptic gene-TE fusions are predicted to induce aberrant expression of ALS relevant genes, nonsense mediated decay (NMD) products, as well as novel peptides from gene-TE fusions within the gene coding sequence. Using coupled long-read RNA (Iso-seq) and single-nucleus (snRNA-seq) profiles from postmortem ALS tissues, we further verified that many of these crypTE transcripts are enriched in frontal cortex samples from ALS donors with cognitive involvement (ALSci) and associated with altered expression of those genes in deep layer cortical excitatory neurons. In short, TDP-43 dependent crypTEs greatly expand the catalogs of TDP-43 dependent cryptic splice isoforms and represent a novel mechanism by which TE dysregulation impacts ALS.}, }
@article {pmid41542616, year = {2026}, author = {Cheng, T and Tripathi, S and Guo, Y and Vedula, P and Li, R and Potanin, M and Soley, N and Yan, AY and Vatsaraj, I and Harris, C and Greenstein, JL and Taylor, CO and Coyne, AN and Rothstein, JD}, title = {Identification of molecular and clinical ALS subgroups based on TDP-43 loss of function molecular markers from population-based patient-derived iPS motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41542616}, issn = {2692-8205}, support = {R01 NS122236/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease characterized by progressive cortical and spinal motor neuron loss, with most patients surviving only 2-5 years post-diagnosis. While approximately 10% of cases are familial (fALS), the remaining 90% are sporadic (sALS) with unknown genetic drivers. Importantly, clinical presentations are heterogeneous in both sporadic and familial ALS, underscoring the complexity of the disease. A pathological hallmark of ALS is the mislocalization of RNA-binding protein TDP-43 from the nucleus to the cytoplasm. This mislocalization produces both loss of function consequences, such as widespread RNA processing and splicing defects, as well as potential toxic gain of function effects associated with cytoplasmic aggregation.<br><br>RESULTS: In this study, we used RT-PCR data from induced pluripotent stem cell-derived motor neurons derived from 180 sALS and C9orf72 fALS patients from the Answer ALS collection to identify biological subgroups based on TDP-43 loss-of-function signatures. Spectral embedding revealed four distinct molecular clusters, including one subgroup genetically similar to controls and another with the most dysregulated mRNA expression, suggesting differing disease severity. Linear mixed models were then used to assess the longitudinal trajectory of over 90 clinical measures, and the between-cluster interaction effects were evaluated.<br><br>CONCLUSIONS: 36 clinical outcomes showed significant differences across clusters, supporting the presence of biologically and clinically distinct ALS subtypes based on the TDP-43 associated pathogenic cascade. These findings demonstrate a critical role of RNA profiling in uncovering biologically meaningful subtypes of ALS, potentially allowing for more precise prognostic tools and the development of future personalized therapeutic approaches.}, }
@article {pmid41543999, year = {2026}, author = {Robinson, GA and Phillips, MR and Horne, K and Ceslis, A and McCombe, PA and Henderson, RD}, title = {Assessment of language and executive functions in ALS: the brief executive Language screen.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2025.2607398}, pmid = {41543999}, issn = {2167-9223}, abstract = {Objective: Language and executive functioning are two domains commonly impacted in ALS and should be assessed sensitively and briefly. This paper investigates the utility of the Brief Executive Language Screen (BELS) in ALS. Methods: ALS patients (N = 27) were compared to age, education, and pre-morbid intelligence-matched healthy controls (N = 91) at the group level using ANCOVA and t-tests. A case series was also conducted to explore individual and subgroup performance on the BELS and Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Results: Groups were largely matched on neuropsychology baseline measures. The ALS group performed significantly worse on BELS Propositional Language and Executive Function subtests, and on overall BELS scores. Group results suggest setting a goal can increase phonemic fluency and spontaneous speech output, after controlling for motor speed. The case series revealed almost half of patients (across all subgroups) were impaired on the BELS, compared to 15% impaired on the ECAS (patients on the more severe end of the ALS-FTD spectrum). Conclusions: The BELS rapidly assesses language and executive functions, and provides valuable information for management of cognitive difficulties (i.e., goal setting), which can help improve or maintain conversational speech. The BELS may help to identify subtle impairments that may otherwise go undetected.}, }
@article {pmid41545051, year = {2026}, author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF}, title = {Safety and efficacy of the Atalante exoskeleton in the rehabilitation of French patients with amyotrophic lateral sclerosis: a prospective, monocentric, open, uncontrolled, interventional protocol, EXALS.}, journal = {BMJ open}, volume = {16}, number = {1}, pages = {e109620}, pmid = {41545051}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; Prospective Studies ; *Exoskeleton Device ; France ; Quality of Life ; Female ; Male ; Middle Aged ; Walking ; Gait ; *Exercise Therapy/methods/instrumentation ; Aged ; Muscle Strength ; Adult ; Postural Balance ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Treatment Outcome ; }, abstract = {INTRODUCTION: Robotic rehabilitation on locomotion is a new approach in amyotrophic lateral sclerosis (ALS) and previous studies showed its feasibility. In this study, we aim to evaluate safety, patient's experience and efficacy of a gait training programme with the Atalante exoskeleton, compared with usual care, on walking ability, functional capacity and other symptoms associated with ALS.<br><br>METHODS AND ANALYSIS: EXALS is a monocentric, prospective, interventional, open trial. 20 slowly progressing patients with gait deficits will be recruited. The study is conducted in three phases, each lasting 6&#x2009;weeks, following the ABA procedure. Phase B represents the intervention phase, during which patients practise their gait training at a rhythm of three sessions/week, as an add-on to usual care. In the two phases A, patients receive usual care with no additional treatment. An evaluation is planned before, in the middle and at the end of each phase. The primary outcome of the study is safety and tolerability of the Atalante exoskeleton. Secondary outcomes include: participants' subjective impact and experience, attitude and motivation, efficacy and interactivity of the exoskeleton, walking ability, functional capacity, spasticity, balance, postural stability, lower limb muscle strength, quality of life, pain, fatigue, anxiety and depression. Statistical analyses will include descriptive methods for all variables and adverse events. Quantitative outcomes are analysed using repeated-measures ANOVA (analysis of variance) across the seven visits, with post hoc tests applied when appropriate. Nominal outcomes are evaluated using Cochran's Q test with McNemar pairwise comparisons when significant. Associations between variables are examined using Spearman correlation coefficients. Missing data will be replaced using linear interpolation, and sensitivity analyses will be planned. Qualitative interview data are analysed using thematic analysis.<br><br>ETHICS AND DISSEMINATION: This study was approved by the French ethics committee CPP Nord-Ouest I (no. 23.02378.000201). Participant data are anonymised and securely stored in the laboratory's database, accessible only to the research team. Results will be disseminated through peer-reviewed journals and conferences.NCT06199284.}, }
@article {pmid41545763, year = {2026}, author = {Schmidt, T and Wolkersdorfer, MP and Lee, XY and Jubran, O}, title = {Unconscious cognition without post hoc selection artifacts: From selective analysis to functional dissociations.}, journal = {Behavior research methods}, volume = {58}, number = {2}, pages = {39}, pmid = {41545763}, issn = {1554-3528}, mesh = {Humans ; *Unconscious, Psychology ; *Cognition ; Artifacts ; Signal Detection, Psychological ; }, abstract = {One of the most popular approaches to unconscious cognition is the technique of "post hoc selection": Priming effects and visibility ratings are measured in multitasks on the same trial, and only trials with the lowest visibility ratings are selected for analysis of (presumably unconscious) priming effects. In the past, the technique has been criticized for creating statistical artifacts and capitalizing on chance. Here, we argue that post hoc selection constitutes a sampling fallacy, confusing sensitivity and response bias, wrongly ascribing unconscious processing to stimulus conditions that may be far from indiscriminable. In response to a high-profile "best practice" paper by Stockart et al. (2025) that condones the technique, we use standard signal detection theory to show that post hoc selection only isolates trials with neutral response bias, irrespective of actual sensitivity, and thus fails to isolate trials where the critical stimulus is "unconscious". Our own data demonstrate that zero-visibility ratings are consistent with uncomfortably high levels of sensitivity. As an alternative to post hoc selection, we advocate the study of functional dissociations, where direct (D) and indirect (I) measures are conceptualized as spanning a two-dimensional D-I space wherein simple, sensitivity, and double dissociations appear as distinct curve patterns. While Stockart et al.'s recommendations cover only a single line of that space where D is close to zero, functional dissociations can utilize the entire space. This circumvents requirements like null visibility and exhaustive reliability, allows for dissociations among different measures of awareness, and supports the planful measurement of functional relationships between direct and indirect measures.}, }
@article {pmid41545942, year = {2026}, author = {Sun, W and Luan, H and Li, S and Wang, P and Gong, J and Xu, C and Han, X and Wen, B and Lv, S and Wei, C}, title = {Circulating adipokines level and the risk of neurodegenerative diseases: a two‑sample mendelian randomization study and proteomic analysis.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {90}, pmid = {41545942}, issn = {1471-2377}, support = {2017YFC1310103//the National Key Research and Development Program of China/ ; 2021ZD0201802//the STI2030-Major Projects/ ; }, abstract = {BACKGROUND: Observational studies have suggested associations between circulating adipokines and neurodegenerative diseases, but the causal nature of these relationships remains unclear. This study evaluated the causal effects of adipokines on neurodegenerative diseases using Mendelian randomization (MR) and validated key findings through proteomic analysis.<br><br>METHODS: Two-sample MR was performed using genome-wide association study (GWAS) summary statistics for adiponectin (N&#x2009;=&#x2009;39,883), leptin (N&#x2009;=&#x2009;57,232), resistin (N&#x2009;=&#x2009;21,758), and monocyte chemoattractant protein-1 (MCP-1; N&#x2009;=&#x2009;21,758). Outcomes included Alzheimer&#x2019;s disease (AD; N&#x2009;=&#x2009;63,926), Parkinson&#x2019;s disease (PD; N&#x2009;=&#x2009;482,730), and amyotrophic lateral sclerosis (ALS; N&#x2009;=&#x2009;36,052). The inverse-variance weighted (IVW) method was applied for primary causal estimates, with sensitivity analyses assessing pleiotropy and heterogeneity. Significant MR findings were further examined in a proteomic cohort.<br><br>RESULTS: Higher genetically predicted adiponectin levels were significantly associated with a reduced risk of AD (odds ratio [OR]&#x2009;=&#x2009;0.79, 95% confidence interval [CI]&#x2009;=&#x2009;0.65&#x2013;0.96, p&#x2009;=&#x2009;0.019). This association remained robust across multiple sensitivity analyses, with no evidence of horizontal pleiotropy or heterogeneity. By contrast, no causal relationships were identified for leptin, resistin, or MCP-1 with the risk of AD, PD, or ALS. Complementing the genetic findings, proteomic analysis further revealed that plasma adiponectin levels were downregulated in mild cognitive impairment patients who experienced cognitive deterioration compared with those showing cognitive improvement.<br><br>CONCLUSION: The findings provide genetic evidence supporting a potential protective role of adiponectin in AD, with the proteomic results offering complementary, directionally consistent support. Adiponectin may represent a potential biomarker and therapeutic target for AD.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-026-04636-8.}, }
@article {pmid41546756, year = {2026}, author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Milani, S and Coleman, MP and Barmada, SJ and Sreedharan, J}, title = {Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {370}, pmid = {41546756}, issn = {1559-1182}, mesh = {Animals ; Humans ; *DNA-Binding Proteins/metabolism/toxicity ; *Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/metabolism ; *Caspases/metabolism ; Mice ; Neurons/drug effects/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Phosphorylation/drug effects ; Amyotrophic Lateral Sclerosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by TAR DNA-binding protein 43 kDa (TDP-43) pathology. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. We show that TDP-43 activates GSK3 and promotes caspase-dependent cleavage of TDP-43, generating C-terminal fragments. We determine the functional importance of the N-terminal Asp89 caspase cleavage site in regulating TDP-43 proteostasis in both wild-type and ALS-linked TDP-43 variants and show that GSK3 inhibition selectively reduces truncated TDP-43 species, lowers nuclear TDP-43 levels, and improves neuronal survival. Neuroprotective effects were conserved in primary rodent cortical neurons, primary mouse motor neurons, and human iPSC-derived cortical neurons, highlighting the potentially broad therapeutic potential of GSK3 inhibition. We also find that the GSK3 inhibitor CHIR99021 reduces GSK3 RNA and protein expression and increases GSK3 phosphorylation, indicating novel mechanisms by which it acts to inhibit GSK3 activity. Unexpectedly, an N-terminally truncated variant (TDP-43[N-Del]), originally designed as a negative transfection control, exerted modest toxicity, potentially through retained susceptibility to caspase cleavage. Together, our findings uncover a caspase-mediated mechanism linking GSK3 activity to TDP-43 turnover, localisation, and neurotoxicity, and position GSK3 inhibition as a promising strategy to mitigate TDP-43-driven neurodegeneration in ALS-FTD.}, }
@article {pmid41546910, year = {2026}, author = {Elyasi, L and Wężyk, M}, title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {195}, number = {}, pages = {119001}, doi = {10.1016/j.biopha.2026.119001}, pmid = {41546910}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics/metabolism ; *Tooth, Deciduous/cytology/metabolism ; *Exosomes/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; Animals ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.}, }
@article {pmid41547243, year = {2026}, author = {Dorothy Wong, ZY and Kang, X and Shi, Y and Fan, R and Zhang, C and Min, D and Sun, N and Ma, Y and Tang, ML}, title = {Autophagy-tethering compounds (ATTECs) as an emerging and potentially transformative drug discovery approach.}, journal = {European journal of medicinal chemistry}, volume = {305}, number = {}, pages = {118585}, doi = {10.1016/j.ejmech.2026.118585}, pmid = {41547243}, issn = {1768-3254}, mesh = {Humans ; *Autophagy/drug effects ; *Drug Discovery ; Lysosomes/metabolism/drug effects ; Proteolysis/drug effects ; Molecular Structure ; Animals ; }, abstract = {Targeted protein degradation (TPD) strategies leveraging the ubiquitin-proteasome system (UPS), such as proteolysis-targeting chimeras (PROTACs), have gained wide recognition. While the UPS predominantly degrades short-lived soluble proteins, the lysosome-mediated system (LMS) excels at processing larger substrates, including protein aggregates, organelles, and macromolecular complexes. Recently, autophagy-tethering compounds (ATTECs) have emerged as a promising strategy for targeted degradation, harnessing the autophagy-lysosome system (ALS) to enable proximity-induced degradation. These heterobifunctional molecules, composed of LC3-binding warheads and TOI (target of interest) ligands linked together, provide therapeutic potential against disease-causing targets. This review outlines the therapeutic applications of ATTECs in human diseases, highlights recent progress in their development, and explores future opportunities for expanding this emerging class of degradation technologies through ALS from medicinal chemistry perspective.}, }
@article {pmid41547996, year = {2026}, author = {Iacono, D and Murphy, EK and Perl, DP and Day, RM}, title = {γ-Radiation induces region-specific subcellular alterations of amyotrophic lateral sclerosis and frontotemporal dementia markers in swine brain.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {5627}, pmid = {41547996}, issn = {2045-2322}, support = {312516-1.00-66721//DoW/USU Brain Tissue Repository and Neuropathology Research Program/ ; DM178018//US Defense Medical Research and Development Program/ ; }, mesh = {Animals ; Swine ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/etiology ; *Brain/metabolism/radiation effects/pathology ; Male ; *Gamma Rays/adverse effects ; Biomarkers/metabolism ; *Frontotemporal Dementia/metabolism/pathology/etiology ; Swine, Miniature ; }, abstract = {Low-dose radiation (LDR) effects on the brain have been poorly investigated. Studies have also questioned whether radiation increases ALS risk. We assessed the expression levels of a series of proteins associated with ALS and ALS-FTD in the brains of swine exposed to low-dose radiation to explore this notion. Male Gottingen minipigs were exposed to a single total-body γ-radiation (1.79 Gy). After 28 days, brains from 9 RAD to 6 SH animals were collected. Using neuroanatomically based dissection and Western Blotting, we compared levels of ALS/ALS-FTD markers (SOD1, FUS/TLS, C9orf72, STMN2, ubiquitin, TDP43 (N and C terminal), and pTDP43) in RAD vs. SH animals in frontal cortex (FCtx), striatum (Str), hippocampus (Hip), thalamus/hypothalamus (Thal/Hyp), and cerebellum (Cere). Cytosolic FUS/TLS decreased in the Thal/Hyp and remained unchanged in all other regions; nuclear levels increased in the FCtx and decreased in the Hip of RAD vs. SH. Cytosolic C9orf72 remained unchanged across all brain regions; nuclear levels decreased in the Hip of RAD vs. SH. Cytosolic STMN2 remained unchanged in all brain regions and decreased in the nuclear fraction of the Hip of RAD vs. SH. Cytosolic and nuclear ubiquitin remained unchanged across brain regions, except for an increase in the FCtx. TDP-43 (N and C terminal) levels remained unchanged in cytosolic and nuclear fractions across all brain regions; finally, cytosolic pTDP43 (S403/404) increased in the FCtx, Str and Thal/Hyp of RAD vs. SH. LDR-induced ALS/ALS-FTD-marker changes differ across brain regions and subcellular compartments. These changes are not necessarily associated with increased activation or potentiation of the main molecular processes associated with ALS pathogenesis; surprisingly, they may produce beneficial effects.}, }
@article {pmid41548000, year = {2026}, author = {Potla, KM and Cheerlin Mishma, JN and Vankayalapati, S and Suchetan, PA and Sebastian, R and Gayatri, B and Tawfeek, AM and Alam, M and Islam, MS}, title = {Comprehensive analysis of florasulam: crystal structure, reactivity, sensitivity, and bioactivity using structural, spectroscopic, and computational approaches.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3416}, pmid = {41548000}, issn = {2045-2322}, abstract = {UNLABELLED: The title compound, N-(2,6-difluorophenyl)-8-fluoro-5-methoxy-[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonamide (Florasulam), a triazolopyrimidine sulfonanilide herbicide, was investigated using experimental and computational techniques. Single-crystal X-ray diffraction revealed a V-shaped geometry stabilized by intramolecular C–F···π interactions and a unique 1D ribbon packing formed through N–H···N, C–H···O, and S = O···π interactions. Hirshfeld surface and energy framework analyses confirmed the nature and strength of intermolecular forces. DFT and TD-DFT calculations provided insights into optimized geometry, vibrational frequencies, and electronic transitions consistent with experimental spectra. The HOMO–LUMO gap indicated high chemical stability, while MEP analysis highlighted reactive sites. Autoxidation susceptibility was assessed through bond dissociation energies. Molecular docking against ALS (Acetolactate Synthase) proteins demonstrated strong binding affinity, supported by molecular dynamics simulations confirming protein–ligand complex stability. This integrative study highlights Florasulam’s potential in herbicide design.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-33458-w.}, }
@article {pmid41548100, year = {2026}, author = {Colgrove, N and Snyder, M}, title = {Abortion and Infant Mortality: Termination Does Not Prevent Death.}, journal = {The New bioethics : a multidisciplinary journal of biotechnology and the body}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/20502877.2025.2589634}, pmid = {41548100}, issn = {2050-2885}, abstract = {Alison Gemmill et al. claim that infant mortality in Texas increased following its 2021 abortion restrictions, and several sources reported that abortion restrictions harm infants. This is misleading. Gemmill et al.'s findings show that infant deaths increased primarily because abortion for "congenital anomalies" decreased, and a subset of those subjects died in infancy. In other words, infant mortality rose because fetal mortality fell. By analogy, one can reduce teenage deaths by causing deaths before age thirteen, but this does not save lives. Likewise, abortion restrictions may lead to more infants dying (since fewer subjects are aborted), but this does not imply that abortion restrictions harm infants. The opposite seems true. We argue that it is reasonable to regard Texas's abortion restrictions as a net benefit for infants. We also highlight ableist assumptions surrounding Gemmill et al.'s study and call for bipartisan efforts to support people with disabilities and their families.}, }
@article {pmid41548719, year = {2026}, author = {Li, X and Wan, R and Zhao, Y and Wu, Y and Chen, X and Li, Q and Luo, C}, title = {Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention.}, journal = {Ageing research reviews}, volume = {115}, number = {}, pages = {103028}, doi = {10.1016/j.arr.2026.103028}, pmid = {41548719}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; *Synapses/pathology/metabolism/physiology ; Animals ; Neuronal Plasticity/physiology ; Synaptic Transmission/physiology ; *Aging/pathology ; }, abstract = {Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and age-related neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). This damage emerges prior to the demise of neuronal cell bodies and the manifestation of clinical symptoms, with its location and severity directly shaping disease phenotypes. Importantly, such synaptic dysfunction is closely linked to the pathological proteins specific to each disorder. This review comprehensively synthesizes current research advances regarding synaptic impairment in age-related neurodegenerative diseases. It elaborates on the location-specific pathological features of synaptic damage in AD, PD, HD, and ALS, with particular emphasis on their associations with disease-related pathological markers. Additionally, the work unpacks five core mechanisms driving synaptic dysfunction: the toxic effects of pathological proteins, dysregulated synaptic protein homeostasis, excitotoxicity coupled with disrupted calcium balance, oxidative stress and inflammatory responses, and deficiencies in neurotrophic factors. Ultimately, it summarizes potential biomarkers and targeted intervention strategies, aiming to provide a systematic reference for mechanistic investigations, early diagnosis, and clinical management of neurodegenerative diseases.}, }
@article {pmid41548740, year = {2026}, author = {Qaisar, R}, title = {Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.}, journal = {Neuroscience}, volume = {597}, number = {}, pages = {13-26}, doi = {10.1016/j.neuroscience.2026.01.015}, pmid = {41548740}, issn = {1873-7544}, mesh = {*Neuromuscular Junction/physiopathology/pathology/physiology ; Humans ; Animals ; *Muscle Fibers, Slow-Twitch/physiology/pathology ; *Muscle Fibers, Fast-Twitch/physiology/pathology ; }, abstract = {The neuromuscular junction (NMJ) is a specialized synapse essential for translating neuronal signals into muscle contraction. This review examines the complex structural, functional, and molecular differences in NMJs that innervate fast- and slow-twitch skeletal muscle fibers. Fast-twitch fibers, optimized for rapid and powerful contractions, possess elaborate NMJs with deep folds, high neurotransmitter turnover, and greater vulnerability to synaptic fatigue and degeneration. In contrast, slow-twitch fiber NMJs exhibit simpler but more stable architectures that support sustained, fatigue-resistant activity. These differences are not fixed but subject to activity-dependent plasticity and pathological remodeling. Chronic stimulation, injury, and aging influence NMJ morphology, with fast-twitch junctions more prone to degeneration in conditions such as ALS, myasthenia gravis, and diabetic neuropathy. Slow-twitch NMJs often resist early deterioration due to superior trophic support, metabolic stability, and more robust expression of synaptic organizers, such as agrin and PGC-1α. Several key signaling pathways, including agrin-MuSK-LRP4, Wnt/β-catenin, and neuregulin/ErbB, govern NMJ maintenance with fiber-type-specific nuances. These insights underscore the importance of tailoring therapeutic strategies to the muscle fiber phenotype. Gene therapies, neuromuscular electrical stimulation, and biomaterial scaffolds are emerging as promising modalities for preserving or restoring NMJ integrity, especially in fast-twitch fibers at higher risk of degeneration. Understanding fiber-type-specific NMJ biology enhances our understanding of motor control, muscle aging, and neuromuscular disease progression, and it opens pathways for precision therapeutics that target vulnerable synapses with structural and functional specificity. This review introduces a novel perspective by emphasizing fiber-type-specific NMJ differences and their implications for targeted therapies.}, }
@article {pmid41549027, year = {2026}, author = {Shenouda, M and Shenouda, S and Kartono, B and Eid, S and Cheng, C and Robertson, J}, title = {Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00834}, pmid = {41549027}, issn = {1878-7479}, mesh = {Humans ; Animals ; *beta Karyopherins/metabolism ; *DNA-Binding Proteins/metabolism ; Mice ; Neurons/drug effects/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *Molecular Chaperones/metabolism ; *TDP-43 Proteinopathies/metabolism/drug therapy ; Male ; Cells, Cultured ; }, abstract = {Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.}, }
@article {pmid41551521, year = {2026}, author = {Xu, S and Lu, GR}, title = {Potential of lysine succinylation as a therapeutic target for gallstone formation: An insightful strategy.}, journal = {World journal of gastroenterology}, volume = {32}, number = {1}, pages = {114865}, pmid = {41551521}, issn = {2219-2840}, mesh = {Animals ; Humans ; Mice ; AMP-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Gallbladder/pathology/cytology ; *Gallstones/pathology/metabolism/prevention &amp; control/etiology/drug therapy ; *Lysine/metabolism ; Protein Processing, Post-Translational/drug effects ; Signal Transduction/drug effects ; Succinic Acid/metabolism ; }, abstract = {Cholelithiasis has a complex pathogenesis, necessitating better therapeutic and preventive strategies. We recently read with interest Wang et al's study on lysine acetyltransferase 2A (KAT2A)-mediated adenosine monophosphate-activated protein kinase (AMPK) succinylation in cholelithiasis. Using mouse models and gallbladder mucosal epithelial cells, they found that KAT2A inhibits gallstones through AMPK K170 succinylation, thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis. This study is the first to connect lysine succinylation with cholelithiasis, offering new insights and identifying succinylation as a potential therapeutic target. Future research should confirm these findings using patient samples, investigate other post-translational modifications, and use structural biology to clarify succinylation-induced conformational changes, thereby bridging basic research to clinical applications.}, }
@article {pmid41551727, year = {2026}, author = {Singh, S and Singh, P and Varada, MP and Vijaivasudev, MJ and Kumar, R and Malik, I}, title = {eVGeMdb: a manually curated database for experimentally validated genetic modifiers of neurodegenerative disorders.}, journal = {NAR molecular medicine}, volume = {3}, number = {1}, pages = {ugaf044}, pmid = {41551727}, issn = {2976-856X}, abstract = {Genetic modifiers are genes that, while not directly causing disease, can alter the onset, progression, severity, or specific phenotypes of a disease by interacting with the primary disease-causing genes. Despite their importance, knowledge of these modifiers remains fragmented across different experimental models of neurodegenerative disorders (NDs). To address this lacuna, we developed eVGeMdb (https://project.iith.ac.in/cgntlab/eVGeMdb/), a manually curated, comprehensive database of experimentally validated genetic modifiers of major NDs, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinocerebellar ataxias, Fragile X-associated Tremor/Ataxia Syndrome, and other general PolyQ disorders. eVGeMdb integrates modifiers from commonly used diverse experimental model systems, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, cellular models (human, mice, Drosophila cells), and mouse. The database currently incorporates over 17000 entries, each annotated with experimental context, gene-specific functional information, relevant human orthologs, and links to protein-protein interaction networks and enriched pathways. The resource enables cross-disease and model-specific comparisons, allowing the identification of both universal and disease-specific modifiers. By consolidating dispersed genetic modifier information into a single, accessible platform, eVGeMdb provides a comprehensive tool for researchers in the field to explore modifier effects, prioritize experimental validations, formulate novel hypotheses, and investigate pathophysiological mechanisms underlying neurodegenerative disorders.}, }
@article {pmid41552526, year = {2026}, author = {Turcatel, GA and Moura, S}, title = {Glutamate Receptor Agonists as Triggers of Neurotoxicity: Decoding Pathways of Five Neurotoxins and Potential Therapeutic Targets.}, journal = {ACS omega}, volume = {11}, number = {1}, pages = {70-81}, pmid = {41552526}, issn = {2470-1343}, abstract = {l-Glutamate (l-Glu) is one of the primary excitatory neurotransmitters in the nervous system, functioning through both ionotropic and metabotropic receptors. The release of l-Glu into the synaptic cleft, its interaction with receptors, and its reuptake are meticulously regulated by excitatory amino acid transporters. The structural similarity of various compounds to l-glutamate is crucial to their ability to interact with NMDA, AMPA, and kainate receptors. These interactions can significantly influence neural communication and function. Overstimulation of these receptors, which operate as ion channels, results in an increased level of calcium ion influx, a phenomenon known as excitotoxicity, which is often linked to neurodegeneration. Many neurodegenerative conditions are linked to both acute and chronic exposures to neurotoxins, whether they originate within the body (endogenous) or from external sources (exogenous). These neurotoxins often function as l-glutamate receptor agonists, potentially contributing to the progression of these diseases. This perspective focuses on key neurotoxins, including β-N-methylamino-l-alanine (l-BMAA), quinolinic acid (QUIN), domoic acid, β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP), homocysteine (Hcy), and l-homocysteate, all of which exhibit complementary mechanisms of action. We will explore their structural characteristics and mechanisms through which they induce neurotoxicity. Understanding the neurotoxic mechanisms of these compounds is essential for elucidating the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis, neurolathyrism, and amnesic shellfish poisoning. This review summarizes the findings of 64 studies to clarify these relationships involving classic events associated with neurodegeneration such as mitochondrial damage, oxidative stress, and activation of proapoptotic pathways. In summary, the distinctive properties of these neurotoxins provide valuable insights that could help in the development of future therapeutic drugs aimed at treating and alleviating the effects of neurodegenerative diseases. Understanding how these neurotoxins interact with neuronal pathways can guide researchers in designing more effective interventions.}, }
@article {pmid41552817, year = {2025}, author = {Chen, Y and Xiao, W and Qian, C and Huang, L and Lv, J and Wang, Z and Luo, Y}, title = {System Xc-pathway as a potential regulatory target in neurological disorders.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1701320}, pmid = {41552817}, issn = {1663-9812}, abstract = {The System Xc-pathway is composed of the 12-transmembrane transporter protein SLC7A11 (xCT) and the single-channel transmembrane protein SLC3A2 (CD98hc). We detail the pathway's characteristics and distribution within the central nervous system, as well as its canonical role in maintaining glutathione synthesis and inhibiting ferroptosis, and its emerging non-canonical functions in metabolic coupling and neuroimmunity. A core theme is the pathway's context-dependent and often paradoxical role across major neurological disorders, including ischemic stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Critically, we analyze how pathological activation of N-methyl-D-aspartate receptors (NMDARs) can dysregulate System Xc-through mechanisms involving calcium overload, reactive oxygen species, and specific signaling axes (e.g., Nrf2, PP2A/AMPK/HMGB1), thereby exacerbating excitotoxicity and oxidative damage. Conversely, System Xc-dysfunction can further fuel NMDAR-mediated injury, creating vicious pathogenic cycles. This analysis reveals that System Xc-is not a unitary target but a dynamic node within a complex network. Consequently, effective therapeutic strategies must move beyond broad inhibition and instead aim for nuanced, cell-type-specific, and disease-stage-precise modulation. This approach will selectively correct the dysfunction of System Xc-while preserving its essential physiological roles. It presents both a significant challenge and a promising frontier for future neuroprotective drug development.}, }
@article {pmid41553037, year = {2026}, author = {Shahid, N and Azhar, L and Hussain, I and Khan, MS}, title = {Emerging Alzheimer's therapies: clinical efficacy versus economic feasibility.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/17582024.2026.2617857}, pmid = {41553037}, issn = {1758-2032}, }
@article {pmid41553108, year = {2026}, author = {Rudnicki, SA and Giacomelli, E and Herder, K and Ingre, C and Kupfer, S and Malik, FI and Meng, L and Paganoni, S and Schellenberg, K and Scirocco, E and Simkins, T and Wei, J and Shefner, JM and , }, title = {The Use of Durable Medical Equipment in COURAGE-ALS, a Phase 3, Multicentre, Randomized Clinical Trial for ALS.}, journal = {Muscle &amp; nerve}, volume = {73}, number = {4}, pages = {608-614}, doi = {10.1002/mus.70150}, pmid = {41553108}, issn = {1097-4598}, support = {//Cytokinetics, Incorporated/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; Middle Aged ; Double-Blind Method ; Aged ; *Durable Medical Equipment ; Noninvasive Ventilation/instrumentation ; *Wheelchairs ; Treatment Outcome ; Canada ; }, abstract = {INTRODUCTION/AIMS: Durable medical equipment (DME)-wheelchairs, non-invasive ventilation, gastrostomy tubes, and communication devices-provides vital support for individuals with amyotrophic lateral sclerosis (ALS). Here, we describe DME use in COURAGE-ALS evaluating reldesemtiv's efficacy and safety in ALS, to evaluate if DME use can be considered an endpoint of interest in ALS trials.<br><br>METHODS: COURAGE-ALS, a multicentre, double-blind, randomized, placebo-controlled clinical trial was conducted at 83 sites in the United States, Canada, Europe, and Australia. Participants were randomized 2:1 to receive reldesemtiv or placebo for 24&#x2009;weeks, followed by 24&#x2009;weeks of active drug treatment. Exploratory outcomes included reasons for prescribing, extent of use, DME types, and regional differences.<br><br>RESULTS: Among 482 participants, 166 (34.4%) were using at least one DME item at baseline. Among 276 participants completing study visits through Week 24, 130 (47.1%) initiated use of a total of 188 new DME items post-baseline through 24&#x2009;weeks. Manual wheelchairs were most used at baseline (89 items) and initiated (47 items) during the trial. Both baseline DME use and initiating a new item were associated with lower ALS Functional Rating Scale-Revised scores and worse quality of life. The trial was terminated early due to futility. Treatment assignment did not impact DME use. Regional disparities were noted.<br><br>DISCUSSION: This study shows that DME is commonly prescribed to ALS trial participants. Further understanding of geographic differences in DME access and their impact on clinical outcomes is warranted prior to including DME use as an endpoint in ALS trials.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT04944784).}, }
@article {pmid41553204, year = {2026}, author = {Sánchez-Lloria, P and Barcala-Furelos, R and Otero-Agra, M and Aranda-García, S and Martínez-Isasi, S and Muñoz-Barús, I and Rodríguez-Núñez, A and Iglesias-Vázquez, JA}, title = {[Intentional drowning as a method of self-inflicted injury and suicide: a 21-year analysis of Galicia].}, journal = {Revista espanola de salud publica}, volume = {100}, number = {}, pages = {}, pmid = {41553204}, issn = {2173-9110}, mesh = {Humans ; Female ; Male ; Retrospective Studies ; Adult ; Middle Aged ; *Drowning/epidemiology ; Spain/epidemiology ; Adolescent ; Young Adult ; Aged ; Child ; Child, Preschool ; Aged, 80 and over ; Longitudinal Studies ; Infant ; *Self-Injurious Behavior/epidemiology ; *Suicide/statistics &amp; numerical data ; *Suicide, Attempted/statistics &amp; numerical data ; }, abstract = {OBJECTIVE: Drowning and suicide are interconnected complex phenomena and represent significant Public Health issues. The aim of this paper was to identify and describe the characteristics and factors associated with intentional drownings in Galicia (Spain), analyzing a retrospective cohort of twenty-one years.<br><br>METHODS: A descriptive, retrospective, and longitudinal study (2001-2021) was conducted analyzing a cohort of patients aged 0 to 100 years who were treated by Basic and Advanced Life Support (BLS/ALS) units of the FPUS 061 and by hospitals within the Galician Health Service (SERGAS). Records coded with a diagnosis of drowning or near-drowning were included and were recoded as fatal or non-fatal drowning according to international recommendations. Additionally, records containing the terms suicide, self-harm, or suicide attempt in prehospital or hospital documentation were also included.<br><br>RESULTS: Ninety-nine cases were documented, representing 9% of all drownings in Galicia and 14% of individuals aged over sixty five who drowned. Eighty-two percent of the victims were residents of the municipality where the incident occurred, and 60% were women. Ninety-nine percent had a prior diagnosis of mental health disorder. Individuals over sixty five accounted for 53% of the cases, with a mortality rate of 50%. The presence of witnesses was associated with lower mortality.<br><br>CONCLUSIONS: There is a relationship between intentional drownings and mental health disorders. In these events, the presence of witnesses is a protective factor, while advanced age is a risk factor for mortality. Intentional drowning is a complex and understudied health issue, so prevention and Public Health strategies should be implemented to reduce these preventable deaths.}, }
@article {pmid41553546, year = {2026}, author = {Dey, A and Baumeister, TR and Evans, KC and Koppelmans, V and Luk, C and McLaren, DG and Parnianpour, P and Seres, P and Kalra, S and , }, title = {Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {87}, pmid = {41553546}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/classification/drug therapy ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: In a clinically-heterogeneous disease such as ALS, it is crucial to identify early disease changes that impair real-world functioning. The lack of consensus across clinical approaches, coupled with the subjectiveness of their evaluation, impedes our understanding of disease processes underlying early and advanced disease. This study presents neuroimaging as a potential supplementary approach that provides objectivity to the identification and evaluation of disease stage-specific ALS subgroups.<br><br>METHODS: Cerebral functional connectivity and its association with clinical function was evaluated in 174 ALS patients and 165 healthy controls enrolled in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants were subgrouped using two approaches: (1) a data-driven hierarchical clustering of cerebral activation and 2) contemporary clinical criteria. The data-driven approach utilized data from resting-state functional magnetic resonance imaging. The clinical approach utilized three clinical subgrouping methods - two derived from trial enrollment criteria for the drugs Riluzole and Edaravone, and the third on the median disease progression rate of the patient sample.<br><br>RESULTS: Each subgrouping approach identified two patient subgroups with different symptom durations, disease progression rates, and cognitive/motor/lung functions - albeit with differences across approaches. The data-driven approach identified greater spatial extents of cerebral connectivity alterations compared to the clinical approaches.<br><br>CONCLUSION: Observations of clinical and cerebral connectivity differences were specific to the stratification approach. Given the ability of the data-driven approach to identify alterations in both clinical and cerebral function corresponding to disease stage, this approach presents a potential biomarker for patient stratification, clinical trial enrichment, disease and therapeutic monitoring.}, }
@article {pmid41553588, year = {2026}, author = {Bjørklund, G and Butnariu, M and Caunii, A and Peana, M}, title = {Metallothioneins in Neurodegenerative Diseases: Metal Homeostasis, Autoimmunity, and Therapeutic Potential.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {373}, pmid = {41553588}, issn = {1559-1182}, mesh = {Humans ; *Homeostasis/physiology ; *Metallothionein/metabolism ; *Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy ; *Autoimmunity/physiology ; Animals ; *Metals/metabolism ; }, abstract = {Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.}, }
@article {pmid41554189, year = {2026}, author = {Pehlivanova, M and Lange, R and Greyson, B and Houran, J}, title = {Operationalizing near‑death experiences: Stability of the NDE Rasch hierarchy over two decades.}, journal = {Consciousness and cognition}, volume = {139}, number = {}, pages = {103979}, doi = {10.1016/j.concog.2025.103979}, pmid = {41554189}, issn = {1090-2376}, mesh = {Humans ; *Psychometrics/instrumentation/standards ; Female ; Male ; Adult ; Middle Aged ; Young Adult ; *Death ; Aged ; }, abstract = {This study presents the first comprehensive psychometric comparison of Greyson's (1983) 16-item Near-Death Experience Scale (NDE Scale) and Martial et al.'s (2020) 20-item Near-Death Experience Content Scale (NDE-C) using Rasch modeling and differential item functioning (or response bias) analyses. A total of 705 self-identified "near-death experiencers" (64% women) completed both measures, which were randomly intermingled and rated for experiential relevance. Results confirmed that the two scales measure the same underlying construct of NDE phenomenology, as evidenced by a near-perfect disattenuated Pearson correlation (r = 0.98, p < 0.001). However, Rasch analysis revealed limitations in the category structures of both scales-particularly the NDE-C-and identified psychometric and conceptual weaknesses in its five novel items. Critically, the core Rasch item hierarchy derived from the original NDE Scale was replicated both in this sample and a previously simulated dataset based on the NDE-C's development research, confirming its long-term structural stability. Based on the present evidence and the principle of parsimony, we recommend the original NDE Scale supported by Rasch scoring and a validated cut-off of 7 (out of 32), as it is conceptually coherent and psychometrically robust, while maintaining historical comparison with previous research. These findings reinforce the value of Rasch modeling for cumulative theory-building and underscore the Rasch NDE hierarchy's foundational role in operationalizing legitimate near-death experiences.}, }
@article {pmid41554495, year = {2026}, author = {Phillips, EM and Edwards, JG and Aiello, L and Gilliam, CA and Seltz, LB and Spencer, DJ and Rassbach, CE}, title = {The Effect of Mistreatment From Patients and Families on Pediatric Resident Professional Identity Formation.}, journal = {Academic pediatrics}, volume = {26}, number = {3}, pages = {103221}, doi = {10.1016/j.acap.2026.103221}, pmid = {41554495}, issn = {1876-2867}, abstract = {OBJECTIVE: Mistreatment by patients and families is linked to adverse patient outcomes and physician burnout, and particularly affects women and underrepresented in medicine (UIM) physicians. We sought to explore how this source of mistreatment affects trainee professional identity formation (PIF), a key process in the development of altruistic physicians.<br><br>METHODS: We conducted this multi-institutional qualitative study between May and October 2023 with semistructured interviews of pediatric residents. We used the constant comparative method consistent with modified grounded theory to analyze data through a lens of Cruess et al's model of PIF in medicine.<br><br>RESULTS: We interviewed 32 pediatric residents and identified 4 primary themes, which we used to develop a conceptual model. 1) Residents identify patient- and family-centered care as core to their professional identity, while acknowledging their vulnerability to mistreatment from patients and families. 2) Mistreatment threatens resident PIF through fractured patient-provider relationships, negative impacts on patient care, and decreased psychological safety of the learning environment. 3) Mistreatment that is frequent, unaddressed, and centered around personal traits is particularly damaging to PIF. 4) Residents employ various strategies to mitigate the negative impacts of mistreatment and ultimately deepen their professional identity.<br><br>CONCLUSIONS: Mistreatment from patients and families negatively affects pediatric residents' well-being, learning, and professional identity, with particular impacts on women and UIM residents. Our study informs ways that institutions can best structure support to navigate mistreatment while optimizing trainee learning and PIF, along with patient care.}, }
@article {pmid41555948, year = {2026}, author = {Deniz, R and Çiftçi, B}, title = {Emphasizing the biopsychosocial dimension in post-traumatic orthopedic recovery.}, journal = {World journal of psychiatry}, volume = {16}, number = {1}, pages = {115015}, pmid = {41555948}, issn = {2220-3206}, abstract = {Chronic pain and disability following acute orthopedic trauma are not only physical concerns but also deeply intertwined with psychological well-being. The recent retrospective cohort study by Yang et al, published, provides compelling evidence of significant associations between depression, anxiety, and postoperative recovery. These findings align with an expanding body of literature that confirms the need for orthopedic rehabilitation to adopt a biopsychosocial perspective. This letter contextualizes Yang et al's study within current evidence, highlighting the roles of sleep disturbance, catastrophizing, stress, neurobiological mechanisms, and coping strategies in shaping recovery. It further emphasizes the importance of integrating nursing-led and multidisciplinary interventions to address both physical and psychological domains, ultimately promoting holistic recovery.}, }
@article {pmid41556284, year = {2026}, author = {Cao, W and Yu, L and Wang, Z and Deng, B and Fan, D}, title = {Neutrophil-Secreted Enzymes and ALS Risk: Exploring a Potential Mechanistic Link.}, journal = {Annals of neurology}, volume = {99}, number = {3}, pages = {591-605}, doi = {10.1002/ana.78161}, pmid = {41556284}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/enzymology/epidemiology/blood ; Female ; Male ; *Neutrophils/enzymology ; Middle Aged ; Aged ; Neurofilament Proteins/blood/metabolism ; Biomarkers/blood ; Risk Factors ; }, abstract = {OBJECTIVE: Peripheral immunity plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously showed that elevated neutrophil counts are associated with increased risk of ALS occurrence and faster disease progression, potentially through axonal damage. However, the mechanisms linking neutrophils to ALS occurrence remain unclear. Neutrophil-secreted enzymes, key markers of neutrophil activity, may mediate these effects. We therefore investigated the role of neutrophil-secreted enzymes in ALS occurrence.<br><br>METHODS: Six neutrophil-secreted enzymes were selected from the UK Biobank-Proteomics Platform. Cox proportional hazards regression was used to examine associations between these enzymes and ALS occurrence. Multiple sensitivity analyses were conducted to ensure robustness. Stratified analyses evaluated potential effect modifications by age, sex, and body mass index (BMI). To investigate whether neutrophil-secreted enzymes contribute to ALS occurrence via a "dying-back" mechanism, mediation analysis was performed to assess the indirect effect of neurofilament light chain (NfL) levels in this relationship.<br><br>RESULTS: Individuals who later developed ALS showed significantly higher levels of neutrophil-secreted enzymes prior to disease onset, suggesting that neutrophil activation occurs before ALS occurrence. Elevated enzyme levels were associated with an increased risk ALS occurrence. Furthermore, we observed a linear positive correlation between enzyme levels and NfL concentrations. Mediation analysis indicated that the effects of MPO and S100A12 on ALS onset were partially mediated through axonal injury.<br><br>INTERPRETATION: Elevated neutrophil-secreted enzymes are associated with an increased risk of ALS occurrence. This finding provides mechanistic insight into neutrophil involvement in ALS and identifies these enzymes as potential therapeutic targets. ANN NEUROL 2026;99:591-605.}, }
@article {pmid41556400, year = {2026}, author = {Howard, I and Lyerly, M and Reimer, R and Patwa, H and Darling, L}, title = {Symptom Burden and Care Satisfaction in US Military Veterans With ALS: Results of a National Survey.}, journal = {Muscle &amp; nerve}, volume = {73}, number = {4}, pages = {623-629}, doi = {10.1002/mus.70147}, pmid = {41556400}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology ; United States/epidemiology ; *Veterans/psychology ; Male ; Female ; Middle Aged ; *Patient Satisfaction ; Aged ; United States Department of Veterans Affairs ; Surveys and Questionnaires ; Adult ; *Cost of Illness ; Symptom Burden ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) affects military veterans at a higher rate than the general civilian population. The aim of the present study is to assess symptom burden and satisfaction with care among persons with ALS care enrolled in the US Veterans Health Administration (VA).<br><br>METHODS: A custom online survey was created with questions about symptom prevalence and management as well as care satisfaction. A survey link was sent by email to all veterans with an ICD-10 diagnosis of ALS in the VA for whom an email address was available in the electronic health record.<br><br>RESULTS: Responses were received from 413 individuals (16% response rate). Respondents reported high care satisfaction and higher prevalence of treatment of symptoms compared to prior surveys of persons with ALS in the United States. Self-reported outcomes, including treatment, education, and satisfaction, were better for Veterans receiving care exclusively within the VA compared to those receiving care at both VA and non-VA facilities or receiving care exclusively at non-VA facilities. Areas for further improvement identified in the survey include education on genetic testing and research and management of non-motor symptoms.<br><br>DISCUSSION: This survey indicates that, overall, veterans with ALS receive comprehensive symptom-based care within the nationalized VA care system and report high levels of satisfaction. Furthermore, this study provides baseline data and findings that may be used for quality improvement efforts across a large healthcare system and may serve as a model for similar efforts in other health systems.}, }
@article {pmid41557054, year = {2026}, author = {Shi, Y and Wang, H and Chen, J and Ren, J and Sun, X and Qu, M and Zhao, T and Han, C and Yuan, J and Meng, F and Lu, L}, title = {α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in Olfactory Bulb.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {378}, pmid = {41557054}, issn = {1559-1182}, mesh = {*alpha-Synuclein/deficiency/metabolism/genetics ; Animals ; *TOR Serine-Threonine Kinases/metabolism ; *Signal Transduction/physiology ; *Olfactory Bulb/metabolism/pathology ; *Autophagy/physiology ; Mice, Knockout ; *Phosphatidylinositol 3-Kinases/metabolism ; *Olfaction Disorders/pathology/metabolism/genetics ; Apoptosis ; *Gene Deletion ; Proto-Oncogene Proteins c-akt/metabolism ; Mice ; Mice, Inbred C57BL ; }, abstract = {α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.}, }
@article {pmid41557441, year = {2026}, author = {Wu, J and Pyko, A and Chourpiliadis, C and Hu, Y and Hou, C and Brauner, S and Piehl, F and Ljungman, P and Ingre, C and Fang, F}, title = {Long-Term Exposure to Air Pollution and Risk and Prognosis of Motor Neuron Disease.}, journal = {JAMA neurology}, volume = {83}, number = {3}, pages = {213-222}, pmid = {41557441}, issn = {2168-6157}, mesh = {Humans ; Male ; *Motor Neuron Disease/epidemiology/diagnosis/etiology ; Female ; *Air Pollution/adverse effects ; Sweden/epidemiology ; Case-Control Studies ; Middle Aged ; Aged ; Prognosis ; *Environmental Exposure/adverse effects ; Particulate Matter/adverse effects ; Registries ; Risk Factors ; Disease Progression ; }, abstract = {IMPORTANCE: Air pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression.<br><br>OBJECTIVE: To determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND.<br><br>This population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025.<br><br>EXPOSURES: Mean yearly concentrations of particulate matters of 2.5 &#xb5;m or less, 10 &#xb5;m or less, or 2.5 to 10 &#xb5;m in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure.<br><br>MAIN OUTCOME AND MEASURES: Association between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression.<br><br>RESULTS: The study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis.<br><br>CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.}, }
@article {pmid41557593, year = {2026}, author = {Meyer, T and Maier, A and Grehl, T and Weyen, U and Rödiger, A and Smesny, U and Steinbach, R and Grosskreutz, J and Göricke, B and Bernsen, S and Weydt, P and Fabian, R and Petri, S and Lumi, R and Bjelica, B and Boentert, M and Lingor, P and Kettemann, D and Norden, J and Walter, B and Riitano, A and Schumann, P and Münch, C and Spittel, S}, title = {Minimum important slowing of disease progression as determined by the ALS functional rating scale - a survey of patient expectations toward disease-modifying drugs in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2615117}, pmid = {41557593}, issn = {2167-9223}, abstract = {Objective: To define the minimum important slowing (MIS) of ALS progression that patients would expect from disease-modifying drug treatment in ALS. Methods: In a survey of ALS patients, the MIS in ALS progression (change in the ALS Functional Rating Scale-Revised, ALSFRS-R) was assessed by asking: "At what point of slowing of ALS, as determined by the ALSFRS-R, do you consider a drug to be important?" Data were collected during clinic visits or remotely via the ALS App. Participants were differentiated in the prognostic groups of slower (<0.5), intermediate (≥0.5 and ≤1.0), or faster (>1.0) ALS progression (ALSPR; ALSFRS-R/month). Results: Of 522 participants (ALS App, n = 397; clinic, n = 125), 395 (75.7%) completed the survey, while 127 (24.3%) selected the option "cannot estimate". The distribution of MIS was as follows: modest slowing of ALS progression (5% and 10% slowing, n = 146 patients, 36.9%), moderate slowing (20%, 30%, and 40% slowing, n = 135, 34.2%), and major slowing (≥50% slowing, n = 114, 28.9%). Median MIS was 20% (IQR 10-50%). Patients with faster ALSPR more frequently assessed a major slowing as the MIS (n = 18, 36.0%) compared to those with slower ALSPR (n = 54, 25.2%). Conclusion: A considerable number of participants viewed a modest slowing in ALS progression as the MIS, followed closely by preferences for moderate and major slowing. Expectations varied according to patients' individual ALS progression. These insights may inform the design of future clinical trials in ALS. Study limitations include potential selection and response biases, as well as the predominantly remote digital assessment.}, }
@article {pmid41558230, year = {2026}, author = {Ye, J}, title = {Beyond binary diagnosis: Key questions on AI accuracy, real-world applicability, and safety in clinical decision support.}, journal = {International journal of medical informatics}, volume = {209}, number = {}, pages = {106292}, doi = {10.1016/j.ijmedinf.2026.106292}, pmid = {41558230}, issn = {1872-8243}, mesh = {*Artificial Intelligence ; *Decision Support Systems, Clinical ; Humans ; *Patient Safety ; }, abstract = {This comment relates to Kücking et al.'s (2026) study on the bidirectional effects of artificial intelligence recommendations and healthcare provider related factors on the accuracy of wound impregnation diagnosis. While acknowledging the valuable contributions of this research, including distinguishing between correct/incorrect artificial intelligence outputs, rigorous simulation design, and emphasis on clinical safety, we have raised key questions to enhance the interpretation of results and real-world translation. The main focuses include the moderating role of artificial intelligence system accuracy in automation bias, external effectiveness in real clinical environments, potential mechanisms for gender differences in diagnostic performance, the impact of visual cue design on decision-making, and the potential of explainable artificial intelligence (XAI) in risk mitigation. This review aims to promote further research and facilitate the safe and effective integration of artificial intelligence based clinical decision support systems (CDSS) into clinical practice.}, }
@article {pmid41558795, year = {2026}, author = {Yi, W and Xu, Z and Feng, D and Guan, L and Tang, J and Zou, Y}, title = {Computational Exploration of the Molecular Mechanism of Epigallocatechin Gallate against TDP-43 Aggregation.}, journal = {Journal of chemical information and modeling}, volume = {66}, number = {3}, pages = {1826-1839}, doi = {10.1021/acs.jcim.5c02616}, pmid = {41558795}, issn = {1549-960X}, mesh = {*Catechin/analogs &amp; derivatives/pharmacology/chemistry/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism/antagonists &amp; inhibitors ; *Protein Aggregates/drug effects ; Humans ; }, abstract = {Cytoplasmic accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates represents the primary pathological hallmark of TDP-43 proteinopathies including amyotrophic lateral sclerosis (ALS) and chronic traumatic encephalopathy (CTE). Inhibiting TDP-43 aggregation or disrupting its preformed fibrils might be promising strategies to prevent or delay the development of TDP-43 proteinopathies. Recently, the green tea polyphenol, epigallocatechin gallate (EGCG), was observed to prevent the formation of TDP-43 oligomeric species and fibrillar aggregates. Nevertheless, the atomic-level mechanism of this inhibition has been incompletely characterized. In this study, we performed a multitude of replica exchange with solute tempering 2 (REST2) and all-atom molecular dynamics (MD) simulations of 46.8 μs in total on TDP-43 models with and without EGCG. The REST2 simulation results revealed that EGCG impedes the β-sheet structure formation and interferes the interchain interaction of TDP-43304-348 dimer. Subsequent analyses show that EGCG could alter the distribution of free energy landscape and hinder the residue-residue interaction of the dimer. The binding analyses confirmed that EGCG preferentially bound to M307, F313, F316, W334, M339, Q344, and Q346 residues, and hydrophobic, polar, and π-π stacking interactions dominate the binding of EGCG on the dimer. Additional conventional molecular dynamics (MD) simulations demonstrated that the protofibrillar tetramer is the minimal stable TDP-43304-348 protofibril. Taking the tetramer as a protofibril model, we found that EGCG could reduce the structural stability and disrupt the β-sheet structure of TDP-43304-348 protofibril, thus possessing a destabilization effect on its higher-order structure. This investigation unveils the atomic-level mechanism by which EGCG against TDP-43 aggregation, which may provide potential fundamental knowledge of therapeutic strategies for TDP-43 proteinopathies.}, }
@article {pmid41558895, year = {2026}, author = {Gupta, AK and Patil, C and Vadhithala, V and Paul, JR}, title = {Improving risk-stratified use of preoperative MRI in young women with breast.}, journal = {Clinical imaging}, volume = {131}, number = {}, pages = {110721}, doi = {10.1016/j.clinimag.2026.110721}, pmid = {41558895}, issn = {1873-4499}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging/surgery ; *Magnetic Resonance Imaging/methods ; *Preoperative Care/methods ; Adult ; Risk Assessment ; Mastectomy ; }, abstract = {This Letter to the Editor critiques Erguven et al.'s single centre study of universal preoperative breast MRI in women 40 years or younger with newly diagnosed breast cancer. We place their findings within mixed evidence on the effect of MRI on re-excision, mastectomy rates and outcomes, and highlight design and reporting limitations that restrict causal inference and generalisability in this young, higher risk population. We then outline priorities for future prospective, risk stratified research and policy, linking MRI use to tumour biology, surgical planning, patient reported outcomes and equity to ensure that expanded imaging leads to better and fairer care.}, }
@article {pmid41559796, year = {2026}, author = {Jun, YW and Hass, EP and Lee, S and Fazzio, TG and Gao, FB}, title = {Mislocalization of FTD3-associated mutant CHMP2B to the nucleus of human neurons due to loss of a nuclear export signal.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {45}, pmid = {41559796}, issn = {2051-5960}, support = {R01 HD072122/HD/NICHD NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neurons/metabolism/pathology ; *Cell Nucleus/metabolism ; *Nuclear Export Signals/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Mutation/genetics ; *beta Karyopherins/metabolism/genetics ; Active Transport, Cell Nucleus ; Cells, Cultured ; Exportin 1 Protein ; Endosomal Sorting Complexes Required for Transport ; }, abstract = {Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2B[In5] and CHMP2B[Δ10]. Here, we found that wildtype CHMP2B (CHMP2B[WT]) is mostly present in the cytoplasm, but CHMP2B[In5] is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2B[WT] and ALS-associated CHMP2B[Q206H], and its loss in CHMP2B[In5] is responsible for the observed nuclear mislocalization. CHMP2B[Δ10] remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2B[In5] in FTD3 pathogenesis.}, }
@article {pmid41560764, year = {2026}, author = {Ge, Y and Zhu, J and Ren, Y and Wu, X and Zhou, B and Wu, Y and Ge, Y}, title = {Trans-Generational Morphological Trait Plasticity in Parthenogenetic Offspring of Two Brachionus dorcas Morphotypes Induced by Asplanchna Kairomones.}, journal = {Ecology and evolution}, volume = {16}, number = {1}, pages = {e72956}, pmid = {41560764}, issn = {2045-7758}, abstract = {We compared trans-generational (F0-F12) morphological trait plasticity induced by Asplanchna kairomones between two Brachionus dorcas morphotypes (long-posterior spines, LS; short-posterior spines, SS) along with life-table parameters of the non-induced morphotypes. Under control conditions, SS rotifers tended to show higher fertility and smaller body size than LS rotifers. Low kairomone concentrations (50 and 200 ind./L) tended to increase body size in SS offspring, while exposure to 50, 200, and 800 ind./L kairomones induced spine elongation in both morphotypes, with posterolateral spine (PS) length increasing with kairomone concentration. Compared to the F0 generation, offspring of both morphotypes in unexposed controls showed generational fluctuations in body size; LS offspring exhibited shortening or no change in anteromedian spine (AMS) and anterolateral spine (ALS) lengths, while SS offspring showed elongation or no change in these spine lengths and PS length. Across all kairomone treatments, significant elongation of AMS and ALS in LS offspring was typically observed only in later generations, whereas SS offspring exhibited significant elongation from F1 through F12; LS offspring showed significant PS elongation from F2 through F12, with maximum lengths in the later generations (F5-F12), while SS offspring showed significant PS elongation from F1 through F12, peaking in early generations (F2-F4). Notably, the multi-generational mean PS length in SS offspring remained significantly shorter than that in LS offspring under each kairomone treatment. Overall, SS offspring appeared to employ a synergistic defense combining increased body size and spine elongation favoring a "rapid and moderate response," whereas LS offspring exhibited a "slow and extreme defense" strategy. These divergent strategies may result from evolutionary trade-offs involving resource allocation, environmental predictability, and genetic constraints.}, }
@article {pmid41561436, year = {2025}, author = {Ishaq, SM and Russell, AP}, title = {Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1686230}, pmid = {41561436}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.}, }
@article {pmid41561437, year = {2025}, author = {Kim, SH and Boos, CE and Scalf, M and Wilkemeyer, AK and Smith, LM and Tibbetts, RS}, title = {Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS/FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1720347}, pmid = {41561437}, issn = {1662-5099}, support = {R01 CA180765/CA/NCI NIH HHS/United States ; R35 GM126914/GM/NIGMS NIH HHS/United States ; RF1 AG069483/AG/NIA NIH HHS/United States ; T32 HG002760/HG/NHGRI NIH HHS/United States ; }, abstract = {Ubiquilin-2 (UBQLN2) is a ubiquitin (Ub)-binding shuttle protein that is mutated in X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS/FTD-linked mutations in UBQLN2 disrupt its conformation, increasing its tendency to form cytoplasmic aggregates that may disrupt cellular regulation through loss-of-function (LOF) and gain-of-function (GOF) effects. Here, we performed quantitative mass spectrometry (MS)-based interactome analysis of wild-type (UBQLN2[WT]) and ALS-mutant UBQLN2 (UBQLN2[ALS]) proteins using inducible pluripotent stem cells (iPSCs) and induced motor neurons (iMNs). Proteins showing enhanced association with UBQLN2[ALS] proteins included PEG10, a known degradation target of UBQLN2, and BAG6, a chaperone involved in the triage of mislocalized proteins (MLPs). BAG6 knockdown inhibited the solubility recovery of both UBQLN2[WT] and UBQLN2[ALS] proteins following heat stress (HS), suggesting it functions as a UBQLN2 holdase. In addition, knockdown of BAG6 or knockout of UBQLN2 led to PEG10 accumulation, implicating both in PEG10 turnover; however, neither BAG6 nor UBQLN2 was required for PEG10 degradation in response to HS. A highly aggregation-prone UBQLN2[4XALS] mutant harboring four different ALS-associated mutations showed increased PEG10 binding and modestly delayed PEG10 turnover while PEG10 degradation was not significantly different between UBQLN2[WT] and iPSCs expressing a UBQLN2[P497H] clinical mutant. The combined findings implicate BAG6 as a UBQLN2 holdase and identify a suite of proteins whose altered binding may contribute to pathologic changes in UBQLN2-associated ALS/FTD.}, }
@article {pmid41561680, year = {2026}, author = {Lizio, A and Lops, J and Farè, M and Pezzera, S and Piras, R and Sideri, R and Tornabene, D and Lunetta, C and Diamanti, L and Sansone, VA and Cerri, F}, title = {Development and validation of predictive models for 6-month gastrostomy timing in amyotrophic lateral sclerosis.}, journal = {BMJ neurology open}, volume = {8}, number = {1}, pages = {e001336}, pmid = {41561680}, issn = {2632-6140}, abstract = {BACKGROUND: Dysphagia is common in amyotrophic lateral sclerosis (ALS), contributing to malnutrition and accelerated disease progression. Although early nutritional intervention is recommended, the optimal timing for percutaneous endoscopic gastrostomy (PEG) placement remains uncertain. This study aimed to develop and validate simple prediction models, accessible via an online calculator, to identify ALS patients likely to require PEG within 6 months.<br><br>METHODS: We conducted a retrospective cohort study including ALS patients followed at three Italian reference centres between February 2018 and October 2023. Predictors of PEG placement within 6&#x2009;months were identified using univariate and multivariable binary logistic regression models. Prediction models were developed following Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and underwent both internal and external validation.<br><br>RESULTS: In the development cohort (n=263; median age 63.8 years), 138&#x2009;patients (52.5%) underwent PEG within 6&#x2009;months. Three models were developed: the Anamnestic Prediction Model, based on age, onset site and non-invasive ventilation (NIV), showed fair predictive performance. The Anamnestic and Functional Prediction Model, incorporating age, bulbar subscore of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-r) and forced vital capacity (%), demonstrated strong predictive performance (Brier score: 0.1230), excellent discrimination (concordance index (c-index) 0.91) and good calibration (Hosmer-Lemeshow p=0.59). The Anamnestic and Nutritional Prediction Model, including age, onset site, NIV, body mass index and weight loss, showed good predictive performance (Brier score: 0.1719), discrimination (c-index 0.81) and calibration (Hosmer-Lemeshow p=0.48). These findings were confirmed in an external validation cohort of 116 ALS patients.<br><br>CONCLUSIONS: The prediction models provide accurate, easily implementable tools to predict PEG need within 6&#x2009;months, enabling timely nutritional interventions that may improve outcomes and care quality in ALS.}, }
@article {pmid41562832, year = {2026}, author = {Aranda-Abreu, GE and Rojas-Durán, F and Hernández-Aguilar, ME and Herrera-Covarrubias, D and Tlapa-Monge, LR and Mestizo-Gutiérrez, SL}, title = {The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms.}, journal = {NeuroSci}, volume = {7}, number = {1}, pages = {}, pmid = {41562832}, issn = {2673-4087}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis.}, }
@article {pmid41562880, year = {2026}, author = {Fiorella, ML and Ballini, L and Lavermicocca, V and Ragno, MS and Restivo, DA and Marchese-Ragona, R}, title = {Dysphagia and Dysarthria in Neurodegenerative Diseases: A Multisystem Network Approach to Assessment and Management.}, journal = {Audiology research}, volume = {16}, number = {1}, pages = {}, pmid = {41562880}, issn = {2039-4330}, abstract = {Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024), focusing on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included "dysphagia", "dysarthria", "neurodegenerative diseases", "neural networks", "swallowing control" and "speech production." Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life.}, }
@article {pmid41563042, year = {2026}, author = {Bergh, S and Simonsson, O and Petersén, &#xc5;}, title = {Analyses of the Effects of Wild-Type TDP-43 Overexpression in Oxytocin Neurons in Mice.}, journal = {Neuropathology and applied neurobiology}, volume = {52}, number = {1}, pages = {e70059}, pmid = {41563042}, issn = {1365-2990}, support = {2022/01092//Swedish Research Council/ ; //Brain Foundation/ ; //Region Sk&#xe5;ne/ ; 2019.0467//Knut and Alice Wallenberg Foundation/ ; }, mesh = {Animals ; *Oxytocin/metabolism ; *Neurons/metabolism ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Paraventricular Hypothalamic Nucleus/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; }, abstract = {Selective TDP-43 overexpression in oxytocin neurons in the paraventricular nucleus of the hypothalamus causes a decrease in oxytocin-immunopositive cells compared to uninjected mice. AAV-mediated TDP-43 overexpression in oxytocin neurons does not appear to be a major driver of behavioural and metabolic phenotypes in mice.}, }
@article {pmid41563518, year = {2026}, author = {Boomsma, A and Doyle, C and Sai, N and Rogers, ML and Lee, SH and Benyamin, B}, title = {The differences in sex ratio between sporadic and familial amyotrophic lateral sclerosis: a systematic review.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {92}, pmid = {41563518}, issn = {1432-1459}, support = {Research Training Program//Australian Government/ ; DIS-202303-00932//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; *Sex Ratio ; Male ; Female ; *Sex Characteristics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is more prevalent in males than in females. However, it is unclear whether the difference in sex ratio is observed similarly in sporadic compared to familial ALS. Here, we conducted a systematic review to investigate the differences in sex ratio between familial and sporadic ALS. Following the meta-analysis of observational studies in epidemiology (MOOSE) guidelines, this study searched Ovid MEDLINE, Embase, Emcare, SCOPUS and Cochrane databases. We used a random-effects meta-analysis to estimate sex ratios in a total of 9269 ALS patients (4135 female, 5134 male) across 20 included studies. We confirmed that ALS is more prevalent in males than in females (sex ratio: 1.25 (95%CI 1.14-1.37). However, when we stratified the analyses, the sex ratio was only different in sporadic ALS. Male-to-female ratios were 1.29 (95% CI 1.16-1.42) for sporadic ALS and 1.05 (95% CI 0.93-1.18) for familial ALS. A further analysis showed a pooled risk ratio of 1.07 (95% CI 1.00-1.15), indicating a 7% higher likelihood of males being diagnosed with sporadic rather than familial ALS. These findings highlight the importance of considering sex-specific factors in ALS research and clinical practice.}, }
@article {pmid41564501, year = {2026}, author = {Han, L and Zang, S and Li, W and Yue, H and Zhou, X and Chen, J and Geng, M and Duan, W and Xie, Z and Zhan, Z}, title = {Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {135}, number = {}, pages = {118571}, doi = {10.1016/j.bmc.2026.118571}, pmid = {41564501}, issn = {1464-3391}, mesh = {Humans ; Animals ; *Membrane Proteins/antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; Mice ; Molecular Structure ; *Drug Discovery ; Dose-Response Relationship, Drug ; *Thiazines/pharmacology/chemistry/chemical synthesis ; STING Protein ; }, abstract = {The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound 11 h as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC50 of 8.8 or 11.5 nM. Compound 11 h markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, 11 h achieved robust in vivo activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of 11 h-STING indicates that 11 h engages the transmembrane area of STING.}, }
@article {pmid41564770, year = {2026}, author = {Lee, H and Jo, Y and Jung, M and Lee, JH and Kim, TH and Lee, J and Kim, DJ and Rahmati, M and Smith, L and Pizzol, D and Son, Y and Park, J and Ahn, SH and Yon, DK and Choi, DW and Kang, J}, title = {Heavy metal exposure and all health outcomes: An umbrella review of meta-analyses.}, journal = {Journal of hazardous materials}, volume = {503}, number = {}, pages = {141141}, doi = {10.1016/j.jhazmat.2026.141141}, pmid = {41564770}, issn = {1873-3336}, mesh = {Humans ; *Metals, Heavy/toxicity ; *Environmental Exposure/adverse effects ; Meta-Analysis as Topic ; *Environmental Pollutants/toxicity ; Female ; Arsenic ; }, abstract = {We aimed to systematically evaluate the strength and credibility of evidence linking exposure to five major heavy metals, including arsenic, cadmium, lead, mercury, and chromium, with health outcomes (PROSPERO, CRD420251169899). Literature searches of PubMed/Embase, CINAHL, and Google Scholar up to April 20, 2025, identified meta-analyses of observational studies assessing these associations. Effect sizes were recalculated using random-effects models and expressed as equivalent odds ratios (eOR) with 95 % confidence intervals (CIs). The methodological quality of the included reviews was assessed using the AMSTAR2, and the credibility of associations was graded according to predefined criteria: Class I (convincing), Class II (highly suggestive), Class III (suggestive), Class IV (weak), and non-significant (NS). A total of 35 meta-analyses encompassing 103 health outcomes were included. Arsenic exposure was associated with melanoma (eOR 1.50 [95 % CI, 1.0-2.24], CE=IV), digestive cancers (1.23 [1.07-1.41], CE=III), gestational diabetes mellitus (1.47 [1.11-1.95], CE=III), hypertension (1.15 [1.06-1.24], CE=III), and preterm birth (1.12 [1.04-1.21], CE=III). Lead exposure showed significant associations with autistic disorder in children (12.70 [3.93-41.10], CE=IV), hearing loss (7.55 [6.69-8.53], CE=III), age-related eye disease (9.80 [1.72-55.85], CE=IV), and amyotrophic lateral sclerosis (1.46 [1.16-1.83], CE=III). Mercury exposure was linked to increased risk in membranous nephropathy (5.75 [1.54-21.44], CE=IV) and thyroid cancer (1.90 [1.55-2.33], CE=IV). Cadmium exposure was associated with renal cancer (1.47 [1.26-1.71], CE=II), cardiovascular disease (1.33 [1.05-1.69], CE=IV), stroke (1.36 [1.10-1.68], CE=III), diabetes mellitus (1.27 [1.07-1.52], CE=III), fracture risk (1.30 [1.13-1.49], CE=III), and age-related eye disease (113.26 [16.86-760.68], CE=III). Chromium exposure was associated with stomach cancer (1.28 [1.16-1.41], CE=I), supporting convincing evidence. Overall, exposures to these metals were consistently associated with diverse diseases across organ systems and life stages, suggesting proactive implications against heavy metal exposures.}, }
@article {pmid41565003, year = {2026}, author = {Baek, Y and Lee, H and Park, ES and Park, M and Wee, Y and Kim, H and Roh, SH and Ha, NC}, title = {Structural Comparison of the Human G93A Mutant SOD1 to the Wild-type SOD1 Filaments.}, journal = {Journal of molecular biology}, volume = {438}, number = {6}, pages = {169642}, doi = {10.1016/j.jmb.2026.169642}, pmid = {41565003}, issn = {1089-8638}, mesh = {*Superoxide Dismutase-1/chemistry/genetics/metabolism/ultrastructure ; Humans ; Cryoelectron Microscopy ; Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Models, Molecular ; Protein Conformation ; Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by Cu, Zn-superoxide dismutase (SOD1) misfolding and aggregation, particularly in familial cases. The G93A mutation in SOD1, strongly associated with familial ALS, is widely studied in transgenic mouse models of the disease. In this study, we investigated the filament structure of the G93A mutant SOD1 using cryo-electron microscopy. The resulting fibrils consisted of a single protofilament with a left-handed helical twist, closely resembling those formed by wild-type (WT) SOD1 under identical conditions. Self- and cross-seeding experiments promoted filament formation in both WT and G93A mutant SOD1, compared to the no-seed condition. Notably, the G93A mutant exhibited significantly higher susceptibility to proteolysis in its native state than WT SOD1. Mass spectrometry analysis suggested that the structurally disordered electrostatic loop acts as a key common intermediate structure in filament formation for both WT and G93A mutant SOD1. These findings suggest that shared filament formation pathways underlie the aggregation of both WT and G93A mutant SOD1, providing new insights into the molecular mechanisms contributing to ALS pathogenesis.}, }
@article {pmid41565302, year = {2026}, author = {Warita, H and Urushitani, M and Atsuta, N and Izumi, Y and Kano, O and Shimizu, T and Nakayama, Y and Narita, Y and Nodera, H and Fujita, T and Mizoguchi, K and Morita, M and Aoki, M}, title = {Addendum to the 2023 clinical practice guidelines for amyotrophic lateral sclerosis in Japan: approval and integration of novel disease-modifying therapies.}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {66}, number = {2}, pages = {67-73}, doi = {10.5692/clinicalneurol.cn-002198}, pmid = {41565302}, issn = {1882-0654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Japan ; *Practice Guidelines as Topic ; Edaravone/administration &amp; dosage ; Vitamin B 12/administration &amp; dosage/analogs &amp; derivatives ; Genetic Therapy ; Drug Approval ; Oligonucleotides/administration &amp; dosage ; Genetic Testing ; Oligonucleotides, Antisense/administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an intractable motor neuron disease characterized by progressive degeneration of motor neurons with varying degrees of frontotemporal lobe dysfunction. This English summary of the addendum to the Japanese clinical practice guidelines for ALS outlines major recent advances in pharmacological therapy in Japan. Following the development of the 2023 guidelines, three additional medications-oral edaravone, high-dose intramuscular mecobalamin, and tofersen-have been introduced. Oral edaravone, with its ease of administration, demonstrates pharmacokinetics comparable to the intravenous formulation. High-dose mecobalamin reduces functional decline when initiated early in the disease course. Tofersen, an antisense oligonucleotide, is the first gene-targeted therapy approved in Japan for patients with copper/zinc superoxide dismutase gene-related ALS, highlighting the importance of genetic testing and counseling in all ALS cases. This addendum provides updated expert consensus recommendations for the use, dosing, and monitoring of these therapies, while emphasizing the need for thorough communication about the ethical and psychological dimensions of genetic testing. It also addresses practical considerations for combination therapy, noting that up to three or four anti-ALS agents are now available in Japan. The long-term safety and efficacy of these therapies, as well as their potential synergistic or additive effects, remain to be clarified through real-world data and prospective registries. The objectives of this addendum are twofold: to present these advances and recommendations in English to foster international collaboration, and to inform the global ALS community about the latest therapeutic strategies in Japan. In addition, ongoing efforts to harmonize clinical evaluation standards and promote international clinical trials are highlighted, with the goal of improving patient outcomes and advancing ALS research worldwide.}, }
@article {pmid41565509, year = {2026}, author = {Lee, NC and Lin, CH and Chien, YH and Hwu, WL}, title = {Genetic testing for adult-onset neurodegenerative diseases: A clinical perspective.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jfma.2026.01.021}, pmid = {41565509}, issn = {0929-6646}, abstract = {Adult-onset neurodegenerative diseases (AOND), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, severely affect patients' quality of life. Pathogenic single-nucleotide variations (SNVs) and small insertions and deletions (indels) can disrupt genes involving ANOD, and expansion of short tandem repeats such as trinucleotide repeats is an important etiology of hereditary ataxia. Variations in more than one gene combined to create polygenic risk scores (PRS) for multifactorial types of AOND. Recently, genome structural variations (SVs) like copy number variations (CNVs) and expansion of long repeats are increasingly identified as the etiologies of AOND. Tools for molecular diagnosis of AOND have evolved from Sanger sequencing to next-generation sequencing (NGS) such as short-read whole-exome sequencing (WES) and whole-genome sequencing (WGS), and long-read sequencing is especially helpful in solving SVs and expansions of long repeats. Patients might have affected and/or at-risk family members at the time of diagnosis, so genetic counseling for risk handling and birth planning need to be conducted with caution. This review will help readers to better understand the genetic testing for AOND.}, }
@article {pmid41567979, year = {2025}, author = {Hamdalla, RH and Bhaskar, VB and Tian, C}, title = {Brain-derived extracellular vesicles potentially mediate crosstalk with peripheral organs in neurodegenerative diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1710150}, pmid = {41567979}, issn = {2296-634X}, support = {R01 HL153176/HL/NHLBI NIH HHS/United States ; }, abstract = {Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.}, }
@article {pmid41569095, year = {2026}, author = {Charbonnel, T and Richard, E and Dupuis, A and Palla, M and Vourc'h, P and Corcia, P and Al Ojaimi, Y and Blasco, H}, title = {The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt?.}, journal = {Expert opinion on drug discovery}, volume = {21}, number = {2}, pages = {147-160}, doi = {10.1080/17460441.2026.2619067}, pmid = {41569095}, issn = {1746-045X}, mesh = {*Edaravone/pharmacology/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; Animals ; *Neuroprotective Agents/pharmacology/administration &amp; dosage ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/administration &amp; dosage/pharmacokinetics ; Drug Development/methods ; Drug Discovery/methods ; Oxidative Stress/drug effects ; Mice, Transgenic ; Mice ; Drug Evaluation, Preclinical ; Blood-Brain Barrier/metabolism ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with limited therapeutic options. Among the few approved drugs, edaravone, a free radical scavenger developed originally for ischemic stroke, has attracted particular attention for its ability to counteract oxidative stress, a key driver of neurodegeneration. Its amphipathic structure and ability to cross the blood-brain barrier support its potential neuroprotective action.<br><br>AREAS COVERED: The authors discuss preclinical studies demonstrating edaravone's ability to reduce oxidative damage, preserve mitochondrial function, and modulate neuroinflammatory responses in ALS cellular and animal models. They discuss variations in dosage, timing, and disease models that produced heterogeneous results. In transgenic mice, edaravone may delay symptom onset and modestly extend survival, but these effects are inconsistent and often limited to early disease stages.<br><br>EXPERT OPINION: Clinically, edaravone provides modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges in ALS drug discovery, including limited model predictivity, methodological variability, and lack of patient stratification. The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS.}, }
@article {pmid41569391, year = {2026}, author = {Raymond, KF and Hodge, T and St Jean, B and Liu, BF}, title = {Barriers to Long COVID Care in the U.S.: An Application of Levesque et al.'s Access Framework.}, journal = {Health care analysis : HCA : journal of health philosophy and policy}, volume = {}, number = {}, pages = {}, pmid = {41569391}, issn = {1573-3394}, support = {Pandemic Readiness Initiative//University of Maryland/ ; Pandemic Readiness Initiative//University of Maryland/ ; }, abstract = {Long COVID is a condition that arose during the COVID-19 pandemic in individuals who developed the multi-system chronic condition after a COVID-19 infection. During the pandemic in the United States (U.S.), these "COVID long-haulers" navigated a complex and overburdened health care system in pursuit of diagnoses and treatments. This qualitative secondary analysis used the 2013 Levesque et al. Conceptual Model of Healthcare Access to examine multidimensional health care access issues faced by 29 COVID long-haulers in the U.S. Our analysis showed that long-haulers faced complementary issues from both individual and health systems perspectives related to the inability to get diagnoses or treatments, long waiting times for providers and difficulty reaching services, underinformed providers and biased interpersonal experiences, and struggles with the financial costs of treating the condition, which impacted care decisions. Interviewees also described relying on alternative medicine to provide symptom relief. Overall, this study extends international research by offering a comprehensive examination of Long COVID health care access issues in the U.S. and identifying specific insights related to health care access that made obtaining Long COVID care difficult, such as the mismatch between individual expectations of what health care should look like and how it actually operates. Our use of the full Conceptual Model of Healthcare Access provides new insights into the overlap across layers of access issues and offers suggestions for how public health and clinical health practitioners can collaborate to meet the needs of vulnerable populations such as these in future health emergencies.}, }
@article {pmid41569660, year = {2026}, author = {Özkan, B and Ramge, JM and Wiesner, D and Scekic-Zahirovic, J and Antonucci, S and Nungeß, S and Gebauer, D and Ignatius, A and Weishaupt, JH and Haffner-Luntzer, M and Roselli, F}, title = {Reduced osteogenic factors and early osteoblast senescence in SOD1(G93A) ALS mouse model.}, journal = {JCI insight}, volume = {11}, number = {5}, pages = {}, doi = {10.1172/jci.insight.197475}, pmid = {41569660}, issn = {2379-3708}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/physiopathology ; *Osteoblasts/metabolism/pathology ; Disease Models, Animal ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Osteogenesis/genetics ; Mice, Transgenic ; *Cellular Senescence/genetics ; X-Ray Microtomography ; Bone Density ; Male ; Humans ; Cell Differentiation ; Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. Emerging evidence suggests manifestations beyond the neuromuscular system. Bone alterations are part of the ALS clinical picture; it remains unclear whether they are secondary to muscle denervation or due to an autonomous process. We investigated skeletal involvement in the SOD1(G93A) mouse model at presymptomatic (P45) and symptomatic (P110) stages through biomechanical and transcriptomic approaches. Three-point bending revealed significant reductions in femoral rigidity and maximum bending force in SOD1 mutants at P45, indicating early structural deficits. Micro-CT analysis demonstrated reduced trabecular bone mineral density and thickness at P45, with progressive trabecular loss and cortical thinning by P110. Histological examination revealed marked osteoblast loss at P45, suggesting impaired bone formation as the primary early mechanism. Transcriptomics of bulk bone and cultured osteoblasts from P45 mice identified dysregulation of bone differentiation, including downregulation of osteoblast differentiation genes and upregulation of negative regulators of ossification and increased cell senescence signatures. Unfolded protein response was upregulated in SOD1 osteoblasts. Immunohistochemistry confirmed the senescence phenotype with increased p16Ink4a level in SOD1 osteoblasts. These findings suggest that bone deterioration precedes overt motor symptoms and is linked to osteoblast premature senescence.}, }
@article {pmid41569987, year = {2026}, author = {Wang, WR and Liu, GD and Ren, DX and Liu, XY}, title = {Allostatic load in thyroid cancer is higher than that of other cancers: A secondary analysis using NHANES.}, journal = {PloS one}, volume = {21}, number = {1}, pages = {e0341063}, pmid = {41569987}, issn = {1932-6203}, mesh = {Humans ; *Thyroid Neoplasms/physiopathology/pathology ; Female ; Male ; Middle Aged ; Cross-Sectional Studies ; Nutrition Surveys ; *Allostasis/physiology ; Adult ; Aged ; ROC Curve ; }, abstract = {BACKGROUND: To compare the levels of allostatic load score (ALS) between thyroid cancer patients and patients with other types of cancer and explore whether ALS mediates the association between thyroid cancer and alterations in physiological function.<br><br>METHODS: This cross-sectional study conducted a secondary analysis of 181 cancer patients using NHANES data from 2007 to 2020, including 91 individuals with thyroid cancer. Generalized linear regression, logistic regression, and sensitivity analysis were used to analyze the association between thyroid cancer and ALS in three different models. Receiver operating characteristic (ROC) curve analysis and feature importance analysis were utilized to assess the clinical predictive value of thyroid cancer. We also conducted a series of mediation analyses to examine the mediating role of ALS.<br><br>RESULTS: The ALS in thyroid cancer patients was higher than that in other cancer types (P&#x2009;<&#x2009;0.05). Thyroid cancer was significantly associated with ALS even after adjusting for demographic variables (&#x3b2;&#x2009;=&#x2009;0.770, 95%CI: 0.315-1.480; OR=2.255, 95%CI: 1.111-4.575). This association remained robust to missing data (all P&#x2009;<&#x2009;0.05) and was not confounded by drinking, diabetes, or thyroid disease (all P&#x2009;>&#x2009;0.05). Although thyroid cancer had limited predictive value on ALS, it exerted strong explanatory power. The mediation analysis conducted with imputed data and adjusted for confounding variables revealed that ALS fully mediated the effect of thyroid cancer on red cell distribution width (RDW) (IE: &#x3b2;&#x2009;=&#x2009;0.103, P&#x2009;=&#x2009;0.008; DE: &#x3b2;&#x2009;=&#x2009;0.389, P&#x2009;=&#x2009;0.056), with a mediation proportion of 20.93%.<br><br>CONCLUSION: Our findings revealed that thyroid cancer condition were associated with elevated AL. AL mediated the relationship between thyroid cancer and RDW.}, }
@article {pmid41570741, year = {2026}, author = {Genin, EC and Paquis-Flucklinger, V}, title = {ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies.}, journal = {Current opinion in neurobiology}, volume = {97}, number = {}, pages = {103163}, doi = {10.1016/j.conb.2025.103163}, pmid = {41570741}, issn = {1873-6882}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; Animals ; *TDP-43 Proteinopathies/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Mitochondrial Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often overlaps clinically and pathologically with frontotemporal dementia (FTD), the second most common form of dementia. Like many neurodegenerative disorders, both ALS and FTD share a crucial pathological hallmark, the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. This process is referred to as proteinopathy. This review focuses on the proteinopathies associated with ALS, including aggregates of TDP-43, SOD1, FUS, and CHCHD10, which disrupt critical cellular processes such as RNA metabolism, mitochondrial function, and protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10-related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating ALS, as they directly target fundamental pathogenic mechanisms.}, }
@article {pmid41571168, year = {2026}, author = {Malvandi, AM and Gerosa, L and Maroni, P and Orlando, ME and Mohammadipour, A and Lombardi, G}, title = {miRNA-206 in muscle and central nervous system crosstalk during exercise: A double-edged sword with therapeutic potential.}, journal = {Neuroscience and biobehavioral reviews}, volume = {183}, number = {}, pages = {106569}, doi = {10.1016/j.neubiorev.2026.106569}, pmid = {41571168}, issn = {1873-7528}, mesh = {Humans ; *MicroRNAs/metabolism ; *Exercise/physiology ; *Muscle, Skeletal/metabolism ; Animals ; *Central Nervous System/metabolism ; }, abstract = {Physical activity triggers complex molecular responses in skeletal muscle, with increasing evidence showing systemic signaling roles for muscle-derived microRNAs (myomiRs). Among these, miR-206 has attracted attention for its dual function: promoting muscle regeneration but potentially harming the central nervous system (CNS). This review examines how miR-206 expression is regulated during exercise and its effects on muscle biology-such as fiber-type specification, mitochondrial changes, and neuromuscular junction (NMJ) repair. It also explores the paradoxical effects of high miR-206 levels in the CNS, where it targets brain-derived neurotrophic factor (BDNF), reducing neuroplasticity and increasing vulnerability to neuropsychiatric and neurodegenerative diseases. The review highlights disease-specific aspects, showing miR-206 as harmful in Alzheimer's, stroke, and depression, but potentially protective in amyotrophic lateral sclerosis (ALS). We discuss its potential as a biomarker and therapeutic target, stressing tissue-specific regulation approaches. Overall, miR-206 plays a key role in muscle-brain communication, with important implications for exercise, aging, and CNS disorders.}, }
@article {pmid41571758, year = {2026}, author = {Lacour, A and Vassallu, F and Romussi, S and Rayes, D and Igaz, LM}, title = {Cytoplasmic TDP-43 leads to early behavioral impairments without neurodegeneration in a serotonergic neuron-specific C. elegans model.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {6068}, pmid = {41571758}, issn = {2045-2322}, support = {PICT 2019-0480 (To DR)//Agencia Nacional de Promoci&#xf3;n de la Ciencia y la Tecnolog&#xed;a ANPCYT Argentina/ ; P40 OD010440/OD/NIH HHS/United States ; PIP No. 11220200101606CO (To DR)//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PGI: 24/B291 (To DR)//Universidad Nacional del Sur/ ; PICT 2019-1585 (To LMI)//Agencia Nacional de Promoci&#xf3;n de la Ciencia y la Tecnolog&#xed;a ANPCYT Argentina/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Serotonergic Neurons/metabolism/pathology/drug effects ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Humans ; *Behavior, Animal ; *Cytoplasm/metabolism ; Serotonin/metabolism ; Animals, Genetically Modified ; Caenorhabditis elegans Proteins/metabolism/genetics ; Frontotemporal Dementia ; Locomotion ; }, abstract = {TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because in C. elegans they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors-including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter-with the cytoplasmic ΔNLS form causing more severe deficits. These behavioral impairments are evident even while the serotonergic neurons remain apparently normal in structure, suggesting that neuronal dysfunction precedes overt neurodegeneration. Moreover, the serotonergic HSN neurons that control egg-laying were also partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release remains functional to some extent. Altogether, our findings demonstrate that TDP-43 expression causes neuronal dysfunction leading to behavioral deficits, even in the absence of detectable structural pathology and that its mislocalization to the cytoplasm results in more severe behavioral impairments. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated neuronal dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.}, }
@article {pmid41571890, year = {2026}, author = {Lee, J and Lee, GR and Lee, HI and Kwon, M and Kim, T and Lee, JR and Lee, SY and Jeong, W}, title = {Rgnef regulates bone mass through the activation of RhoA and Rac1.}, journal = {Experimental &amp; molecular medicine}, volume = {58}, number = {1}, pages = {243-253}, pmid = {41571890}, issn = {2092-6413}, support = {RS-2024-00357657//National Research Foundation of Korea (NRF)/ ; RS-2023-00217798//National Research Foundation of Korea (NRF)/ ; 2019R1A6C1010020//Korea Basic Science Institute (KBSI)/ ; RP-Grant 2022//Ewha Womans University (Ewha)/ ; }, mesh = {Animals ; *rhoA GTP-Binding Protein/metabolism ; *rac1 GTP-Binding Protein/metabolism ; Osteogenesis/genetics ; Mice ; Osteoblasts/metabolism/cytology ; NF-kappa B/metabolism ; Osteoclasts/metabolism/cytology ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; Cell Differentiation ; Female ; *Bone and Bones/metabolism ; Mice, Transgenic ; Mice, Knockout ; Signal Transduction ; Neuropeptides ; }, abstract = {Rho guanine nucleotide exchange factor (Rgnef/p190RhoGEF), a RhoA-specific guanine nucleotide exchange factor, has been implicated in cancer and amyotrophic lateral sclerosis, but little is known about its role in bone. Here we investigate the roles of Rgnef in bone metabolism using Rgnef-deficient and overexpressing mice. Compared with littermate wildtype mice, Rgnef-deficient mice had increased bone mass owing to lower osteolysis and higher osteogenesis, and Rgnef-overexpressing transgenic mice had the opposite bone phenotype. Rgnef deficiency inhibited osteoclast formation and resorptive function and promoted osteoblast differentiation and mineralization, whereas Rgnef overexpression had the reverse effect. Mechanistically, Rgnef promotes osteoclastogenesis by enhancing the activity of nuclear factor kappa B (NF-κB), mitogen-activated protein kinases and AKT through the activation of RhoA and Rac1 and attenuates osteoblastogenesis through the RhoA/Rac1-mediated NF-κB activation. Moreover, Rgnef-deficient mice were protected from bone loss caused by lipopolysaccharide-induced inflammation or ovariectomy. Thus, Rgnef is a crucial regulator of bone metabolism and could serve as a potential new target for treating bone diseases.}, }
@article {pmid41572285, year = {2026}, author = {Straczkiewicz, M and Burke, KM and Calcagno, N and Premasiri, A and Carney, KT and Vieira, FG and Onnela, JP and Berry, JD}, title = {Short prescribed exercises can quantify upper limb functioning in neurodegenerative disease.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {23}, number = {1}, pages = {28}, pmid = {41572285}, issn = {1743-0003}, mesh = {Humans ; Male ; Female ; *Upper Extremity/physiopathology ; Middle Aged ; Accelerometry ; Longitudinal Studies ; Aged ; *Exercise Therapy/methods ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; Wearable Electronic Devices ; }, abstract = {BACKGROUND: Digital health technologies (DHTs) can quantify movements in daily routines but rely heavily on participant adherence over prolonged wear times.<br><br>METHODS: We analyzed accelerometry data from wrist-worn devices during short at-home episodes of prescribed exercises performed by 329 individuals living with amyotrophic lateral sclerosis (ALS) in a longitudinal study. We developed an automated and interpretable signal processing method to estimate four metrics describing exercise repetitions, i.e., their count, duration, intensity, and similarity. We examined their associations with time elapsed from enrollment and ALS Functional Rating Scale-Revised (ALSFRS-R) using linear mixed effect models. We also compared them with previously validated free-living metrics that require substantial sensor wear-time. Finally, we studied how many repetitions are sufficient to determine participants' upper limb functioning.<br><br>RESULTS: Three out of four exercise metrics (all but count) demonstrated significant association with ALSFRS-R outcomes. The duration of exercise repetitions increased, while intensity and similarity of movement decreased over time (all p-value&#x2009;<&#x2009;0.001), indicating longer but less vigorous and less consistent upper limb movements over time. Exercise intensity was determined as the most robust exercise-based predictor of changes in upper limb function, and it was comparable to free-living metrics, which required at 21&#xa0;h of sensor wear time (R-squared 0.899 vs. 0.860, respectively). Sensitivity analysis indicated that as few as five exercise repetitions were sufficient to yield statistically significant associations with ALSFRS-R.<br><br>CONCLUSIONS: These results suggest that prescribed exercise can effectively quantify upper limb function and track longitudinal decline comparably to free-living observation. The proposed method may serve as an alternative that decreases participation burden, increases study adherence, and extends diagnostic accessibility.}, }
@article {pmid41572495, year = {2026}, author = {Zaman, A and Drake, SS and Fournier, AE}, title = {Extracellular Vesicle-Derived microRNAs as Fluid Biomarkers in Neurodegenerative Diseases: A Systematic Review.}, journal = {Journal of neurochemistry}, volume = {170}, number = {1}, pages = {e70323}, pmid = {41572495}, issn = {1471-4159}, support = {//MS Canada/ ; /CAPMC/CIHR/Canada ; //Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9;/ ; //Myelin Repair Foundation/ ; //Fonds de recherche du Qu&#xe9;bec/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics/cerebrospinal fluid/blood/metabolism ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/cerebrospinal fluid/metabolism/blood ; Biomarkers/cerebrospinal fluid/blood/metabolism ; Animals ; }, abstract = {Given the absence of curative treatments for neurodegenerative diseases, early detection and therapeutic intervention are critical to slowing disease progression. Extracellular vesicles (EVs) have emerged as promising biomarkers for neurodegeneration, owing to their accessibility in bodily fluids and dynamic molecular cargo, including microRNAs (miRNAs). The last decade has seen accumulating evidence for miRNA dysregulation in circulating EVs from people with neurodegenerative diseases; however, assessing reproducibility between studies remains challenging, largely due to clinical and methodological heterogeneity. In this systematic review, we comprehensively searched the MEDLINE database for studies investigating miRNA expression in biofluids from people with neurodegenerative diseases. We extracted miRNA expression data from 185 peer-reviewed publications, published until June of 2025, reporting altered miRNA levels in fluid-derived EVs from people with neurodegenerative diseases. We consolidated results between studies to identify the most frequently dysregulated miRNAs across diseases, with a focus on Alzheimer's disease, Parkinson's disease, mild cognitive impairment, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, stroke, traumatic brain injury, and schizophrenia. Evaluating tissue specificity of frequently dysregulated miRNAs revealed enrichment of select miRNAs in the nervous system relative to blood and immune compartments. Summarizing miRNA regulation across biofluids emphasized consistencies between cerebrospinal fluid and plasma, but not serum. We highlight circulating miRNAs that may be reflective of neuropathology, including miR-143-3p, miR-127-3p, miR-9-5p, miR-15a-5p, and miR-125b-5p. Finally, we provide a repository of miRNA expression data from over 30 neurodegenerative conditions which can be exploited to further investigate miRNA regulation in diseases of interest.}, }
@article {pmid41572578, year = {2026}, author = {She, JW and Lin, LA and Aerathupalathu Janardhanan, J and Wang, IC and Hsu, FC and Tseng, HS and Hsiao, YS and Yu, HH}, title = {Precision Channel Engineering of Nanotube-Embedded Organic Electrochemical Transistors for Ultrasensitive Neurofilament Light Chain Detection.}, journal = {ACS applied bio materials}, volume = {9}, number = {4}, pages = {2271-2281}, pmid = {41572578}, issn = {2576-6422}, mesh = {*Nanotubes/chemistry ; *Neurofilament Proteins/analysis ; *Transistors, Electronic ; *Biosensing Techniques ; *Electrochemical Techniques/instrumentation ; *Biocompatible Materials/chemistry/chemical synthesis ; Humans ; Particle Size ; Materials Testing ; Surface Properties ; }, abstract = {The quantitative monitoring of neurofilament light chain (Nf-L) is critical for the early diagnosis and prognosis of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), yet achieving femtomolar sensitivity in a portable, label-free format remains a formidable challenge. Here, we report a high-performance organic electrochemical transistor (OECT) immunosensor engineered via the precise template-free electropolymerization of a dual-functional poly(EDOT-COOH-co-EDOT-EG3) copolymer. By systematically modulating the polymerization kinetics, we elucidated a decisive structure-function relationship governing biosensing efficacy: while microstructured channels formed at longer deposition times exhibited superior intrinsic transconductance due to maximized volumetric capacitance, the optimized nanotubular architecture provided the ideal balance of open porosity and accessible surface area. This specific nanotopography facilitated a significantly higher density of covalent antibody immobilization compared to its microstructured counterpart, thereby dominating the signal transduction mechanism through enhanced dielectric barrier formation upon antigen binding. Capitalizing on this morphology-governed sensitivity, the platform achieved a theoretical limit of detection (LOD) of 0.062 fg/mL (3σ criterion) and a rigorous LOD of 32.77 fg/mL (Hubaux-Vos method) across a broad dynamic range, along with exceptional selectivity and operational stability over 500 cycles. These findings underscore the critical role of precision channel engineering in bioelectronics, establishing a robust, lithography-free pathway for next-generation point-of-care diagnostics targeting diseases.}, }
@article {pmid41572777, year = {2026}, author = {Liu, X and Lv, Z and Xu, G and Chen, Y and Liu, H and Xu, P}, title = {Investigating the Multiple Regulatory Mechanisms and Therapeutic Targets of PHLDA1 in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X413561251125064110}, pmid = {41572777}, issn = {1875-6190}, abstract = {PHLDA1 (pleckstrin homology-like domain family A member 1) is a pleiotropic regulatory protein that affects key biological processes such as apoptosis, pyroptosis, immune inflammation, autophagy, metabolism, and oxidative stress. PHLDA1 plays a significant role in the pathological mechanisms of neurological diseases. This article systematically reviews the molecular characteristics of PHLDA1 and its core role in cerebrovascular diseases such as cerebral ischemia/ reperfusion injury, cerebral hemorrhage, subarachnoid hemorrhage, epilepsy, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Studies have shown that PHLDA1 promotes disease progression by regulating signalling pathways such as the NF-κB, MAPK, NLRP3 inflammasome, PPARγ, and Nrf2 pathways, thereby exacerbating neuroinflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and pyroptosis in neurons. Its expression is regulated by the dynamic balance of miRNAs (such as miR-194 and miR-101), transcription factors (Egr1 and BHLHE40), and heat shock proteins (HSPs/HSF1). In addition, PHLDA1 has become a potential target for intervention in neurodegenerative and ischemic injuries by inhibiting FundC1-mediated mitochondrial autophagy, regulating microglial polarization, and activating TRAF6-dependent neuroinflammation. This article not only clarifies the pathogenic mechanism of PHLDA1 but also summarizes the relevant intervention strategies targeting PHLDA1, hoping to provide a corresponding theoretical basis and reference for the development of precision therapies for neurological diseases.}, }
@article {pmid41573237, year = {2026}, author = {Triyono, T and Nita, RW and Suarja, S and Handayani, PG and Feberiani, RD and Hidayat, H}, title = {Self-Efficacy as the Key Mechanism in Student Help-Seeking: A Commentary on Patricio et al (2025).}, journal = {Chronic stress (Thousand Oaks, Calif.)}, volume = {10}, number = {}, pages = {24705470261416642}, pmid = {41573237}, issn = {2470-5470}, abstract = {This commentary highlights the significance of Patricio et al.'s (2025) findings on the mediating role of self-efficacy in the relationship between shyness and help-seeking among Filipino college students. The study challenges assumptions that shyness directly hinders help-seeking and emphasizes the cultural influence of hiya. Notably, self-efficacy mediates help-seeking for suicidal ideation, underscoring its importance in high-risk situations and its relevance for suicide-prevention initiatives in higher education. We further discuss the roles of stigma, social support, and cultural expectations, as well as the need for gender-sensitive research. The commentary advocates culturally grounded interventions to strengthen student mental-health help-seeking.}, }
@article {pmid41573891, year = {2025}, author = {Gomberg, TA and Elmsaouri, S and Kopalle, HM and Baughn, MW and Beccari, MS and McAlonis-Downes, M and Artates, JW and Pant, D and Mak, H and Smargon, AA and Sander, TC and Garcia, E and Lee, DP and Cleveland, DW and Yeo, GW}, title = {Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.01.691001}, pmid = {41573891}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by the selective deterioration of motor neurons in the central nervous system (CNS). A key driver of this pathogenesis is nuclear loss of ALS-associated protein TDP-43, leading to mis-splicing of TDP-43 targets including important neuronal genes STMN2 and UNC13A . Here, we have developed a gene therapy strategy for ALS and related TDP-43 proteinopathies, to correct mis-splicing of both STMN2 and UNC13A cryptic exons using small nuclear RNAs (snRNAs) encoded from a single vector. We identified promoter sequence elements to increase therapeutic snRNA expression by 10-fold, then further optimized the expression cassette with combinatorial snRNA targeting to rescue multiple cryptic splicing targets. The engineered snRNAs restored normal pre-mRNA processing of both STMN2 and UNC13A transcripts despite TDP-43 loss of function, rescuing stathmin-2 protein levels in iPSC derived motor neurons, restoring their axonal regeneration capacity to wild-type levels. In addition, adeno-associated virus (AAV) delivery of the snRNAs to the murine central nervous system in the constitutive cryptic splicing model Stmn2 [HumΔGU] fully restored cortical Stmn2 pre-mRNA processing, highlighting the utility of snRNAs as a therapeutic modality in vivo . Together, this study demonstrates that snRNAs are a promising and versatile therapeutic strategy for the simultaneous correction of multiple aberrant transcripts affected by cryptic splicing in TDP-43 proteinopathies.}, }
@article {pmid41574092, year = {2026}, author = {Khurana, S and Gourie-Devi, M and Vats, Y and Verma, S and Ganguly, NK and Chugh, P and Sharma, A and Khanna, L and Dhawan, U and Taneja, V}, title = {Clinical and genetic determinants of survival in amyotrophic lateral sclerosis patients from North India.}, journal = {Brain communications}, volume = {8}, number = {1}, pages = {fcag003}, pmid = {41574092}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, with significant clinical and genetic variability. While the role of genetic factors is well-established in ALS pathogenesis, their impact on survival outcomes remains poorly understood, particularly in the Indian population. We performed whole-exome sequencing in 159 ALS patients from North India (familial = 2, sporadic = 157). Clinical parameters, including age at onset, site of onset, sex, family history and survival, were recorded. Males exhibited shorter survival than females, but did not achieve statistical significance (median: 48 versus 60 years, P = 0.05). Bulbar-onset patients developed ALS at a significantly older age (mean: 59.7 versus 54 years, P = 0.007) and experienced poorer survival outcomes than spinal-onset patients (median: 48 versus 60 months, P = 0.03). A small subset of ALS patients (6.3%, n = 10) had very long survival duration of more than 10 years. We identified 102 genetic variants in 92 ALS patients, of which 45 variants were novel. According to American College of Medical Genetics and Genomics guidelines, 13.5% of total variants were pathogenic, 19.8% were likely pathogenic, and 66.7% were variants of uncertain significance. The presence of genetic variations was significantly associated with delayed onset (mean: 53.4 versus 57.1 years, P = 0.049) and diminished life expectancy (median: 48 versus 60 months, P = 0.029). Variations in more than one gene were detected in 16.7% of the patients, supporting the theory of oligogenic basis for ALS. After adjusting for age at onset, increased risk of mortality was associated with males [hazard ratio = 1.740, 95% confidence interval (CI) = 1.105-2.740] and rare genetic variations (hazard ratio = 1.533, 95% CI = 1.001-2.350). Furthermore, bulbar onset (hazard ratio = 1.75, 95% CI = 1.11-2.75) was found to be a negative prognostic factor for survival. Our study provides valuable insights into the genetic complexity and its impact on clinical outcomes in ALS patients of North Indian origin.}, }
@article {pmid41575675, year = {2026}, author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M}, title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.}, journal = {Biogerontology}, volume = {27}, number = {1}, pages = {42}, pmid = {41575675}, issn = {1573-6768}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/therapy/microbiology ; *Aging/physiology ; Animals ; Probiotics/therapeutic use ; }, abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.}, }
@article {pmid41577086, year = {2026}, author = {Mercadante, S and Petronaci, A and Casuccio, A}, title = {Clinical Changes in Patients With Amyotrophic Lateral Sclerosis Admitted to a Home Care Program.}, journal = {Journal of pain and symptom management}, volume = {71}, number = {4}, pages = {560-566}, doi = {10.1016/j.jpainsymman.2025.12.026}, pmid = {41577086}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology/physiopathology/diagnosis/epidemiology ; Male ; Female ; *Home Care Services ; *Palliative Care ; Middle Aged ; Aged ; Advance Care Planning ; Italy ; Karnofsky Performance Status ; Longitudinal Studies ; }, abstract = {BACKGROUND: There is a lack of information in the literature about patients with amyotrophic lateral sclerosis (ALS) followed at home.<br><br>AIM: To characterize ALS patient demographics, longitudinal symptom trajectories, cognition, healthcare utilization, and advance care planning of an Italian home-based palliative care program cohort.<br><br>METHODS: New patients with ALS who required home palliative care were recruited for a period of one year and followed up for six months. Demographics, Karnofsky, ALS subtype, date of diagnosis, awareness, as well as ECAS (Edinburgh Cognitive and Behavioral ALS Screen) were recorded, as well as the date of diagnosis and initiation of home palliative care were collected. The use of noninvasive ventilation (NIV), mechanical ventilation by tracheostomy, gastrostomy, nasogastric tube, parenteral nutrition, were recorded at admission and during home care assistance. The existence of advance directives and shared advance care planning (ACP) was also collected. The ALS Functional Rating Scale-Revised (ALS-FRS-R) and symptom burden was measured by Edmonton Symptom Assessment System (ESAS) were measured at two-month intervals for six months.<br><br>RESULTS: Data from 34 consecutive patients with ALS admitted to palliative home care were analyzed over the period considered. While Karnofsky level significantly decreased, ECAS did not show significant changes. The need for vital supports, particularly NIV, increased over time. Only one patient provided an ACP decision at admission, and none provided a living will. The involvement of a legal administrator facilitated the use of ACP significantly over the six months. Seven patients died at home during the first six months of home palliative care, and one patient was lost to follow-up, because they were transferred to another region. No patient was admitted to hospice in the first six months of home palliative care.<br><br>CONCLUSION: In patients with ALS admitted to home palliative care Karnofsky level, total ESAS and ALS-FRS-R score slowly but significantly decreased over six months. Only six patients died within this period. The use of NIV increased over time. No patient required hospital or hospice admission. ACP and living wills were minimal, although ACP rate increased during the study period. The program enabled patients to remain in their homes, reducing the need for hospital care.}, }
@article {pmid41577127, year = {2026}, author = {Padilla-Lichtenberger, F and Hem, S and Haumont, E and Jungberg, E and Pajanoti, G and Astur, N and Guiroy, A and Landriel, F}, title = {Spanish Translation, Cross-Cultural Adaptation and Validation of the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) for Patients With Spinal Metastases.}, journal = {World neurosurgery}, volume = {207}, number = {}, pages = {124822}, doi = {10.1016/j.wneu.2026.124822}, pmid = {41577127}, issn = {1878-8769}, abstract = {BACKGROUND: Spinal metastases significantly impair health-related quality of life (HRQoL), particularly neurological function, pain, and physical independence. The Spinal Oncology Study Group Outcome Questionnaire (SOSGOQ 2.0) is a disease-specific PROM, but no validated Spanish version exists. This study aimed to translate, culturally adapt, and validate the SOSGOQ 2.0 for Spanish-speaking patients with spinal metastases.<br><br>METHODS: Following Beaton et al.'s cross-cultural adaptation guidelines, the SOSGOQ 2.0 was forward- and back-translated, reviewed by experts, and pretested with 10 patients. Psychometric validation was performed prospectively in 81 patients. Internal consistency was assessed using Cronbach's &#x3b1;, test-retest reliability using intraclass correlation coefficients (ICC, n = 21), and construct validity through correlations with SF-36 and EQ-5D domains. Known-groups validity was analyzed according to neurological status (ASIA scale) and pain severity (VAS).<br><br>RESULTS: The Spanish SOSGOQ 2.0 showed excellent internal consistency (overall &#x3b1; = 0.89; domain range 0.70-0.93) and high test-retest reliability (ICC = 0.88; 95% CI, 0.81-0.93). Convergent validity was supported by moderate-to-strong correlations with SF-36 domains (r = 0.67-0.71). Known-groups analysis demonstrated expected differences between ambulatory (ASIA D-E) and non-ambulatory (ASIA A-C) patients, and between low (VAS &#x2264;4) and high pain (VAS &#x2265;5) groups. Neurological improvement post-treatment was observed in 32% of the patients. The questionnaire was well understood and culturally appropriate.<br><br>CONCLUSIONS: The Spanish SOSGOQ 2.0 is a reliable and valid tool for assessing HRQoL in Spanish-speaking patients with spinal metastases, enabling standardized, disease-specific outcome measurement and supporting patient-centered care and international research collaboration.}, }
@article {pmid41577334, year = {2026}, author = {Berner, KJ and Mese, PO and Bowblis, JR and Applebaum, R}, title = {The Prevalence and Impact of Vaccination Programs: Differences Between Nursing Homes and Assisted Living Communities.}, journal = {Journal of the American Medical Directors Association}, volume = {27}, number = {3}, pages = {106107}, doi = {10.1016/j.jamda.2025.106107}, pmid = {41577334}, issn = {1538-9375}, mesh = {Humans ; *Nursing Homes/statistics &amp; numerical data ; *Assisted Living Facilities/statistics &amp; numerical data ; *Immunization Programs/statistics &amp; numerical data ; COVID-19/prevention &amp; control/epidemiology ; Ohio/epidemiology ; Prevalence ; *Vaccination/statistics &amp; numerical data ; Male ; Surveys and Questionnaires ; Aged ; Female ; }, abstract = {OBJECTIVES: To compare the prevalence of vaccination programs between nursing homes (NHs) and assisted living communities (ALs) and examine how these programs relate to perceived hospitalization risk and temporary admission suspensions due to outbreaks.<br><br>DESIGN: Descriptive analysis of facility-level survey data from the 2023 Ohio Biennial Survey of Long-Term Care Facilities, which has a >90% response rate.<br><br>SETTING AND PARTICIPANTS: All licensed NHs and ALs in Ohio were surveyed and answered questions related to vaccination programs (n = 736; n = 623).<br><br>METHODS: Three measures were analyzed: presence of a vaccination program for 7 vaccine-preventable illnesses [influenza; COVID-19; respiratory syncytial virus (RSV); pneumococcal; hepatitis B; shingles; and tetanus, diphtheria, and pertussis (Tdap)], perceived risk of transferring residents to the hospital for these illnesses, and temporary suspension of admissions due to outbreaks. All measures were binary and sample averages were calculated separately for NHs and ALs. Facility characteristics associated with COVID-19-related admission suspensions were compared.<br><br>RESULTS: NHs had a higher prevalence of vaccination programs for all 7 vaccine-preventable illnesses compared with ALs. The largest differences were observed for RSV, pneumococcal, hepatitis B, shingles, and Tdap. ALs reported higher perceived risk of transferring residents to the hospital for all illnesses, whereas NHs reported the highest perceived risk for respiratory illnesses. Temporary admission suspensions due to outbreaks were uncommon; when reported, they were primarily associated with COVID-19. Facilities with COVID-19-related suspensions were more likely to be smaller and not-for-profit/government owned. NHs with outbreaks were more often located in rural areas, and ALs with outbreaks were more often located in urban areas.<br><br>CONCLUSIONS AND IMPLICATIONS: Significant disparities exist in vaccination program implementation between NHs and ALs. Expanding vaccination programs in ALs may reduce hospitalization risk and strengthen outbreak prevention. Targeted policy efforts, improved education, and resource allocation are needed to ensure equitable access to comprehensive vaccination programs across long-term care settings.}, }
@article {pmid41578918, year = {2026}, author = {Silva, ST and de Queiroz Aquino, LM and Aires, DN and de Souza, AA and de Macedo, JVB and da Silva Teixeira, S and de Melo, LP and de Macedo Borges, LRD and Lindquist, ARR and de Medeiros Valentim, RA and Ribeiro, T}, title = {Pain and fatigue in amyotrophic lateral sclerosis: a multiple methods study.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/17582024.2026.2617856}, pmid = {41578918}, issn = {1758-2032}, abstract = {INTRODUCTION: Pain and fatigue are frequent symptoms in individuals with Amyotrophic Lateral Sclerosis (ALS) and the literature is controversial regarding the effectiveness of physiotherapy practices for managing these symptoms.<br><br>OBJECTIVE: To analyze the profile of pain and fatigue symptoms in a Brazilian sample with ALS and identify physiotherapy practices.<br><br>METHODS: A multimethods study composed of prospective cross-sectional design and systematic retrospective design. Data on pain and fatigue were collected and literature searches were conducted and risk of bias (PEDRro scale) and evidence quality (SIGN system) were evaluated.<br><br>RESULTS: The sample (72 individuals) had a mean score of 4.31 (pain) and 37.2 (fatigue), indicating moderate levels of symptoms. The systematic review identified various physiotherapy practices for treating pain and fatigue.<br><br>CONCLUSION: Prospective analysis of pain and fatigue profiles in individuals with ALS in Brazil revealed moderate levels of both symptoms. The systematic retrospective analysis indicated uncertainty regarding the effect of physiotherapy.}, }
@article {pmid41579294, year = {2026}, author = {Foffani, G and Urso, D and Hiller, J and Piccininni, M and Marin, B and Logroscino, G}, title = {The multistep pathogenic hypothesis of amyotrophic lateral sclerosis is incompatible with the epidemiological data.}, journal = {European journal of epidemiology}, volume = {41}, number = {1}, pages = {1-13}, pmid = {41579294}, issn = {1573-7284}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/genetics ; Incidence ; Bayes Theorem ; Female ; Middle Aged ; Male ; Aged ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease whose incidence increases with age. According to the gene-time-environment hypothesis, ALS onset occurs through the interaction between genes and environmental exposures during ageing, which may involve a continuous accumulation process. Alternatively, the multistep pathogenic hypothesis, based on the Armitage-Doll multistep model from cancer research, posits that a discrete number of specific sequential "hits" are necessary to trigger ALS. Here we analyzed three large population-based epidemiological datasets of ALS to formally test whether the ALS age-incidence curve is better described by a power law, as predicted by the Armitage-Doll model, or by an exponential function, which is generally associated to continuous accumulation of damage and is incompatible with the Armitage-Doll model. We obtained moderate-to-extreme Bayesian evidence in favor of the exponential function compared to the power law. Cancer data were instead better aligned, as expected, with the power law. These results suggest that the multistep pathogenesis hypothesis based on the Armitage-Doll model cannot be extended from cancer to ALS, because it is incompatible with the epidemiological data. This calls for a re-consideration of the current understanding of ALS pathogenesis. Our work also warns against extending the Armitage-Doll multistep model from cancer to other aging-related diseases solely based on age-incidence curves.}, }
@article {pmid41579663, year = {2026}, author = {Casabona, E and Cusato, J and Clari, M and Albanesi, B and Cattaneo, D and Giulio, PD and Dimonte, V}, title = {Association between anticholinergic burden scales and recurrent falls in independently living older adults: a cross-sectional study.}, journal = {Geriatric nursing (New York, N.Y.)}, volume = {69}, number = {}, pages = {103853}, doi = {10.1016/j.gerinurse.2026.103853}, pmid = {41579663}, issn = {1528-3984}, abstract = {This study examined the association between medications with anticholinergic (ACh) activity and the risk of falls in community-dwelling older adults enrolled in a home monitoring service. A cross-sectional design was applied, and logistic regression analyses were adjusted for age, sex, comorbidities, and functional status. The sample included 84 participants who had experienced at least one fall, of whom 72.6% were single fallers and 27.4% recurrent fallers (≥2 falls in 12-months of observation). Participants were divided into two groups: those taking medications (n = 55) and those not on medication (n = 29). A total of 126 falls were reported, with no significant difference in the number of falls between the two groups. The prevalence of ACh burden, assessed using ten different scales, ranged from 5.4% to 30.9% among fallers. Within the medication group, no significant differences were observed in the presence of ACh burden (≥1) between single and recurrent fallers. However, recurrent fallers in this group (n = 15) had higher scores on some scales compared with single fallers. Despite this, the discriminative ability of the ACh burden scales for identifying recurrent fallers were limited, with several, particularly the ALS and CrAS scales, failing to reach acceptable thresholds. After adjustment, the AAS scale suggested that older adults were over nine times more likely to experience recurrent falls compared with a single fall (OR=9.24; 95% CI 1.02-77.49; p = 0.004). Overall, these findings highlight the limited clinical utility of current ACh burden scales in supporting medication review as part of fall prevention strategies for older adults.}, }
@article {pmid41579806, year = {2026}, author = {Sarwar, S and Mehmood, T and Iqbal, M}, title = {Advanced spectral modeling for bacterial strains: A MARS-PLS2 approach with Lasso regularization and baseline optimization.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {351}, number = {}, pages = {127506}, doi = {10.1016/j.saa.2026.127506}, pmid = {41579806}, issn = {1873-3557}, mesh = {Least-Squares Analysis ; *Bacteria/chemistry/classification ; Spectrophotometry, Infrared/methods ; Algorithms ; }, abstract = {The natural characteristics of the infrared spectroscopic data are that it tends to distort the baseline, there is high-dimensionality and non-linear correlation that hinder reliable prediction of biochemical properties. To overcome these obstacles, this study introduces an integrated MARS-PLS2-Lasso framework that incorporates the effective baseline correction, non-linear regression, latent variable extraction, and sparse variable selection to promote the chemometric modeling accuracy and interpretability. Out of four baseline correction methods, viz. Asymmetric Least Squares (ALS), AirPLS, Polynomial fitting, and Wavelet baseline correction, the Wavelet method (sym8, Level 5) was found to be the most successful, in that it was able to represent local spectral variation with low-frequency noise. This technique achieved high predictive accuracy with RMSE = 0.2846-0.6857, MAE = 0.2371-0.5445 and MSE = 0.0810-0.4705 specifying both high model fit and minimal residual error across bacterial spectra. The Wavelet-corrected spectra revealed six key functional regions that contributed most significantly to bacterial differentiation: 720cm[-1] to 750cm[-1] (C-Cl stretching, CH bending), 1000cm[-1] to 1300cm[-1] (C-O stretching, esters, carboxylic acids), 1500cm[-1] to 1650cm[-1] (CC stretching), 1687cm[-1] to 1793cm[-1] (CO stretching, conjugated carbonyls), 2771cm[-1] to 3143cm[-1] (CH stretching, alkanes, alkenes), 3290cm[-1] to 3595cm[-1] (O-H and NH stretching). Vibrational domains of interest are biochemical components of lipids, proteins, amides and polysaccharides that determine the structural integrity and metabolic activity of bacteria. The proposed MARS-PLS2-Lasso model leverages Multivariate Adaptive Regression Splines (MARS) to capture nonlinear relationships through adaptive basis functions, while Partial Least Squares (PLS2) extracts latent components that maximize covariance between spectral predictors and multiple bacterial responses. Lasso regularization adds sparsity to the model and reduces the complexity of the model, as well as penalizes less interesting basis functions, which overfit the model. Such a combination is used to provide a reasonable approximation of the parameter even in high-dimensional spectral data. In general, MARS-PLS2-Lasso provides a sound, interpretable, and chemically consistent way of high dimensional infrared spectral modeling. It is highly predictive, less noisy and has a more adequate manner of interpreting spectral-biochemical interactions, and thus, a bright way of bacteria modeling, spectral diagnostics and further use in bio-analytical spectroscopy.}, }
@article {pmid41579929, year = {2026}, author = {Murakami, K and Sudou, N and Kurata, A and Kawaguchi-Niida, M}, title = {An ALS-associated mutant SOD1 protein can be eliminated in microglia culture by selective autophagy.}, journal = {Neuroscience}, volume = {598}, number = {}, pages = {47-58}, doi = {10.1016/j.neuroscience.2026.01.017}, pmid = {41579929}, issn = {1873-7544}, mesh = {*Microglia/metabolism/pathology ; Animals ; Superoxide Dismutase-1/metabolism/genetics ; *Autophagy/physiology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Mice, Transgenic ; Mice ; Mutation ; *Superoxide Dismutase/metabolism/genetics ; Spinal Cord/metabolism/pathology ; Cells, Cultured ; Humans ; }, abstract = {The acquired toxicity of the familial amyotrophic lateral sclerosis (ALS)-associated mutant Zn-superoxide dismutase 1 (SOD1) protein has been implicated in motoneuron death, and cytosolic aggregates or inclusions have been observed in the cytoplasm of motoneurons, astrocytes, and neuronal axons but not in that of microglia. This study elucidates the mechanisms by which mutant SOD1 does not aggregate in and is cleared by microglia. We generated pcDNA3-Venus-tagged SOD1 constructs: wild-type SOD1 and mutant SOD1 were used as controls, and the A4V, D90A, and G93A SOD1 mutants were used as disease-related constructs; these plasmids were introduced into the Ra2 microglia line for subsequent evaluation. In spinal cords collected from postsymptomatic G93A mice, very little aggregation of the mutant SOD1 protein was detected in microglia, consistent with previous reports. Our new findings, which were based on immunohistochemical, Western blot, and enzyme immunoassay analyses, revealed that the protein expression of mutant SOD1 in microglia is significantly lower than that of wild-type SOD1. Furthermore, we observed the recovery of mutant SOD1 protein levels in autophagy suppression experiments and its colocalization with WDFY3, a selective autophagy-related protein. These in vitro results demonstrate that only the mutant SOD1 protein (i.e., not wild-type SOD1) is degraded by selective autophagy. Furthermore, we found that both wild-type and mutant SOD1 are secreted directly from microglia. These findings provide an opportunity to elucidate the precise mechanism through which microglia manage mutant SOD1 proteins during the pathological process of ALS and are likely to lead to improvements in ALS treatment strategies.}, }
@article {pmid41581145, year = {2026}, author = {McCourt, B and Lemr, K and Chakrabarti, S and Woidke, E and Ramaiah, S and Singh, V and Sangwan, N and Brown, JM and Cominelli, F and Rodriguez-Palacios, A and Burberry, A}, title = {C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen.}, journal = {Cell reports}, volume = {45}, number = {2}, pages = {116906}, pmid = {41581145}, issn = {2211-1247}, support = {K99 AG057808/AG/NIA NIH HHS/United States ; R00 AG057808/AG/NIA NIH HHS/United States ; R01 AG085316/AG/NIA NIH HHS/United States ; R03 AG080175/AG/NIA NIH HHS/United States ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Animals ; Humans ; Amyotrophic Lateral Sclerosis/microbiology/genetics/metabolism/pathology ; *Glycogen/metabolism ; Mice ; *Inflammation/pathology/metabolism ; *Myeloid Cells/metabolism ; Gastrointestinal Microbiome ; Male ; Female ; Frontotemporal Dementia ; Mice, Inbred C57BL ; Brain/metabolism ; }, abstract = {Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation. Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain. A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.}, }
@article {pmid41581418, year = {2026}, author = {Aphale, P and Dokania, S and Shekhar, H}, title = {Critique of Gammenthaler-Zaugg et al.'s Study on Point-of-Care Electroencephalography for Seizure Detection.}, journal = {Pediatric neurology}, volume = {176}, number = {}, pages = {124-125}, doi = {10.1016/j.pediatrneurol.2026.01.005}, pmid = {41581418}, issn = {1873-5150}, }
@article {pmid41581503, year = {2026}, author = {Hung, ST and Linares, GR and Chang, WH and Eoh, Y and Krishnan, G and Mendonca, S and Hong, S and Shi, Y and Santana, M and Kueth, C and Macklin-Isquierdo, S and Perry, S and Duhaime, S and Maios, C and Chang, J and Perez, J and Couto, A and Lai, J and Li, Y and Alworth, SV and Hendricks, E and Wang, Y and Zlokovic, BV and Dickman, DK and Parker, JA and Zarnescu, DC and Gao, FB and Ichida, JK}, title = {PIKFYVE inhibition mitigates disease in models of diverse forms of ALS.}, journal = {Cell}, volume = {189}, number = {3}, pages = {987-992}, doi = {10.1016/j.cell.2026.01.004}, pmid = {41581503}, issn = {1097-4172}, }
@article {pmid41581940, year = {2026}, author = {Behera, P and Rangappa, N and Chandrashekar, M and Mishra, A and Chinnathambi, S and Mishra, M}, title = {The multifaceted role of antimicrobial peptides in neurodegeneration: Insights from Drosophila and beyond.}, journal = {Advances in protein chemistry and structural biology}, volume = {149}, number = {}, pages = {419-444}, doi = {10.1016/bs.apcsb.2025.08.003}, pmid = {41581940}, issn = {1876-1631}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/immunology/metabolism/pathology ; *Antimicrobial Peptides/metabolism/immunology ; *Drosophila ; Disease Models, Animal ; Immunity, Innate ; }, abstract = {Antimicrobial peptides (AMPs) are tiny proteins essential for innate immunity in various taxa, including mammals and insects. They provide defence against a wide range of pathogens, including bacteria, viruses, fungi, and parasites. Apart from their antimicrobial properties, new studies have revealed the roles of AMPs in brain ageing, neurodegeneration, and neuroinflammation. With an emphasis on their dysregulation in glial and neuronal tissues and their role in neuroinflammation, mitochondrial dysfunction, and neuronal loss, we reviewed the new function of AMPs beyond their antimicrobial activity. Findings from Drosophila models of Huntington's disease, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Ataxia-telangiectasia show that immune pathways, like Toll and immune deficiency, drive persistent or ectopic AMP expression, which is similar to the inflammatory processes seen in human neurodegenerative diseases. Furthermore, the dual function of AMPs as mediators of sterile inflammation and protective immunological agents reveals a universal paradox. The translational relevance of these findings is further supported by comparisons with human AMPs, such as LL-37 and β-defensins. LL-37 and β-defensins levels were found to be increased in the cerebrospinal fluid of patients suffering from meningitis. LL-37 is released from neurons and activates glial cells, boosting the production of inflammatory cytokines and decreasing neuronal survival. This chapter redefines AMPs as not only sentinels of microbial defence but also as important participants in preserving or disturbing brain homeostasis by establishing them as a link between immunity and neurobiology.}, }
@article {pmid41582437, year = {2026}, author = {Chen, X and Cao, Z and Liang, X and Zhao, T and Wang, Y}, title = {TRIM9 and TRIM26 Interact with UBQLN2[P497H] to Modulate Its Proteasomal Degradation.}, journal = {ACS chemical biology}, volume = {21}, number = {2}, pages = {230-234}, pmid = {41582437}, issn = {1554-8937}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Proteasome Endopeptidase Complex/metabolism ; *Autophagy-Related Proteins/metabolism/genetics ; Proteolysis ; *Ubiquitin-Protein Ligases/metabolism ; *Tripartite Motif Proteins/metabolism/genetics ; HEK293 Cells ; *Cell Cycle Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Protein Binding ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. ALS-linked mutations in UBQLN2 promote protein aggregation and disrupt proteostasis, yet the mutation-specific protein interactomes and their functional relevance remain poorly defined. We employed APEX2 proximity labeling, together with affinity enrichment of biotinylated peptides and LC-MS/MS analysis, to profile the interactomes of wild-type UBQLN2 and two ALS-linked variants, UBQLN2[P497H] and UBQLN2[P497S]. We identified 785 unique biotinylated proteins, many of which exhibit augmented enrichment in the proximity proteomes of the two mutants over wild-type UBQLN2. Notably, the E3 ubiquitin ligases TRIM9 and TRIM26 were selectively enriched in the proximity proteome of UBQLN2[P497H], which we validated by coimmunoprecipitation followed by Western blot analysis. Fractionation analysis revealed coaccumulation of TRIM9 and TRIM26 with UBQLN2[P497H] in the insoluble fraction, consistent with its heightened aggregation propensity. Treatment of UBQLN2[P497H]-expressing cells with a proteasomal inhibitor led to elevated accumulation of a C-terminal UBQLN2 fragment that is absent in cells expressing wild-type UBQLN2 or its P497S mutant. Individual knockdown of TRIM9 and TRIM26 significantly increased the abundance of the fragment, establishing UBQLN2[P497H] as a substrate for TRIM9- and TRIM26-mediated ubiquitinylation and subsequent proteasomal degradation. These findings nominate TRIM9 and TRIM26 as specific interactors of UBQLN2[P497H] and as regulators of a previously underexplored C-terminal UBQLN2 fragment, suggesting that impaired clearance of this species may contribute to ALS pathogenesis.}, }
@article {pmid41582654, year = {2026}, author = {Long, C and Horty, LG}, title = {Synthesis of Florasulam Stable Isotopes to Enable Identification of Degradants by Mass Spectrometry for Re-registration Studies.}, journal = {Journal of labelled compounds &amp; radiopharmaceuticals}, volume = {69}, number = {2}, pages = {e70005}, doi = {10.1002/jlcr.70005}, pmid = {41582654}, issn = {1099-1344}, mesh = {*Herbicides/chemical synthesis/chemistry ; Mass Spectrometry/methods ; *Pyrimidines/chemical synthesis/chemistry ; *Triazoles/chemical synthesis/chemistry ; Carbon Isotopes/chemistry ; Chemistry Techniques, Synthetic ; Nitrogen Isotopes/chemistry ; Isotope Labeling ; }, abstract = {Florasulam is a triazolopyrimidine herbicide that controls broadleaf and grass weeds in cereal crops and turf. It acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. Due to its potency, florasulam is effective at very low application rates making it cost-effective with reduced environmental off-target effects. As is common practice, florasulam has been subject to periodic reviews by regulatory agencies during re-registration requirements since its introduction into the market in 1998. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this re-registration process for florasulam, new environmental fate studies were conducted to meet new European Food Safety Authority (EFSA) guidelines. Consequently, florasulam-[triazole([13]C,[15]N2)] and florasulam-[phenyl([13]C6)] stable isotopes were synthesized to support the re-registration process.}, }
@article {pmid41583004, year = {2025}, author = {Hu, Z and Wan, JJ and Yan, QQ and Fan, Y and Liu, J}, title = {Exploring rare coding variants in UK biobank: preliminary associations with motor neuron disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1735522}, pmid = {41583004}, issn = {1663-4365}, abstract = {INTRODUCTION: Previous studies have illuminated a significant genetic component in motor neuron disease (MND) pathogenesis, with several causative genes identified. However, a substantial proportion of MND cases remain genetically unexplained, particularly regarding the comprehensive contribution of rare, high-impact variants across the exome.<br><br>METHODS: Leveraging whole-exome sequencing data from nearly half a million UK Biobank participants, we systematically investigated the association between high-confidence protein-truncating variants (HC PTVs) and MND risk in a Caucasian subset. Our large-scale gene-based association analysis utilized REGENIE software and LOFTEE-defined HC PTVs.<br><br>RESULTS: We identified significant preliminary associations between HC PTVs in 14 genes and an increased risk of MND. Notably, while NEK1 has been previously implicated in ALS, the remaining 13 genes (BLVRB, KLHL32, RIMS2, DYDC2, DCBLD1, ANXA4, COMP, TRIM42, ANO4, NFX1, CFAP206, CKAP2L, and ANGPTL4) show preliminary associations as novel candidate loci for the disease. Functional enrichment analyses further indicated that these genes are significantly involved in critical biological pathways, including collagen-containing extracellular matrix organization and ciliary function. Furthermore, tissue specificity analysis highlighted a strong enrichment of these genes' expression in brain regions, with the hypothalamus showing the highest specificity.<br><br>DISCUSSION: These findings suggest a potential expansion of the known genetic landscape of MND, and highlight novel biological pathways implicated in its pathogenesis. This study underscores the power of large-scale population genetics in uncovering critical disease mechanisms and offers new avenues for mechanistic research and therapeutic development for MND, pending independent validation.}, }
@article {pmid41583923, year = {2026}, author = {Gonzalez, M and Lato, TJ and Alonzo, EA and Park, S and Green, MT and Soto-Rodriguez, N and Shaw, BF}, title = {Does sod1 encode a molecular clock? Mutations that mimic asparagine deamidation inhibit heterodimerization with ALS-mutant SOD1.}, journal = {RSC chemical biology}, volume = {7}, number = {3}, pages = {473-484}, pmid = {41583923}, issn = {2633-0679}, support = {R01 EY036371/EY/NEI NIH HHS/United States ; }, abstract = {The self-exchange of subunits by protein homodimers is a common protein-protein interaction in vivo. In heterozygous genetic disorders involving homodimeric gene products, both mutant and WT proteins can exchange subunits (heterodimerize). This form of heterodimerization can be analytically challenging to study. In this paper, we used capillary electrophoresis to investigate how deamidation of multiple asparagine residues (to aspartate) in homodimeric Cu, Zn superoxide dismutase-1 (SOD1) affected the rate and free energy of heterodimerization between WT and mutant SOD1 that cause amyotrophic lateral sclerosis (ALS). To model asparagine deamidation, Asn to Asp substitutions were introduced at five Asn residues predicted to undergo the most rapid deamidation in SOD1 (N26D, N131D, N139D, N65D, N19D). This model of penta-deamidated SOD1 did not heterodimerize with WT SOD1 or E100K SOD1 (linked to ALS). In contrast, the quad-variant N26D/N131D/N139D/N19D SOD1 did heterodimerize. These results suggest that the WT SOD1 protein has an intrinsic "timer" or "molecular clock" (as spontaneous Asn deamidation has been described) that effectively stops its heterodimerization after the SOD1 protein has existed in solution for ∼3 months.}, }
@article {pmid41583971, year = {2018}, author = {Lawson, V and Robbins, NM}, title = {The Potential Misdiagnosis of Multifocal Motor Neuropathy as Amyotrophic Lateral Sclerosis-A Case Series.}, journal = {US neurology}, volume = {14}, number = {2}, pages = {102-107}, pmid = {41583971}, issn = {1758-4000}, support = {K23 NS042713/NS/NINDS NIH HHS/United States ; }, abstract = {Multifocal motor neuropathy (MMN) is a rare neuropathy that is often treatable with immunomodulatory therapy if diagnosed early. However, accurate diagnosis is difficult due to a significant overlap of symptoms with other neurological conditions, such as amyotrophic lateral sclerosis (ALS). Evidence of immunoglobulin M (IgM) anti-ganglioside GM1 antibodies and electrodiagnostic findings of conduction block are useful diagnostic criteria for MMN but are not universal findings. This review explores the differential diagnosis of MMN and ALS and discusses three cases of MMN initially diagnosed as ALS, in which the correct diagnosis allowed effective treatment. These cases highlight the need for greater awareness of MMN among physicians.}, }
@article {pmid41585268, year = {2025}, author = {Srivastav, J and Sharma, S}, title = {Viral and non-viral cellular therapies for neurodegeneration.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1718669}, pmid = {41585268}, issn = {2296-858X}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.}, }
@article {pmid41585784, year = {2026}, author = {Jilani, SB and Ashok, N and Bomble, YJ and Guss, AM and Olson, DG}, title = {Engineering Clostridium thermocellum for production of 2,3-butanediol from cellulose.}, journal = {Metabolic engineering communications}, volume = {22}, number = {}, pages = {e00269}, pmid = {41585784}, issn = {2214-0301}, support = {P20 GM113132/GM/NIGMS NIH HHS/United States ; }, abstract = {Clostridium thermocellum is a promising host for consolidated bioprocessing due to its ability to directly ferment cellulose into fuels and chemicals. However, natural product formation in this organism is limited. Here, we report engineering C. thermocellum for the production of 2,3-butanediol (23BD), a valuable industrial chemical. We functionally expressed a thermophilic 23BD pathway in this organism resulting in a 23BD titer of 19.7 mM from cellulose, representing a metabolic yield of 24%. We used a cell-free systems biology approach to identify limiting steps in the 23BD pathway, revealing that exogenous 23BD dehydrogenase (BDH) activity was essential for production, while native acetolactate synthase (ALS) and acetolactate decarboxylase (ALDC) activities were present but limiting in the parent strain. This approach also revealed redox balance limitations. We demonstrated that this improved understanding of redox balance limitations could be used to increase 23BD titer in vivo, showing that adding acetate could be used to increase 23BD yield. This work establishes a foundation for developing C. thermocellum into a robust platform for 23BD production directly from cellulose and highlights the utility of cell-free systems for guiding metabolic engineering in non-model organisms.}, }
@article {pmid41586107, year = {2025}, author = {Berthiaume, AA and Kleist, KN and Reda, SM and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Church, KJ}, title = {ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1582765}, pmid = {41586107}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration, muscle atrophy, and paralysis. The complexity of ALS pathology, driven by factors such as TDP-43 pathology, excitotoxicity, and neuroinflammation, has hindered therapeutic development. While riluzole (an anti-excitotoxic agent) is the current standard treatment, additional therapeutics are needed to address the broad spectrum of ALS-related pathology. ATH-1105, a small-molecule positive modulator of hepatocyte growth factor (HGF) signaling, has shown promise in preclinical models of ALS. Given the multifactorial nature of ALS and the growing recognition that combination approaches may represent the best treatment options, we investigated the therapeutic potential of ATH-1105 in a TDP-43-driven mouse model of ALS, by comparing and combining it with the known efficacious treatment of riluzole. Additionally, we characterize the mechanism by which ATH-1105 induces neuroprotective effects, emphasizing its effects on TDP-43 pathology.<br><br>METHODS: In vivo, the impact of daily oral treatment with ATH-1105, alone and in combination with riluzole, was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice. In vitro, the impact of ATH-1105 on TDP-43-related pathology was assessed in rat primary spinal motor neurons subjected to glutamate toxicity. To demonstrate target engagement, the neuroprotective effects of ATH-1105 were assessed via siRNA-mediated knockdown of MET (HGF receptor).<br><br>RESULTS: In vivo, ATH-1105 significantly improved neuromuscular function and reduced body weight loss, neurodegeneration, inflammation, and TDP-43 phosphorylation. The combination of ATH-1105 with riluzole led to greater therapeutic effects than either treatment alone. In vitro, the neuroprotective effects of ATH-1105 were shown to be associated with MET activation in motor neurons, which was confirmed via siRNA-mediated knockdown of MET. In motor neurons subjected to glutamate toxicity, ATH-1105 reduced extranuclear and phosphorylated TDP-43, and increased GSK3&#x3b2; phosphorylation (inactivation), a kinase involved in TDP-43 pathology. Additionally, ATH-1105 reduced the abnormal increase in autophagic proteins following glutamate toxicity.<br><br>DISCUSSION: Our study underscores the therapeutic potential of ATH-1105 in treating ALS, both as a standalone treatment and in combination with riluzole. ATH-1105 demonstrates neuroprotective effects that slow neuromuscular deterioration in a relevant mouse model, aligning with the need to counteract the neurodegeneration central to ALS.}, }
@article {pmid41586560, year = {2026}, author = {Muñoz-Rugeles, L and Alvarez-Idaboy, JR and Espinosa Rincón, N and Mejía-Ospino, E}, title = {Chemical repair of oxidized aromatic amino acids by monohydroxylated 2-pyridones.}, journal = {The Journal of chemical physics}, volume = {164}, number = {4}, pages = {}, doi = {10.1063/5.0307155}, pmid = {41586560}, issn = {1089-7690}, mesh = {Oxidation-Reduction ; *Pyridones/chemistry ; Density Functional Theory ; *Amino Acids, Aromatic/chemistry ; Tryptophan/chemistry ; *Antioxidants/chemistry ; Kinetics ; Free Radicals/chemistry ; }, abstract = {The oxidative modification of tryptophan and tyrosine residues in proteins has been strongly associated with the onset and progression of neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis. Consequently, the identification of small molecules capable of repairing these oxidized residues is of considerable medicinal interest. In this study, the antioxidant activity of four hydroxy-2-pyridones against tyrosyl and tryptophanyl radicals was investigated in silico using density functional theory, with the aim of elucidating their structure-activity relationships at the molecular level. Thermochemical analyses were conducted to evaluate the most favorable repair pathways, focusing on formal hydrogen transfer (FHT) and single electron transfer (SET) processes. For exergonic reactions, kinetic parameters were determined within the quantum mechanics-based overall free radical scavenging activity (QM-ORSA) protocol, providing predictive data on radical-scavenging efficiency. The results indicate that three of the tested pyridones can repair the tyrosyl radical and that two of them react at rates comparable with the dityrosine formation, thereby competing with this deleterious pathway. In contrast, all four pyridones are able to reduce the tryptophanyl radical, although the calculated kinetics suggest that they may not efficiently suppress the Trp-Trp cross-linking in small peptides. Mechanistic analysis further revealed that FHT proceeds through proton-coupled electron transfer for tyrosyl radical repair, whereas tryptophanyl radical repair involves a proton-electron sequential transfer mechanism. These findings establish hydroxy-2-pyridones as promising scaffolds for the rational design of neuroprotective antioxidants and provide molecular insights that may guide the development of new therapeutic agents targeting oxidative stress.}, }
@article {pmid41586932, year = {2026}, author = {Ma, H and Liu, M and Yang, J and Li, J and He, A and Li, M and Guan, W and Shi, J and Teng, J}, title = {Lipid Metabolic Mediators Bridge Ischemic Heart Disease and Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {396}, pmid = {41586932}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Lipid Metabolism/genetics ; *Myocardial Ischemia/metabolism/genetics/complications ; Mendelian Randomization Analysis ; MicroRNAs/metabolism/genetics ; Protein Interaction Maps ; }, abstract = {While epidemiological studies have linked cardiovascular disease (CVD) and amyotrophic lateral sclerosis (ALS), the causal pathways remain unclear. This study aims to clarify the causal relationship between CVD and ALS, with a focus on lipid metabolism as a potential mediator. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between CVD and ALS. Furthermore, we utilized mediation MR, summary-data-based MR analysis (SMR), the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) pathway analysis, miRNA interaction prediction analysis, and protein-protein interaction (PPI) studies to validate the mediating effect of lipid metabolism on the risk of CVD and ALS onset, as well as to predict potential signaling pathways and mechanisms. The MR analysis revealed a significant association between CVD, particularly IHD, and an increased risk of ALS. Mediation analysis indicated that the level of sphingomyelin (d34:0) in serum may mediate the effect of IHD on ALS, along with the identification of seven additional types of plasma metabolites. Furthermore, KEGG and GO analyses highlighted lipid metabolism pathways, including "cholesterol metabolism" and the "phospholipid metabolic process." Additionally, miRNA interaction prediction analysis identified MFGE8 as a potential therapeutic target. Our study identifies IHD as a vascular risk factor for ALS, driven by lipid metabolic dysregulation. The identification of sphingomyelin (d34:0) and MFGE8 as key mediators in lipid metabolic dysregulation offers potential preventive and therapeutic strategies for CVD patients at elevated risk of ALS.}, }
@article {pmid41587040, year = {2026}, author = {Tanaka, H and Black, LE and Forrest, SL and Danics, K and Sadia, N and Khodadadi, M and Tator, C and Smith, DH and Tartaglia, MC and Stewart, W and Kovacs, GG}, title = {Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy.}, journal = {JAMA neurology}, volume = {83}, number = {3}, pages = {231-241}, pmid = {41587040}, issn = {2168-6157}, support = {U01 NS137500/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/metabolism ; Male ; Female ; *Chronic Traumatic Encephalopathy/pathology/metabolism ; Aged ; *Spinal Cord/pathology/metabolism ; Middle Aged ; Case-Control Studies ; Retrospective Studies ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; DNA-Binding Proteins/metabolism ; Aged, 80 and over ; Autopsy ; Adult ; }, abstract = {IMPORTANCE: Exposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood.<br><br>OBJECTIVE: To evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain.<br><br>This case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025.<br><br>EXPOSURES: RHI history and CTE-NC presence.<br><br>MAIN OUTCOMES AND MEASURES: Informant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), &#x3b1;-synuclein, and amyloid-&#x3b2; (A&#x3b2;), as well as amyloid precursor protein and human leukocyte antigen DR.<br><br>RESULTS: Of 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n&#x2009;=&#x2009;14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), A&#x3b2; deposits (13 of 14 cases [93%]), and &#x3b1;-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE.<br><br>CONCLUSIONS AND RELEVANCE: This case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, A&#x3b2;, and &#x3b1;-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.}, }
@article {pmid41588209, year = {2026}, author = {Hou, M and Xie, X and Hu, J and Rominger, A and Shi, K and Xiao, L and Tang, Y and Hu, S}, title = {Systemic brain-body metabolic coupling patterns in amyotrophic lateral sclerosis: a whole-body [[18]F] fluorodeoxyglucose PET/CT study across clinical phenotypes.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {41588209}, issn = {1619-7089}, support = {81801740//National Natural Science Foundation of China/ ; 82272045//National Natural Science Foundation of China/ ; 2023LNJJ16//Clinical Research Foundation of the National Clinical Research Center for Geriatric Diseases(XIANGYA)/ ; 2022M723561//China Postdoctoral Science Foundation/ ; 2024JJ2094//Science Fund for Distinguished Young Scholars of Hunan Province/ ; grant number:Z2023004//National Key Clinical Specialty Scientific Research Project/ ; 2021RC4056//Science and Technology Innovation Program of Hunan Province/ ; CEIEC-2022-ZM02-0219//Key Program of Ministry of Industry and Information Technology of China/ ; }, }
@article {pmid41588556, year = {2026}, author = {Wei, Z and Wang, R}, title = {Vanadium Nitride Decorated Graphene With Abundant Active Sites as Chemical Anchor of Polysulfides and Redox Catalysts in Aluminum Sulfur Batteries for Enhanced Performance.}, journal = {ChemSusChem}, volume = {19}, number = {2}, pages = {e202501845}, pmid = {41588556}, issn = {1864-564X}, abstract = {Aluminum-sulfur (Al-S) batteries are garnering significant interest as candidates for affordable energy storage systems due to their high theoretical capacity of 1672 mAh g[-1] and the cost-effectiveness of naturally abundant aluminum and sulfur. Nevertheless, challenges such as poor cyclic reversibility and limited practical capacity have resulted in only a few reversibly operating Al-S cells to date. In this study, we introduce an improved Al-S battery configuration by incorporating a novel VN@graphene catalyst into the sulfur cathode in Al-S battery applications. Comprehensive electrochemical tests and ex situ characterizations reveal that, during discharge, the catalyst effectively suppresses the polysulfide shuttle effect through strong adsorption, whereas during charging, it enhances sulfide redox kinetics. Consequently, the modified Al-S cell delivers an initial capacity of approximately 1354 mAh g[-1], maintaining around 507 mAh g[-1] after 200 cycles.}, }
@article {pmid41588889, year = {2026}, author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R}, title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050421604251108045622}, pmid = {41588889}, issn = {1875-5828}, abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.}, }
@article {pmid41589677, year = {2026}, author = {Ozkan, A and Padmanabhan, HK and Shipman, SL and Azim, E and Kumar, P and Sadegh, C and Basak, AN and Macklis, JD}, title = {Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {41589677}, issn = {2050-084X}, support = {NS045523/NS/NINDS NIH HHS/United States ; DP1 NS106665/NS/NINDS NIH HHS/United States ; NS049553/NS/NINDS NIH HHS/United States ; Regeneration Project Fellowship//McKnight Brain Research Institute/ ; }, mesh = {Animals ; *SOXD Transcription Factors/metabolism ; Mice ; *Cell Differentiation ; Basic Helix-Loop-Helix Proteins/metabolism ; Nerve Tissue Proteins/metabolism ; *Neurons/physiology/cytology ; *Neural Stem Cells/physiology ; *Proteoglycans/metabolism ; *Cerebral Cortex/cytology ; *Pyramidal Tracts/cytology ; }, abstract = {Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo, or for optimally informative disease modeling and/or therapeutic screening in vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing proneural Neurog2 expression by progenitors. We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2, while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2-driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.}, }
@article {pmid41589772, year = {2026}, author = {Zhu, J and Wen, T and Gao, N and Wu, B and Ma, M and Sun, X and Liu, F and Lin, P and Liu, S}, title = {Elevated Serum SIRT2 Is Associated With Rapid Progression and Cognitive Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70162}, pmid = {41589772}, issn = {1097-4598}, support = {2020M672067//the China postdoctoral science foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; 2025CXPT133//Key R&amp;D Program of Shandong Province, China/ ; Z-2017-24-2509//Yantu Neuroscience Specialized Research Fund Project/ ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) lacks reliable biomarkers to predict disease trajectories or guide therapeutic strategies. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase implicated in cytoskeletal destabilization and neuroinflammatory pathways in preclinical ALS models, represents a promising yet unvalidated biomarker candidate. We aimed to translate preclinical findings by validating SIRT2's role in ALS.<br><br>METHODS: A cross-sectional cohort study was conducted, comparing serum SIRT2 levels, measured via enzyme-linked immunosorbent assay (ELISA), between 182 ALS patients and 65 healthy controls. Clinical progression rates were derived from the ALS Functional Rating Scale-Revised (ALSFRS-R), and cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Edinburgh Cognitive and Behavioral ALS Screen (ECAS).<br><br>RESULTS: SIRT2 levels were significantly elevated in ALS patients versus controls, though diagnostic accuracy was modest (AUC&#x2009;=&#x2009;0.620). Furthermore, SIRT2 levels showed a weak but significant positive correlation with disease progression rate (r&#x2009;=&#x2009;0.182, p&#x2009;=&#x2009;0.014) and inverse correlations with cognitive scores on both MMSE (r&#x2009;=&#x2009;-0.250, p&#x2009;=&#x2009;0.032) and ECAS (r&#x2009;=&#x2009;-0.286, p&#x2009;=&#x2009;0.031). Notably, SIRT2 demonstrated a limited but detectable ability to stratify patients into fast- and slow-progressing subgroups (AUC&#x2009;=&#x2009;0.635).<br><br>DISCUSSION: These findings provide preliminary clinical evidence linking elevated serum SIRT2 to disease progression and cognitive impairment in ALS, thereby supporting its role in disease heterogeneity. This work lends clinical support to preclinical insights, suggesting SIRT2 may aid in prognosis prediction and may represent a potential therapeutic target, necessitating further studies.}, }
@article {pmid41591303, year = {2026}, author = {Zhang, Y and Liu, Y and Yao, Z and Lai, H and Chen, X and Wang, Z and Bao, Y and Li, T and Zhou, X and Chen, X and Yang, P}, title = {Alphaviral Capsid Proteins Inhibit Stress Granule Assembly via Competitive RNA Binding With G3BP1.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e17009}, doi = {10.1002/advs.202517009}, pmid = {41591303}, issn = {2198-3844}, support = {2025YFC3409700//National Key Research and Development Project of China/ ; 2025JCXK02//Interdisciplinary Research Project of Hangzhou Normal University/ ; 2025M772812//China Postdoctoral Science Foundation/ ; 32470733//National Natural Science Foundation of China/ ; 32170696//National Natural Science Foundation of China/ ; WU2022A002//Center of Synthetic Biology and Integrated Bioengineering of Westlake University/ ; }, abstract = {Viral infection is one of the conditions that induce stress granule (SG) formation, a cellular defense mechanism that exerts antiviral effects. To counteract this host response, viruses have evolved a broad spectrum of strategies to inhibit SG formation. However, the molecular mechanisms underlying SG inhibition remain poorly understood. The nucleocapsid proteins play a critical role in virus replication and host interaction. Here, using Semliki Forest Virus (SFV) as a model, we uncover the function of the alphavirus nucleocapsid in SG inhibition. This inhibitory function depends on oligomerization mediated by an N-terminal α-helix and with a positively charged intrinsically disordered region (IDR). We show that SFV capsid directly competes with G3BP1 for RNA binding, thereby disrupting G3BP1-RNA liquid-liquid phase separation (LLPS) in vitro and SG assembly in cells. This mechanism is conserved across the alphavirus family but is not shared by the nucleocapsid of SARS-CoV-2 or other endemic viruses examined. Notably, expression of a peptide from SFV capsid is sufficient to inhibit SG formation induced by Amyotrophic Lateral Sclerosis (ALS)-associated mutations, suggesting potential therapeutic applications. Our findings reveal mechanistic insight into SG modulation by the viral capsid protein and provide a possible bioengineering tool for probing SG dynamics in health and disease.}, }
@article {pmid41591873, year = {2026}, author = {Henkenius, AJ and Banaag, A and Koehlmoos, TP}, title = {Comparison of Musculoskeletal Injury and Behavioral Health Diagnoses Among United States Army Active Duty Servicewomen in Ground Combat Versus Non-Ground Combat Specialties: An Update (2020-2023).}, journal = {Military medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/milmed/usaf642}, pmid = {41591873}, issn = {1930-613X}, support = {# HU0001-11-1-0023//Department of War, Defense Health Agency/ ; }, abstract = {INTRODUCTION: Historically, women in the U.S. Military have been prohibited from serving in ground combat occupational specialties (GCS) until the Secretary of Defense lifted the exclusion in January 2016, prompting studies into health outcomes for this new cohort. Phillips et al.(2016-2019) found that active duty servicewomen (ADSW) in GCS had lower odds of musculoskeletal injury (MSKI) and behavioral health (BH) diagnoses than peers in non-ground combat specialties (NGCS), likely because of a "healthy warrior" selection effect. With continued integration, cohort maturation, and factors such as the COVID-19 pandemic, this study updates MSKI and BH trends among ADSW from 2020 to 2023 and compares findings with the earlier cohort.<br><br>MATERIALS AND METHODS: This retrospective cross-sectional study used data from the Military Health System Data Repository (MDR), including all ADSW (n&#x2009;=&#x2009;77,568) who served from January 1, 2020, to December 31, 2023. Women in the Guard, Reserve, or with pregnancy diagnoses during or in the year prior were excluded. Primary outcomes-MSKI and BH diagnoses-were identified via ICD-10 codes. Adjusted odds ratios (AORs) and 95% CIs were calculated using multivariable logistic regression, comparing GCS vs. NGCS ADSW while adjusting for age, race &amp; ethnicity, rank, and BMI. Two-sample z-tests assessed differences from Phillips et al.s 2016 to 2019 estimates. This study received an exempt determination from the Institutional Review Board at the Uniformed Services University of the Health Sciences.<br><br>RESULTS: Of 77,568 ADSW, 5,024 (6.5%) served in GCS. Compared to NGCS, GCS women were younger (72.1% vs. 47.0% aged 18-23), more often enlisted (68.4% vs. 57.0%), and had lower obesity rates (8.4% vs. 12.6%), but higher rates of tobacco (7.7% vs. 7.6%), alcohol (7.9% vs. 6.7%), and substance use (2.5% vs. 1.9%). Adjusted analyses showed higher MSKI odds in GCS (AOR&#x2009;=&#x2009;1.21, 95% CI: 1.13-1.30), a significant reversal from Phillips et al.(AOR&#x2009;=&#x2009;0.86, 95% CI: 0.79-0.93; z&#x2009;=&#x2009;6.01, P&#x2009;<&#x2009;.001). BH odds were lower in GCS (AOR&#x2009;=&#x2009;0.83, 95% CI: 0.78-0.89), consistent with earlier findings (Phillips AOR&#x2009;=&#x2009;0.87; 95% CI: 0.80-0.95).<br><br>CONCLUSIONS: The increase in MSKI odds for GCS women contrasts sharply with prior findings, suggesting the dissipation of the initial selection effect as more women enter and remain in combat roles. This shift may reflect greater exposure duration, cumulative physical demands, or pandemic-era fitness disruptions. The continued lower BH odds in GCS, despite higher substance use, may reflect resilience, unit cohesion, or underreporting tied to stigma. These findings highlight the need for targeted, female-specific injury prevention and confidential, destigmatized mental health support as the Army moves toward sex-neutral standards in combat fitness.}, }
@article {pmid41592170, year = {2026}, author = {Allen, MD and Diab, V and Lezaic, N and Binet, M and Gentil, BJ and Blanchard, O and Genge, A and Massie, R}, title = {The genetics of autosomal recessive ALS: a review of the common forms and their phenotypes.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2615110}, pmid = {41592170}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of upper and lower motor neurons. Most forms of ALS associated with a suspected causal variant are inherited in an autosomal dominant manner. However, there is an important subset of autosomal recessive (AR) variants, often associated with early-onset or atypical clinical features. Advances in genetic sequencing have led to increased recognition of AR ALS. In this review, we focus on four key confirmed AR ALS-associated genes, which appear to be most common-ALS2, SPG11, OPTN, and the D90A variant of SOD1-reviewing their pathophysiology and unique clinical manifestations. We also highlight very rare AR mutations implicated in ALS, including SYNE1, ATP13A2, and FUS, and some associated with overlap syndromes or debated pathogenicity including SIGMAR1, ERLIN1, and ERLIN2. These genes are involved in an array of processes including axonal transport, endosomal trafficking, oxidative stress response, and autophagy, suggesting distinct mechanisms of motor neuron degeneration. Some forms of AR ALS more frequently present with juvenile onset and slower progression, but other genes are associated with broader phenotypic spectra. This includes overlap with hereditary spastic paraplegia (HSP) and hereditary ataxias. Understanding these AR forms of ALS may enhance diagnostic precision, improve prognostication, and may pave the way for targeted gene therapies. This review underscores the emerging significance of AR inheritance in ALS and calls for deeper investigation into its molecular and clinical dimensions.}, }
@article {pmid41592787, year = {2026}, author = {Mammone, RM and Willis, E and Ruivo, P and Finesso, GE and Cox, A and Assenmacher, CA and Radaelli, E and Piersigilli, A and Miranda, IC}, title = {Pathology associated with human CAR T cell administration in NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice: A retrospective analysis.}, journal = {Veterinary pathology}, volume = {}, number = {}, pages = {3009858251409216}, doi = {10.1177/03009858251409216}, pmid = {41592787}, issn = {1544-2217}, abstract = {Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for neoplasia and autoimmune diseases. Immunocompromised mice are a common model to test the efficacy and safety of CAR T cells of human origin. Preclinical toxicity associated with human CAR T-cell products encompasses a spectrum of morphologic changes, with currently limited documentation in the scientific literature. The purpose of this retrospective study was to characterize the histopathologic features associated with human CAR T-cell administration in immunodeficient NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice (n = 392) submitted to 3 different academic institutions in the United States between 2017 and 2024. Lesions were categorized into xenogeneic graft-versus-host disease (xGvHD) (n = 287), aberrant proliferation of human T cells (n = 188), vascular pathologies (n = 66), on-target/off-tumor (OTOT) toxicity (n = 44), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) in mice previously humanized with human CD34+ hematopoietic stem cells (HSCs) (n = 21), and acute lysis syndrome (ALS) (n = 5). This study provides veterinary pathologists with descriptive guidance on the pathology associated with human CAR T-cell therapy in immunodeficient mice. Additional molecular data and detailed information related to each construct are necessary to further investigate the translatability of such liabilities to the clinical setting.}, }
@article {pmid41593242, year = {2026}, author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.}, journal = {Nature immunology}, volume = {27}, number = {2}, pages = {323-335}, pmid = {41593242}, issn = {1529-2916}, support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; P30 AG066462/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; RF1 NS142171/NS/NINDS NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology ; *Meninges/immunology ; *Alzheimer Disease/immunology ; Female ; Male ; Aged ; Brain/immunology/pathology ; Receptors, Antigen, T-Cell/genetics/immunology ; Microglia/immunology ; Aged, 80 and over ; Middle Aged ; Amyotrophic Lateral Sclerosis/immunology ; *Neurodegenerative Diseases/immunology ; Parkinson Disease/immunology ; Immunologic Memory ; Single-Cell Analysis ; }, abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.}, }
@article {pmid41593729, year = {2026}, author = {Nilsen, P and Kirk, JW and Gunnarsson, KU and Thomas, K}, title = {Matters arising: a critique of "Nuancing the continuum from ideal to real-world implementation" by Eldh et al. 2025.}, journal = {Implementation science communications}, volume = {7}, number = {1}, pages = {12}, pmid = {41593729}, issn = {2662-2211}, abstract = {This critique responds to Eldh et al.'s (Implement Sci Commun 6:113, 2025) commentary on Nilsen et al.'s proposal to distinguish between implementation efficacy and effectiveness along an ideal-to-real-world continuum. While acknowledging the constructive intent of Eldh et al.'s reflections, we clarify that our framework was never intended as a simplistic, one-dimensional model but as a pragmatic heuristic to enhance design transparency. Eldh et al.'s proposed two-axis alternative is conceptually overlapping, as both axes reflect contextual variation rather than independent constructs. Our adaptation of the PRECIS framework - long validated in clinical and health services research - already incorporates multidimensional nuance through distinct domains. We emphasize that the "ideal" end of the continuum denotes highly supported conditions, not normative perfection. Moreover, the proposed "Implementation PRECIS" tool is intended to stimulate integration of contextual transparency and economic evaluation within implementation research. While we concur with Eldh et al.'s emphasis on facilitation, co-production, and contextual complexity, their critique ultimately reinforces our core premise: that explicitly positioning studies along an efficacy-effectiveness spectrum strengthens interpretability, transparency, and real-world relevance in implementation science.}, }
@article {pmid41593859, year = {2026}, author = {Pathak, K and Kumari, T and Aggarwal, L and Singh, V}, title = {Preventive dietary and lifestyle strategies for neurodegenerative diseases: a comprehensive review.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-26}, doi = {10.1080/1028415X.2026.2615456}, pmid = {41593859}, issn = {1476-8305}, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, are rising sharply across the globe. These incurable and progressive conditions lead to severe cognitive and motor impairments, diminish the quality of life, and place a substantial burden on healthcare systems. In response to this growing challenge, the present review offers an integrative and forward-thinking perspective focused on modifiable daily habits that have the potential to preserve brain health and reduce the risk of neurodegeneration. Mounting evidence reveals that everyday lifestyle choices, including food habits, physical activity, sleep, and stress, profoundly shape long-term cognitive outcomes. Neuroprotective diets such as the Mediterranean and ketogenic diets reduce oxidative stress, enhance mitochondrial efficiency, and promote neurogenesis, whereas the Western diet accelerates cognitive decline. Intermittent fasting and caloric restriction trigger autophagy and ketone production, offering metabolic resilience. Functional foods such as berries, walnuts, and leafy greens combat inflammation and oxidative damage. Physical activity and resistance training boost synaptic plasticity and neurotransmitter balance. In addition, high-quality sleep and effective stress control help preserve neuronal integrity and lower neuroinflammatory markers. By integrating insights from neuroscience, nutrition, and behavioral medicine, this review highlights how multiple modifiable factors, when adopted consistently, can work in synergy to preserve cognitive health, delay disease onset, and reduce progression.}, }
@article {pmid41594611, year = {2026}, author = {Dong, C and Lv, D and Dong, Y and Zhang, Z and Li, Q and Chen, Z}, title = {Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.}, journal = {Biomolecules}, volume = {16}, number = {1}, pages = {}, pmid = {41594611}, issn = {2218-273X}, support = {2022CXPT037//the Key R&amp;D Program of Shandong Province, China/ ; 5501290015//the Advanced Researcher Fund of Jiangsu University/ ; 202510299087//National Training Program of Innovation and Entrepreneurship for Undergraduates/ ; }, mesh = {*Cardiolipins/metabolism/analysis ; Humans ; *Central Nervous System Diseases/metabolism/diet therapy ; Animals ; Mitochondria/metabolism ; }, abstract = {Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes recent advances in the analytical techniques employed for CL analysis. The principles and applications of mass spectrometry-based platforms, nuclear magnetic resonance, Fourier-transform infrared spectroscopy, atomic force microscopy-infrared spectroscopy, and fluorescent probes were discussed, with an emphasis on their strengths in revealing the structure, composition, dynamics, and spatial distribution of CL. Furthermore, the evidence of CL abnormalities in various CNS disorders was assessed, often showing decreased CL levels, loss of polyunsaturated species, and increased oxidation associated with mitochondrial dysfunction and neuronal apoptosis. Furthermore, the nutritional interventions for CL modulation were discussed, such as polyunsaturated fatty acids, polyphenols, carotenoids, retinoids, alkaloids, and triterpenoids, which summarize their potential health-beneficial effects in remodeling the CL acyl chain, preventing oxidation, and regulating mitochondrial homeostasis. Overall, this review provided insight into integrating CL analysis and dietary modulation in understanding CL-related pathologies in CNS disorders.}, }
@article {pmid41594924, year = {2026}, author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C}, title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.}, journal = {Biology}, volume = {15}, number = {2}, pages = {}, pmid = {41594924}, issn = {2079-7737}, abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.}, }
@article {pmid41595662, year = {2026}, author = {Stoian, II and Nistor, D and Levai, MC and Popa, DI and Popescu, R}, title = {Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.}, journal = {Biomedicines}, volume = {14}, number = {1}, pages = {}, pmid = {41595662}, issn = {2227-9059}, abstract = {Background and Objectives: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. Methods: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34-PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. Results: Twelve studies met the criteria across tauopathies and Alzheimer's disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington's disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer's hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. Conclusions: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation.}, }
@article {pmid41596063, year = {2025}, author = {Herbert, A}, title = {G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {41596063}, issn = {2076-3921}, abstract = {Expansion of d(GGGGC)n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer's Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.}, }
@article {pmid41596266, year = {2026}, author = {Ryu, IS and Ha, DI and Jung, YJ and Lee, HJ and Kim, I and Lim, YN and Min, HS and Kim, SH and Yoon, I and Cho, HJ and Ryu, JH}, title = {Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596266}, issn = {1422-0067}, support = {RS-2023-00283779//Ministry of SMEs and Startups/ ; }, mesh = {*MicroRNAs/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Nanoparticles/chemistry/administration &amp; dosage ; Mice ; Mice, Transgenic ; Humans ; *Oligonucleotides, Antisense/pharmacology/administration &amp; dosage/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/pathology/drug effects ; Disease Models, Animal ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1[G93A]-expressing HMC3 microglial cells and in the spinal cords of SOD1[G93A] transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1[G93A] transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease.}, }
@article {pmid41596533, year = {2026}, author = {Bogus, K and Marchesi, N and Campagnoli, LIM and Pascale, A and Pałasz, A}, title = {Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596533}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are characterized by progressive neuronal loss and dysfunction, yet increasing evidence indicates that glial cells are central mediators of both disease initiation and progression. Astrocytes, microglia, and oligodendrocyte lineage cells modulate neuronal survival by regulating neuroinflammation, metabolic support, synaptic maintenance, and proteostasis. However, dysregulated glial responses, including chronic microglial activation, impaired phagocytosis, altered cytokine production, and mitochondrial dysfunction, contribute to persistent inflammation and structural degeneration observed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis. Recent advances in single-cell and spatial omics have revealed extensive glial heterogeneity and dynamic shifts between neuroprotective and neurotoxic phenotypes, emphasizing the context-dependent nature of glial activity. This review summarizes current knowledge regarding the multifaceted involvement of glial cells in neurodegenerative disorders.}, }
@article {pmid41598508, year = {2026}, author = {Torikai, T and Ohara, H and Takeuchi, J and Yokoi, T and Itoh, Y and Koto, T and Shiraishi, A and Inoue, M}, title = {Surgical Outcomes and Differences in Values of Ocular Parameters Following Vitrectomy for Macular Hole over a 10-Year Period.}, journal = {Journal of clinical medicine}, volume = {15}, number = {2}, pages = {}, pmid = {41598508}, issn = {2077-0383}, abstract = {Background/Objectives: We aimed to compare the surgical outcomes of macular hole (MH) cases and evaluate how the axial length (AL) affected the outcomes. Methods: Six hundred and sixty-three eyes with MHs that underwent vitrectomy over the past 10 years were reviewed. The changes in AL were compared to those of 1948 eyes with idiopathic epiretinal membranes (ERMs) operated on during the same period. The MH cases for the 5 years from 2014 to 2018 were designated as the MH2014 group, and those from 2019 to 2023 as the MH2019 group. The ERM cases were divided similarly into the ERM2014 and ERM2019 groups. The clinical characteristics of the cases and surgical outcomes were compared. Results: The MH diameter, closure rate, and baseline and postoperative visual acuity were not significantly different. The use of the inverted internal limiting membrane flap technique was significantly higher in the MH2019 group (58%) than in the MH2014 group (24%, p < 0.001). The mean AL was significantly longer in the MH2019 group (25.2 ± 2.4 mm) than in the MH2014 group (24.6 ± 2.1 mm, p = 0.004). The incidence of myopic MHs with AL ≥ 26 mm and AL ≥ 30 mm was higher in the MH2019 group (30.9%, p = 0.008, 6.4%, p = 0.017, respectively). There was a significant trend for longer ALs over 10 years in the MH group (p = 0.002), but not in the ERM group. Conclusions: The increased AL and the rising proportion of eyes with myopic MHs indicate that the patient profile of eyes with MHs has changed over the past decade.}, }
@article {pmid41599185, year = {2026}, author = {Benech, H and Flament, V and Lhotellier, C and Roucairol, C and Joudinaud, T}, title = {New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599185}, issn = {1999-4923}, abstract = {Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.}, }
@article {pmid41599225, year = {2026}, author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K}, title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599225}, issn = {1999-4923}, support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; }, abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.}, }
@article {pmid41599368, year = {2026}, author = {Niziński, P and Szalast, K and Makuch-Kocka, A and Paruch-Nosek, K and Ciechanowska, M and Plech, T}, title = {Experimental Models and Translational Strategies in Neuroprotective Drug Development with Emphasis on Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {2}, pages = {}, pmid = {41599368}, issn = {1420-3049}, support = {2022/47/O/NZ7/00155//National Science Centre/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drug Development ; Animals ; *Translational Research, Biomedical ; Disease Models, Animal ; Induced Pluripotent Stem Cells ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002-2012) estimated ~99.6% attrition, while PD programs (1999-2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron-glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood-brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders.}, }
@article {pmid41599691, year = {2026}, author = {Zhao, X and Zheng, Y and Cai, X and Yao, Y and Qin, D}, title = {The Expanding Role of Non-Coding RNAs in Neurodegenerative Diseases: From Biomarkers to Therapeutic Targets.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {19}, number = {1}, pages = {}, pmid = {41599691}, issn = {1424-8247}, support = {Y202248634//Zhejiang Provincial Department of Education Project/ ; Y202454271//Zhejiang Provincial Department of Education Project/ ; }, abstract = {Non-coding RNAs have emerged as central regulators of gene expression in neurodegenerative diseases, offering new opportunities for diagnosis and therapy. This review synthesizes current knowledge on microRNAs, long non-coding RNAs, and circular RNAs in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, emphasizing their roles in synaptic function, proteostasis, mitochondrial biology, and neuroinflammation. We evaluate evidence supporting non-coding RNAs as circulating and tissue-based biomarkers for early detection, disease monitoring, and patient stratification, and we compare analytical platforms and biofluid sources. Mechanistic insights reveal how non-coding RNAs modulate pathogenic protein aggregation, neuronal excitability, immune cell crosstalk, and blood-brain barrier integrity. Translational efforts toward RNA-targeted interventions are reviewed, including antisense oligonucleotides, small interfering RNAs, miRNA mimics and inhibitors, circular RNA decoys, and extracellular vesicle-mediated delivery systems. We discuss pharmacological modulation, delivery challenges, safety concerns, and strategies to enhance specificity and CNS penetration. Finally, we outline emerging computational and multi-omics approaches to prioritize therapeutic targets and propose a roadmap for advancing non-coding RNA research from preclinical models to clinical trials. Addressing biological heterogeneity and delivery barriers will be pivotal to realizing the diagnostic and therapeutic promise of the non-coding transcriptome in neurodegenerative disease. Collaboration across disciplines and rigorous clinical validation are urgently needed.}, }
@article {pmid41601535, year = {2025}, author = {Zhu, Y and Zhang, G and Liu, H and Yin, T and Zhang, J and Yang, Y and Bai, L and Liu, X and Fan, D and Ye, S}, title = {Depression mediates motor dysfunction's effect on sleep quality in ALS: a mediation analysis study.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1643367}, pmid = {41601535}, issn = {1662-4548}, abstract = {INTRODUCTION: Poor sleep quality affects 50-63% of Amyotrophic lateral sclerosis (ALS) patients, exacerbating disease burden and reducing quality of life. This study aimed to investigate the relationships among disease severity, depressive symptoms, and sleep quality in ALS, with a focus on the mediating effects of depression.<br><br>METHODS: Our study enrolled 408 ALS patients. Disease severity was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R), sleep quality via the Pittsburgh Sleep Quality Index (PSQI), and psychological status using the Hamilton Depression (HAMD) and Anxiety (HAMA) scales. Statistical analyses included Spearman correlations, multivariate regression, and mediation analysis (Hayes' PROCESS macro).<br><br>RESULTS: Poor sleep quality (PSQI > 5) was observed in 54.4% of patients. Multivariate analysis found ALSFRS-R (&#x3b2;&#x202f;=&#x202f;-0.135, p&#x202f;=&#x202f;0.042) and HAMD (&#x3b2;&#x202f;=&#x202f;0.270, p&#x202f;<&#x202f;0.001) correlated with sleep quality. Initial mediation analysis using the full ALSFRS-R and PSQI scales was not significant. Aimed to further explore the correlation, we derived specific subscales ALSFRS-R' (motor/respiratory components) and PSQI' (sleep efficiency/ daytime dysfunction), which more correlated with each other. Mediation analysis of these subscales revealed that depressive symptoms accounted for 36.3% of the indirect effect between ALSFRS-R' and PSQI'.<br><br>DISCUSSION: Our cross-sectional exploratory study suggests that depression may partly mediate the relationship between motor dysfunction and poor sleep quality in patients with ALS. Although our mediation analysis suggested a potential association, further longitudinal cohort studies are needed to confirm these findings. The potential mediating role of depression underscores the need for an integrated clinical management approach addressing not only motor symptoms but psychological well-being as well.}, }
@article {pmid41601590, year = {2025}, author = {Garbuzova-Davis, S and Manora, L and Borlongan, CV}, title = {Apolipoprotein A1 reduces blood-spinal cord barrier leakage, improves astrocytic coverage, and enhances motor neuron survival to restore the neurovascular unit in ALS mice.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1684694}, pmid = {41601590}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, age-related motor neuron degenerative disease with multiple causal factors. Dyslipidemia has been identified as an important pathological element. Impaired lipid protein metabolism manifests in ALS patients and in an ALS mouse model. Apolipoprotein components are the primary regulators of plasma lipid metabolism. Apolipoprotein A1 (ApoA1), a high-density lipoprotein, acts as an antioxidant and reduces inflammation, preventing blood vessel injury. However, the effects of ApoA1 upon the ALS-damaged endothelium in the CNS are unknown. The objective of the study was to determine the effect(s) of injecting ApoA1 into G93A SOD1 mice at the early symptomatic stage.<br><br>METHODS: A single dose of ApoA1 or media was systemically administered into 13-week-old G93A SOD1 male and female mice. Body weight and tests of motor function were evaluated weekly for 4&#x202f;weeks post-injection. Permeability of spinal cord capillaries was determined by Evans blue (EB) fluorescent dye injected into mice at 17&#x202f;weeks of age. Immunohistochemical analyses determined the statuses of glial cells and ApoA1 distributions in ALS mice cervical/lumbar spinal cords. Motor neurons in cervical/lumbar spinal cord ventral horns of ApoA1-treated and media-injected ALS mice were stained with cresyl violet for histological analyses.<br><br>RESULTS: ApoA1 injected into G93A SOD1 mice at the early symptomatic stage significantly benefited both male and female animals by (1) delaying behavioral disease progression; (2) reducing EB capillary leakage into spinal cord parenchyma; (3) lessening astrogliosis and microgliosis; (4) protein incorporation into capillary endothelium and motor neurons; and (5) improving survival of motor neurons in the spinal cord.<br><br>CONCLUSION: Our novel data showed that systemically administered ApoA1 benefited ALS mice of both sexes, likely by beneficial effects on damaged microvessels, possibly engendering restoration of neurovascular unit integrity. Moreover, an anti-inflammatory ApoA1 effect was demonstrated by the reduction of glial cell activation, potentially mitigating vascular injury. The results of our preclinical study suggest that ApoA1 may be a potential protein-mediated therapeutic for restoring vascular function. Our novel strategy may lead to future clinical trials, furthering our goal of effectively treating ALS patients.}, }
@article {pmid41601624, year = {2025}, author = {Yang, J and Song, X and Yan, S and Li, Q and Yang, W}, title = {The gut microbiota influences neurodegenerative diseases through the gut-brain axis: molecular mechanisms and effects on immune function.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1739329}, pmid = {41601624}, issn = {1664-3224}, mesh = {Humans ; *Gastrointestinal Microbiome/immunology ; *Neurodegenerative Diseases/immunology/microbiology/therapy/metabolism/etiology ; Animals ; *Brain/immunology/metabolism ; *Brain-Gut Axis/immunology ; Fecal Microbiota Transplantation ; Probiotics/therapeutic use ; Prebiotics ; }, abstract = {The pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is complex and multifactorial. Recent studies indicate that the microbiota-gut-brain axis (MGBA) plays a crucial role in the development and progression of NDDs. The MGBA concept reveals a complex bidirectional regulatory network between the gut microbiota and the central nervous system (CNS), linking them through immune, neural, endocrine, and metabolic pathways. This review summarizes the components of the MGBA, communication pathways between gut microbiota and the brain, and mechanisms by which gut microbiota influence the onset and progression of NDDs. Finally, preclinical therapeutic approaches for NDDs are discussed, evaluating preclinical trial data for probiotics, prebiotics, and fecal microbiota transplantation.}, }
@article {pmid41601803, year = {2025}, author = {An, X and Hou, D and Miao, MY and Zhou, YM and Qi, S and Zhang, L and Li, H and Zhou, JX}, title = {Noninvasive monitoring of inspiratory effort in mechanical ventilation: a dual-database bibliometric analysis from 1990 to 2025.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1747437}, pmid = {41601803}, issn = {2296-858X}, abstract = {INTRODUCTION: This study conducts a bibliometric analysis to map the intellectual structure, evolution, and emerging trends in research on airway pressure-based indexes for monitoring inspiratory effort.<br><br>METHODS: Systematic searches of the Web of Science Core Collection (WOSCC) and Pubmed were performed for publications dated between 1990 and 2025. Bibliometric parameters, including publication trends, country and affiliation contributions, author influence, journal distribution, keyword co-occurrence, and reference co-citation networks, were analyzed using Bibliometrix and CiteSpace.<br><br>RESULTS: The analysis included 291 publications from WOSCC. The annual publication output showed a near U-shaped trend, with an initial decline after the 1990s, followed by a strong resurgence after 2011. Italy was the most productive country, followed by the USA and France. The Institut National de la Sante et de la Recherche Medicale emerged as the leading institution. The journal Chest published the most articles, while the American Journal of Respiratory and Critical Care Medicine had the highest total citations. Laurent Brochard was identified as the most prolific and influential author. Keyword analysis highlighted "occlusion pressure" and "mechanical ventilation" as core themes. Reference co-citation clustering revealed major research domains, including "acute respiratory distress syndrome," "self-inflicted lung injury," and "nasal high flow." Burst detection analysis indicated that "respiratory drive," "lung injury," and "critically ill patients" are emerging research frontiers. Complementary analysis of 242 PubMed clinical studies confirmed these trends and highlighted growing clinical focus on "fluid responsiveness" and "amyotrophic lateral sclerosis."<br><br>CONCLUSION: Research on airway pressure-based indices has evolved from physiological studies into a crucial clinical tool for respiratory monitoring. The field exhibits strong international collaboration and emphasizes core areas, including acute respiratory failure and lung-protective ventilation. Analysis of clinical study data confirms these trends and highlights emerging applications in the assessment of fluid responsiveness and neuromuscular disorders. These findings support the ongoing development of personalized ventilation strategies based on monitoring respiratory effort.}, }
@article {pmid41602910, year = {2026}, author = {Li, Q and Zhang, G and Zheng, H and Zhao, T and Zhang, H and Zhang, Y and Luo, H and Xu, Y}, title = {ABCA1 acts as a protective modulator in amyotrophic lateral sclerosis.}, journal = {iScience}, volume = {29}, number = {1}, pages = {114320}, pmid = {41602910}, issn = {2589-0042}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease lacking reliable biomarkers and effective therapeutic targets. We performed an integrative multiscale analysis combining global epidemiology, whole-blood transcriptomics, machine learning, and Mendelian randomization (MR). We developed a nine-gene diagnostic signature (AUC = 0.75 in external validation) and identified ATP-binding cassette transporter A1 (ABCA1) as a central feature. MR analyses supported a protective causal relationship between increased ABCA1 expression and reduced ALS risk (OR = 0.93, p = 0.02). We validated this at the protein level, finding serum ABCA1 significantly elevated in an in-house ALS cohort (p = 0.006) and correlated with metabolic parameters (BMI and LDL). Spatiotemporal profiling confirmed ABCA1 upregulation in ALS patient blood and spinal cords, and progressive upregulation in ALS model mice. Collectively, we validated a diagnostic signature and identified ABCA1 as a protective, compensatory biomarker in ALS, emphasizing the link between metabolic adaptation and neurodegeneration.}, }
@article {pmid41602992, year = {2025}, author = {Czyżewski, &#x141; and Petrzak-Nocuń, K and Strząska-Kliś, Z and Wyzgał, J and Religioni, U and Augustynowicz, A and Świtalski, J and Dudziński, &#x141; and Silczuk, A}, title = {Illness acceptance and quality of life in amyotrophic lateral sclerosis: the role of health and environmental factors.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1721044}, pmid = {41602992}, issn = {1664-2295}, abstract = {PURPOSE: To determine the extent to which illness acceptance accounts for variability in health-related quality of life (HRQoL) among adults with amyotrophic lateral sclerosis (ALS) attending a hospital-based outpatient clinic, after controlling for sociodemographic and health variables.<br><br>MATERIALS AND METHODS: We conducted a single-center, cross-sectional study in a hospital outpatient clinic. Adults with ALS completed the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and the Acceptance of Illness Scale (AIS), plus a sociodemographic and health questionnaire.<br><br>RESULTS: Forty-five patients were analyzed (mean age 52&#x202f;&#xb1;&#x202f;14&#x202f;years; 58% women). WHOQOL-BREF domain means were: physical 46.9&#x202f;&#xb1;&#x202f;14.1, psychological 51.2&#x202f;&#xb1;&#x202f;16.9, social 53.0&#x202f;&#xb1;&#x202f;24.6, environment 58.4&#x202f;&#xb1;&#x202f;18.4. Mean AIS was 20.4&#x202f;&#xb1;&#x202f;8.1. AIS correlated positively with all domains (r&#x202f;=&#x202f;0.40-0.52, all p&#x202f;&#x2264;&#x202f;0.006). In age- and sex-adjusted models, AIS independently predicted higher scores: physical &#x3b2;&#x202f;=&#x202f;0.96 (p&#x202f;=&#x202f;0.003), psychological &#x3b2;&#x202f;=&#x202f;0.94 (p&#x202f;=&#x202f;0.013), social &#x3b2;&#x202f;=&#x202f;1.47 (p&#x202f;=&#x202f;0.003), environment &#x3b2;&#x202f;=&#x202f;1.10 (p&#x202f;=&#x202f;0.025). Percutaneous endoscopic gastrostomy (PEG) was associated with lower physical and environment scores than oral feeding. Respiratory status differentiated physical and psychological scores. Better living conditions related to higher psychological and environment scores. Time from first symptoms to diagnosis correlated with AIS (&#x3c1;&#x202f;=&#x202f;0.37, p&#x202f;=&#x202f;0.014).<br><br>CONCLUSION: Illness acceptance is a robust, independent correlate of HRQoL across domains in ALS. Care should pair symptom control with brief acceptance-focused, educational, and family communication interventions, and address environmental needs. Decisions on PEG and non-invasive ventilation (NIV) should include routine dietetic, psychological, and speech-language input. Longitudinal studies should test AIS as a mediator of somatic and environmental interventions on HRQoL.}, }
@article {pmid41603250, year = {2026}, author = {Naumann, M and Wierschin, TM and Kretschmer, S and Dash, BP and Held, A and Salzinger, A and Peikert, K and Karlek, A and Glaß, H and Großmann, D and Günther, R and Petri, S and Rödiger, A and Brenner, D and Pan-Montojo, F and Aronica, E and Kipp, M and Zimyanin, V and Sterneckert, J and Grehl, T and Seebacher, ND and Böckers, TM and Catanese, A and Wainger, BJ and Oeckl, P and Lee-Kirsch, MA and Hermann, A}, title = {RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New Biomarker-Driven Individualized Treatment Options for (FUS-)ALS.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e17135}, doi = {10.1002/advs.202417135}, pmid = {41603250}, issn = {2198-3844}, support = {CRC237 369799452/B21//German Research Foundation (DFG)/ ; CRC237 369799452/A11//German Research Foundation (DFG)/ ; CRC369 501752319/C06//German Research Foundation (DFG)/ ; 01GM2206C (GAIN)//German Federal Ministry of Education and Research (BMBF)/ ; 01GL2405H (DZKJ)//German Federal Ministry of Education and Research (BMBF)/ ; na//Stichting ALS Nederland/ ; na//Hermann und Lilly Schilling-Stiftung f&#xfc;r Medizinische Forschung/ ; //Clinician Scientist program of the Medical Faculty of the University of Rostock (RAS)/ ; }, abstract = {Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUS[mut] iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUS[mut] sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUS[wt] sMNs phenocopied the axonal degeneration of FUS[mut] sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.}, }
@article {pmid41604235, year = {2026}, author = {Al-Ameer, HJ and Basheer, NM and H, M and Shankhyan, A and Panigrahi, R and Arora, V and Azizjanov, K and Eshchanov, E and Ataullaev, Z}, title = {Neuroimmune Cross-Talk and Multilevel Cascades in Fentanyl Toxicity: Interplay of Hypoxic Stress, Glial Activation, and Synaptic Dysregulation in Systems-Level Neurodegeneration.}, journal = {Journal of applied toxicology : JAT}, volume = {}, number = {}, pages = {}, doi = {10.1002/jat.70069}, pmid = {41604235}, issn = {1099-1263}, abstract = {Fentanyl, an ultra-potent synthetic opioid, has traditionally been characterized by its acute toxic effects, particularly respiratory depression. However, accumulating research indicates that its neurobiological influence extends far beyond its short pharmacological window, intersecting with several core mechanisms implicated in major neurodegenerative disorders. This review integrates multiscale evidence to propose a unified conceptual framework in which fentanyl may function not only as an acute neurotoxin but also as a putative accelerator of long-term neurodegenerative vulnerability. Drawing from molecular signaling, cellular stress pathways, glial-neuronal cross-talk, neurovascular regulation, synaptic architecture, and large-scale neural networks, we highlight fentanyl's capacity to trigger a convergent cascade encompassing hypoxic-metabolic reprogramming, mitochondrial fragmentation, TLR4-NF-κB-driven inflammation, NLRP3 inflammasome activation, complement-mediated synaptic pruning, astrocytic EAAT2 downregulation, and blood-brain barrier compromise. These alterations propagate through recursive cross-talk loops that progressively diminish neuronal resilience, destabilize oscillatory coherence, and weaken circuit-level adaptability. Importantly, mechanistic overlaps with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis suggest that fentanyl exposure may be mechanistically associated with processes capable of accelerating disease onset, exacerbating progression, or unmasking latent vulnerabilities, particularly in genetically or metabolically predisposed individuals. By reframing fentanyl as a systems-level destabilizer capable of imprinting persistent neurobiological changes, this model underscores the need for comprehensive biomarker development, longitudinal risk assessment, and targeted neuroprotective interventions. The integrative framework presented herein offers a foundation for predicting the long-term neurological consequences of fentanyl exposure and calls for urgent reconsideration of its role in population-level neurodegenerative risk.}, }
@article {pmid41604971, year = {2026}, author = {Ahamad, S and Akshinthala, P and Fazal, F and Sah, GK and Khan, MH and Upadhyay, A and Bhat, SA and Hussain, MK}, title = {Small-molecule-based activation of Wnt/β-catenin signaling: An underexplored yet promising strategy for neuroprotection.}, journal = {Bioorganic chemistry}, volume = {170}, number = {}, pages = {109540}, doi = {10.1016/j.bioorg.2026.109540}, pmid = {41604971}, issn = {1090-2120}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Small Molecule Libraries/pharmacology/chemistry ; *Wnt Signaling Pathway/drug effects ; Animals ; *beta Catenin/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Molecular Structure ; }, abstract = {The Wnt/β-catenin pathway regulates key processes such as neurogenesis, synaptic plasticity, and neuroinflammation, each disrupted in neurodegenerative disorders like AD, PD, ALS, and stroke. Small molecules have shown potential to restore this signaling axis and confer neuroprotection. While these molecules modulate Wnt activity, none has achieved FDA approval, primarily due to poor brain permeability, off-target effects, and insufficient biomarker-based validation. Moreover, current strategies remain disproportionately focused on GSK-3β, with other viable targets, such as DKK1, NOTUM, SFRP-1, sclerostin, and Dvl-CXXC5 or Axin-β-catenin interactions, largely underexplored. Natural products, particularly flavonoids and diterpenoids, offer valuable scaffolds; however, their SAR remain poorly characterized, and promising synthetic leads often lack further development. This review highlights recent pharmacological advances, emerging molecular targets, and key translational barriers. Future success will depend on optimizing pharmacokinetics, improving brain-targeted delivery, and integrating biomarker-driven strategies into clinical trial design.}, }
@article {pmid41605460, year = {2026}, author = {Martínez-Alesón, P and Benito-Casado, C and Fernández-Martos, CM and Polanco Mora, MJ}, title = {Pleiotrophin/Midkine Pathway Is Dysregulated in a TDP-43[A315T] Mouse Model of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {46}, number = {1}, pages = {e70044}, pmid = {41605460}, issn = {1440-1789}, support = {FUSPBS-PPC03/2018//University San Pablo CEU-Santander precompetitive grants/ ; SBPLY/17/180501/000303//Junta de Comunidades de Castilla-la Mancha/ ; PIPF-2023/SAL-GL-29613//Consejer&#xed;a de Educaci&#xf3;n, Ciencia y Universidades Comunidad de Madrid/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Midkine/metabolism ; *Cytokines/metabolism ; Disease Models, Animal ; Mice ; Signal Transduction/physiology ; *Carrier Proteins/metabolism ; DNA-Binding Proteins/genetics ; Spinal Cord/metabolism/pathology ; Mice, Transgenic ; Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism ; Motor Neurons/metabolism/pathology ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by progressive degeneration of both upper and lower motor neurons, along with skeletal muscles innervated by them. The identification of key molecules involved in disease pathology remains crucial for ALS, as no curative treatment is currently available. Pleiotrophin (PTN) and midkine (MK) are closely related, heparin-binding cytokines with overlapping effects. These molecules have been shown to be neuroprotective by modulating neuroinflammation, supporting neuronal survival, growth, and differentiation, and enhancing synaptic strength and plasticity. Despite their reported neuroprotective properties, the involvement of PTN and MK signaling in ALS has not been previously investigated. In this study, we characterized the expression of the PTN/MK pathway in the lumbar spinal cords (SCs) of TDP-43[A315T] mice across different disease stages. We report a significant upregulation of Ptn, Mdk, and its receptor protein tyrosine phosphatase zeta (Ptprz1) mRNA levels at end-stage of disease in the lumbar SC of TDP-43[A315T] mice compared with age-matched wild-type littermates. Protein levels of PTN and MK were also upregulated at end-stage of disease. By immunofluorescence analysis, we also observed an upregulation of the immunostaining of both cytokines in neurons, astrocytes, microglia, and pericytes-like structures at end-stage of disease in the SC of TDP-43[A315T] mice. These findings open a new avenue to further study the potential role of the PTN/MK signaling axis in the pathogenesis of ALS. Trial Registration: Animal Ethics Committee of the Hospital Nacional de Parapléjicos in Toledo (Spain): Approval No. 26/OH 2018.}, }
@article {pmid41605610, year = {2026}, author = {Oreskovic, E and Petzold, A and Petropoulos, IN and Hau, S}, title = {Corneal confocal microscopy as a paraclinical test in neurodegenerative disease: a scoping review.}, journal = {The British journal of ophthalmology}, volume = {}, number = {}, pages = {}, doi = {10.1136/bjo-2025-328181}, pmid = {41605610}, issn = {1468-2079}, abstract = {Corneal confocal microscopy (CCM) is a non-invasive imaging technique that enables quantification of the corneal sub-basal nerve plexus and has emerged as a potential surrogate biomarker for peripheral neurodegeneration. This scoping review evaluated current evidence on the use of CCM in assessing corneal nerve fibre changes across neurodegenerative diseases (NDDs) and explored its potential as a paraclinical diagnostic and monitoring tool. A comprehensive search of PubMed and Scopus was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines to identify studies reporting quantitative CCM metrics, including corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL). Both cross-sectional and longitudinal studies of patients with NDDs were included, and findings were narratively synthesised. 50 studies were included: Parkinson's disease (n=13), multiple sclerosis (n=11), cerebrovascular accidents (n=7), post-COVID-19 neuropathy (n=5), amyotrophic lateral sclerosis (n=4), chronic inflammatory demyelinating polyneuropathy (n=4), Alzheimer's disease (n=3), Fabry disease (n=2) and neurofibromatosis type 1 (n=1). CNFL and CNFD were consistently reduced in Parkinson's disease, multiple sclerosis, cerebrovascular accidents, amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy and post-COVID-19 neuropathy, whereas CNBD results were inconsistent. The strongest evidence supported the role of CCM in Parkinson's disease and multiple sclerosis. CNFL and CNFD emerged as the most reliable CCM-derived metrics across NDDs, supporting their potential as objective biomarkers for neurodegeneration. While findings support the potential of CCM as a paraclinical diagnostic tool, methodological heterogeneity in image acquisition, analysis software and study design limited comparability. Standardised imaging and analysis protocols are needed to enable broader clinical application and validation across NDDs.}, }
@article {pmid41606859, year = {2025}, author = {Dehbasteh, M and Naderi Tehrani, N and Parastar, H}, title = {Multivariate curve resolution followed by partial least squares-discriminant analysis combined with Vis-NIR hyperspectral imaging for rice authentication.}, journal = {Food research international (Ottawa, Ont.)}, volume = {221}, number = {Pt 1}, pages = {117266}, doi = {10.1016/j.foodres.2025.117266}, pmid = {41606859}, issn = {1873-7145}, mesh = {*Oryza/chemistry/classification ; Least-Squares Analysis ; Discriminant Analysis ; *Hyperspectral Imaging/methods ; Spectroscopy, Near-Infrared/methods ; Iran ; Multivariate Analysis ; *Food Contamination/analysis ; Principal Component Analysis ; }, abstract = {Rice serves as a staple food for nearly half the global population, especially in Asia, where it is a major agricultural commodity. Nonetheless, deceptive practices, like blending premium and inferior rice varieties and selling them at inflated prices, present a considerable challenge to the industry. This study aims to authenticate rice samples using visible-short wavelength hyperspectral imaging (Vis-SWNIR HSI). To achieve this goal, 163 intact rice samples were sourced from three northern provinces of Iran (Gilan, Mazandaran and Golestan), including four different varieties (Hashemi, Shiroodi, Fajr and Neda). Samples were scanned by HSI device to record their cubic data. The HSI data of different samples were used in a column-wise augmented data matrix with pixels of different samples as rows and wavelengths as columns. The pure spatial (distribution maps) and spectral profiles of desired components were extracted using multivariate curve resolution-alternating least squares (MCR-ALS). As low-quality rice samples are considered adulterants for high-quality samples, the obtained data were used to differentiate samples by their origin as well as in adultertation detection. To the best of our knowledge, the MCR-ALS algorithm has not been used for rice authentication before using their intact forms. Further chemometric analyses, including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), were applied to the spectral-resolved profiles of samples. This enables us to discriminate three different origins and four varieties of rice samples, as well as for adulteration detection, providing classification accuracies of 94.4 %, 82.75 % and 100 % in the prediction sets, respectively. Such an outcome indicates the practical feasibility of imaging methods for rapid, cost-effective and non-invasive food authentication purposes.}, }
@article {pmid41606993, year = {2026}, author = {Lindström, L and Ahlsson, F and Axelsson, O and Granfors, M and Lampa, E and Nelander, M and Wikström, AK}, title = {Differences in prediction of adverse perinatal outcome in term pregnancies by choice of fetal growth reference: A validation study.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {105}, number = {3}, pages = {466-478}, pmid = {41606993}, issn = {1600-0412}, support = {LUL-964880//Region Uppsala/ ; //F&#xf6;delsefonden/ ; }, mesh = {Humans ; Female ; Pregnancy ; Sweden/epidemiology ; Infant, Newborn ; *Infant, Small for Gestational Age ; *Fetal Development ; Adult ; *Pregnancy Outcome ; Perinatal Mortality ; *Fetal Growth Retardation/diagnosis ; Birth Weight ; Reference Values ; Cohort Studies ; Growth Charts ; Registries ; }, abstract = {INTRODUCTION: Our objectives were to evaluate the association between fetal growth abnormalities and adverse perinatal outcomes in term pregnancies using four different fetal growth references: the recently published Swedish references by Lindström et al., the currently used Swedish references by Maršál et al., and the international standards by the WHO and INTERGROWTH-21st (IG21st). The study aimed to evaluate the performance of each reference and determine which reference most accurately identifies small for gestational age (SGA) infants at risk of perinatal mortality and morbidity.<br><br>MATERIAL AND METHODS: This population-based cohort study included 1&#x2009;126&#x2009;059 singleton term births in Sweden from 2010 to 2020. Data were obtained from national registers, including the Swedish Medical Birth Register and the Swedish Neonatal Quality Register. Birthweight centiles were calculated using each growth reference. Adverse perinatal outcomes were categorized by severity and included stillbirth, neonatal death, and serious neonatal morbidity. Logistic regression models were used to assess predictive performance, and sensitivity and false positive rates (FPR) were calculated for SGA thresholds (<3rd and <10th centiles).<br><br>RESULTS: The distribution of birthweight centiles varied significantly across references. For SGA <3rd centile, the rate ranged from 9.6% for Lindstr&#xf6;m, 2.5% for Mar&#x161;&#xe1;l, 1.9% for WHO, to 0.7% for IG21st. All references showed similar overall predictive performance (C-index&#x2009;&#x2248;&#x2009;0.67) but with different discriminatory ability. The predicted risk of perinatal death increased at lower centiles for the Lindstr&#xf6;m reference than for the Mar&#x161;&#xe1;l and WHO references, and at higher centiles for the IG21st reference. The Lindstr&#xf6;m reference identified the highest proportion of infants as SGA and had the highest sensitivity but also the highest FPR for detecting adverse outcomes. The&#xa0;IG21st reference classified the smallest proportion as SGA, resulting in the lowest sensitivity and FPR.<br><br>CONCLUSIONS: While all fetal growth references showed comparable predictive ability for adverse perinatal outcomes, they differed substantially in sensitivity and FPR. When the top priority is to identify as many at-risk fetuses as possible, Lindstr&#xf6;m et&#xa0;al.'s reference seems to be the best choice. However, when the top priority is a balanced sensitivity versus FPR, the WHO reference seems most suitable for clinical practice in this population of term births.}, }
@article {pmid41607656, year = {2025}, author = {Ha, LL and Mitra, S and Ho, DT and Fillingham, B and Berry, JD and Swoboda, KJ and Alves, CRR}, title = {Circulating Tau Profiles in Pediatric and Adult Patients with Spinal Muscular Atrophy.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41607656}, support = {K01 NS134784/NS/NINDS NIH HHS/United States ; R01 HD054599/HD/NICHD NIH HHS/United States ; R21 NS108015/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: To determine alterations in circulating Tau and phosphorylated Tau (pTau) profiles in pediatric and adult patients with spinal muscular atrophy (SMA).<br><br>METHODS: Circulating total Tau, pTau-181, pTau-217, pTau-262, and pTau-396 concentrations were measured across three cohorts: 1) adults including healthy controls, SMA patients, and ALS patients; 2) pediatric SMA patients and age-matched controls; and 3) pediatric SMA patients treated with onasemnogene abeparvovec.<br><br>RESULTS: Distinct alterations in circulating Tau species were detected in adult SMA and ALS. Among all measurements, pTau-262 emerged as the only species specifically elevated in adult SMA, while total Tau levels were comparable between adult SMA and controls but significantly increased in ALS. Tau alterations were not consistently observed in pediatric SMA, although a small subset showed elevated levels, underscoring the value of individualized biomarker monitoring upon diagnosis. In gene-therapy-treated infants, Tau levels increased transiently several weeks after onasemnogene abeparvovec injection, paralleling previously described neurofilament kinetics and suggesting acute, treatment-associated neuronal stress.<br><br>CONCLUSIONS: Circulating Tau, particularly pTau-262, may serve as a disease-relevant biomarker in adult SMA, while pediatric profiles appear more heterogeneous. Transient Tau elevations after gene therapy may reflect acute neuronal vulnerability and warrant further investigation.}, }
@article {pmid41607759, year = {2026}, author = {Kirkik, D and Ozadenc, HM and Kalkanli Tas, S}, title = {Machine learning approaches to early detection of delayed wound healing following gastric cancer surgery.}, journal = {World journal of gastrointestinal oncology}, volume = {18}, number = {1}, pages = {114499}, pmid = {41607759}, issn = {1948-5204}, abstract = {Delayed wound healing following radical gastrectomy remains an important yet underappreciated complication that prolongs hospitalization, increases costs, and undermines patient recovery. In An et al's recent study, the authors present a machine learning-based risk prediction approach using routinely available clinical and laboratory parameters. Among the evaluated algorithms, a decision tree model demonstrated excellent discrimination, achieving an area under the curve of 0.951 in the validation set and notably identifying all true cases of delayed wound healing at the Youden index threshold. The inclusion of variables such as drainage duration, preoperative white blood cell and neutrophil counts, alongside age and sex, highlights the pragmatic appeal of the model for early postoperative monitoring. Nevertheless, several aspects warrant critical reflection, including the reliance on a postoperative variable (drainage duration), internal validation only, and certain reporting inconsistencies. This letter underscores both the promise and the limitations of adopting interpretable machine learning models in perioperative care. We advocate for transparent reporting, external validation, and careful consideration of clinically actionable timepoints before integration into practice. Ultimately, this work represents a valuable step toward precision risk stratification in gastric cancer surgery, and sets the stage for multicenter, prospective evaluations.}, }
@article {pmid41609580, year = {2026}, author = {Purvinsh, Y and Matveyenka, M and Kurouski, D}, title = {Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {4}, pages = {823-832}, pmid = {41609580}, issn = {1948-7193}, mesh = {Animals ; *DNA-Binding Proteins/metabolism/toxicity ; Rats ; Humans ; *Amyloid/metabolism ; *Lipid Bilayers/metabolism ; Cardiolipins/metabolism ; Protein Aggregation, Pathological/metabolism ; Autophagy ; Phosphatidylserines/metabolism ; }, abstract = {Progressive aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and limbic predominant age-related TDP-43 encephalopathy (LATE). This highly conserved nuclear RNA/DNA-binding protein is involved in the regulation of RNA processing. The C-terminal domain (CTD) of TDP-43 plays a key role in protein solubility, cellular localization, and protein-protein interactions. CTD is rich in glycine, glutamine, and asparagine, which facilitate TDP-43 aggregation into amyloid oligomers and fibrils observed in the brain. In this study, we examine the role of lipid bilayers in the aggregation properties of the CTD of TDP-43. We found that lipid bilayers composed of anionic phosphatidylserine and cardiolipin accelerated TDP-43 aggregation. Although lipids did not alter the secondary structure, they altered the cytotoxicity that TDP-43 fibrils exerted to rat dopaminergic cells. Using molecular methods, we showed that TDP-43 fibrils damage cell endosomes. This causes aggregate leakage into the cytosol, where TDP-43 fibrils impair cell autophagy, simultaneously triggering a severe unfolded protein response in the endoplasmic reticulum. Our results indicate that TDP-43 aggregation may be linked to pathological changes in the lipid profiles of neurons.}, }
@article {pmid41609605, year = {2026}, author = {Bridges, AJ and Fradley, MF and Karlsson, ME and Zielinski, MJ}, title = {Centering the client in PTSD treatments: Commentary on Rubenstein et al. (2024).}, journal = {The American psychologist}, volume = {81}, number = {1}, pages = {109-111}, doi = {10.1037/amp0001480}, pmid = {41609605}, issn = {1935-990X}, mesh = {Humans ; *Stress Disorders, Post-Traumatic/therapy ; *Implosive Therapy/methods ; }, abstract = {We offer commentary examining conclusions that may be drawn from Rubenstein et al.'s (2024) perspective on the need for exposure-based posttraumatic stress disorder (PTSD) treatments. Here, we employ our shared expertise in implementing and evaluating exposure-based group therapy to reconsider the following impressions garnered from the referenced article: (a) exposure is not necessary for successful PTSD treatment; (b) clients do not want to talk about traumatic memories and will drop out of treatment; (c) exposure may be destabilizing to clients; and (d) clients will spontaneously expose, rendering exposure in therapy unnecessary. In this commentary, we focus on data that center clients' perspectives and acknowledge client choice in the use of exposure. As did Rubenstein et al. (2024), we conclude that exposure is useful for a diverse range of clients, frequently preferred over other forms of treatment, and highly effective for treatment of PTSD. We support efforts to increase access to efficacious PTSD treatments, urging that exposure-based treatments be offered to clients alongside other evidence-based therapies. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, }
@article {pmid41610283, year = {2026}, author = {Hayes, JM and Fornagiel, M and Kipust, A and Peters, GA and Goldberg, SA and Cash, RE}, title = {Statewide Emergency Medical Services Protocols for Field-Initiated Blood Resuscitation.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/10903127.2026.2623431}, pmid = {41610283}, issn = {1545-0066}, abstract = {OBJECTIVES: Prehospital blood transfusion by emergency medical services (EMS) is associated with improved outcomes in trauma patients, but little is known about the statewide protocols that influence the availability and use of prehospital blood. This study aimed to describe statewide EMS protocols regarding field-initiated prehospital blood and blood product transfusion across the U.S.<br><br>METHODS: This was a cross-sectional analysis of publicly available statewide EMS protocols pertaining to field-initiated blood or blood product use during ground transport by advanced life support (ALS) clinicians. We excluded protocols specific to critical care or interfacility transport. We used a standardized data collection tool to compare clinical indications, blood product type, and considerations for pediatrics and biologically female patients who may bear children in the future. Descriptive statistics were used to describe the protocols.<br><br>RESULTS: We identified 31 states and the District of Columbia with publicly available statewide EMS protocols. Thirteen (42%) of these protocols allowed for field-initiated prehospital blood transfusion. There was variability regarding recommendations for transfusion indications and the details of administration in the protocols. All protocols allowed for transfusion in traumatic emergencies, and nine (69%) allowed for transfusion in medical emergencies. Three (23%) protocols specifically recommended low titer group O whole blood, and three (23%) protocols allowed transfusion during cardiac arrest. Nine (69%) protocols allowed for transfusion in pediatric patients. Only four (31%) protocols included special considerations for transfusing blood to biologically female patients.<br><br>CONCLUSIONS: While most statewide EMS protocols in the US did not include field-initiated blood transfusion, the protocols that do exist vary widely. With the increasing implementation of prehospital blood programs, these findings suggest an opportunity to provide more robust evidence-based guidelines for prehospital blood transfusion to improve patient care and outcomes.}, }
@article {pmid41610293, year = {2026}, author = {Gauld, N and Cleland, J and Buchanan, S and Hikaka, J and Frampton, C and Buetow, S}, title = {Riluzole use and reasons for non-use in people with amyotrophic lateral sclerosis in Aotearoa New Zealand.}, journal = {The New Zealand medical journal}, volume = {139}, number = {1628}, pages = {50-57}, doi = {10.26635/6965.7238}, pmid = {41610293}, issn = {1175-8716}, support = {//This research was funded by a Health Research Council Research Activation Grant, a Motor Neurone Disease New Zealand grant and some voluntary time by the authors./ ; }, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; New Zealand ; Male ; Female ; Middle Aged ; Aged ; *Neuroprotective Agents/therapeutic use ; Surveys and Questionnaires ; Adult ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), is a neurodegenerative condition with typically short life expectancy. Riluzole, the only survival prolonging medication funded in Aotearoa New Zealand, has high uptake in other developed countries.<br><br>AIMS: To quantify riluzole use in New Zealand, identify factors associated with its use and explore reasons for non-use.<br><br>METHODS: In 2025, people in New Zealand diagnosed with MND were invited to self-complete questionnaires. Data were collected via Qualtrics, exported to Excel and analysed using descriptive and inferential statistics. Respondents with progressive muscular atrophy or primary lateral sclerosis diagnoses were excluded from this analysis.<br><br>RESULTS: Of 115 respondents, 55 (48%) were currently taking riluzole, 14 (12%) had taken it previously and 42 (36%) had never taken it. Common reasons for non-use included riluzole not being offered and concerns about lack of effectiveness and/or side effects. Uptake was lower with bulbar onset than limb onset (p<0.05).<br><br>CONCLUSIONS: People with ALS in New Zealand have low uptake of riluzole, despite its survival benefits. Prescribers and people with ALS need up-to-date information about riluzole's benefit-risk profile to increase uptake and confidence in prescription and use. Liquid riluzole is needed in New Zealand to aid uptake.}, }
@article {pmid41611003, year = {2026}, author = {Flose, BR and Silva, KCN and Juliano, MA and Trevisani, VFM and França, CN and Corral, MA and Nali, LHDS and Shio, MT}, title = {Antibody response against HERV-K polymerase and envelope by patients with multiple sclerosis.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {584}, number = {}, pages = {120870}, doi = {10.1016/j.cca.2026.120870}, pmid = {41611003}, issn = {1873-3492}, mesh = {Humans ; *Endogenous Retroviruses/enzymology/immunology ; *Multiple Sclerosis/immunology/blood/virology ; Male ; Female ; Adult ; Middle Aged ; Enzyme-Linked Immunosorbent Assay ; *Viral Envelope Proteins/immunology ; *Gene Products, pol/immunology ; *Antibody Formation ; }, abstract = {INTRODUCTION: Human Endogenous Retroviruses (HERVs) are viruses that have infected germ cells of our ancestors millions of years ago and compose 8% of human genome. The expression of HERVs is associated with neurological disorders such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). The humoral immune response against peptides from the envelope proteins, but not to polymerase, of HERV-K has been previously described. The aim of this study is to evaluate anti-HERV- K polymerase (pol) humoral response in patients with MS.<br><br>METHODS: GenBank platform were used to select peptides with similarity above 50%, comparing HERV sequences (K or W) with the protein Myelin Oligodendrocyte Glycoprotein (MOG). The synthesized peptides were used in the ELISA test for anti-HERV-K (pol - polymerase) and W (env - envelope) antibodies in serum of patients with MS (31) and healthy population (54) with no history of autoimmune diseases.<br><br>RESULTS: One peptide (pep) related to HERV-W env and 8 peptides of HERV-K env or pol were selected and synthesized. Validation of the indirect ELISA with sera from MS patients showed that there was immunoreactivity for all peptides compared to healthy population (p&#xa0;<&#xa0;0.0001). HERV-K env peptide 5 (WSGNQTLETRD) and 7 (ECVANSAVIL) showed the highest values of sensitivity and specificity, as well as diagnostic accuracy with 95.16% and 96.77%, respectively. HERV-K pol peptides 6 (LGIPTYAM), 8 (VTHVPSFR) and 9 (STVKTFTYLD) have demonstrated high values of accuracy 82.26, 80.65 and 82.26, respectively. These cutoff values were used to calculate the ELISA index - EI. The MS samples had a higher EI compared to the healthy population for almost all peptides of HERV-K pol (p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: The present work showed a humoral response related to HERV-K pol and env, as well as HERV-W env, by patients with MS. All diagnostic parameters are appreciable, which makes it possible to use this tool to better understand the mechanisms related to viral immunology in patients.}, }
@article {pmid41611468, year = {2026}, author = {Ivankov, DN and Zorin, EM}, title = {Sign Epistasis Can be Absent in Multi-peaked Landscapes With Neutral Mutations.}, journal = {Genome biology and evolution}, volume = {18}, number = {2}, pages = {}, pmid = {41611468}, issn = {1759-6653}, support = {25-14-00491//Russian Science Foundation/ ; }, mesh = {*Epistasis, Genetic ; *Mutation ; *Models, Genetic ; Genetic Fitness ; *Evolution, Molecular ; Phenotype ; Genotype ; }, abstract = {Fitness landscapes provide a rigorous mathematical framework for analyzing evolutionary dynamics, including the study of epistasis, the main obstacle to predicting phenotype from genotype. In 2011, Poelwijk et al. formulated a foundational theorem stating that in any multi-peaked fitness landscape, "at least two mutations exhibit reciprocal sign epistasis" (Poelwijk et al., J. Theor. Biol., 272:141). The proof relied on the implicit assumption that neutral mutations are absent, commonly accepted in theoretical studies in evolutionary biology. In this study, we extend Poelwijk et al.'s analysis by incorporating genotypes with equal fitness, specifically, accounting for neutral mutations. We demonstrate that when neutral mutations are considered, conventional pairwise reciprocal sign epistasis (RSE) may be entirely absent from a multi-peaked landscape. Instead, RSE is guaranteed only when considering "distant" RSE defined through composite mutations, wherein groups of mutations are treated collectively across all their possible combinations. Applying these concepts to empirical fitness landscapes faces a practical limitation: phenotypic measurements contain experimental noise, making some mutational effects statistically indistinguishable from zero. Under such conditions, statistically significant detection of RSE in multi-peaked landscapes may be impossible even when composite mutations are considered. Theoretically, our findings imply that in the presence of neutral mutations, compensatory mutations in a multi-peaked fitness landscape need not be adjacent; rather, compensation can occur following one or more neutral steps along an evolutionary path. Practically, in real-world scenarios where fitness measurements contain uncertainty, there may be a fundamental technical limitation to detecting RSE in a statistically significant manner within multi-peaked landscapes.}, }
@article {pmid41611549, year = {2026}, author = {Santurtún, A and Medín, P and Riancho, JA and Santiago-Setién, M and Ortiz, F and López de Munain, A and Almendra, R and Riancho, J}, title = {Corrigendum to "Temporo-spatial analysis of amyotrophic lateral sclerosis in Spain: Altitude and land use as new determinants of the disease" [Sci. Total Environ., 957 (2024), 177796].}, journal = {The Science of the total environment}, volume = {1015}, number = {}, pages = {181474}, doi = {10.1016/j.scitotenv.2026.181474}, pmid = {41611549}, issn = {1879-1026}, }
@article {pmid41612292, year = {2026}, author = {Maritim, B and Mbau, R and Musiega, A and Musuva, A and Amboko, B and Tsofa, B and Mazzilli, C and Vilcu, I and Wong, E and Murira, F and Nzinga, J and Boxshall, M and Mugo, P and Muthuri, RNDK and Ng'ang'a, W and Ravishankar, N and Barasa, E}, title = {"Poverty is a social issue, not a mathematical problem": examining the lessons for beneficiary identification from implementation of the UHC indigent program in Kenya.}, journal = {International journal for equity in health}, volume = {25}, number = {1}, pages = {40}, pmid = {41612292}, issn = {1475-9276}, support = {INV-049230/GATES/Gates Foundation/United States ; INV-049230/GATES/Gates Foundation/United States ; }, abstract = {BACKGROUND: Kenya rolled out a UHC indigent program aimed to expand financial protection and health service access for poor households through subsidized health insurance under the national insurer, National Health Insurance Fund (NHIF). As Kenya transitions to a new social health insurance framework under the Social Health Authority (SHA), understanding the implementation experience of the UHC indigent program is critical for informing the roll out of SHA’s indigent program.<br><br>METHODS: We conducted a qualitative process evaluation of the UHC indigent program using document reviews, semi-structured interviews with 23 key informants from national and county health authorities, development partners, and implementing actors, complemented by a validation workshop with 57 stakeholders. Our analysis was guided by Moore et al.&#x2018;s process evaluation framework and Wu et al.&#x2018;s policy capacity lens, examining implementation fidelity and capacities at multiple levels.<br><br>RESULTS: The program&#x2019;s implementation deviated from its original centralized design, with counties exerting control over beneficiary identification due to national data gaps, incomplete rollout of the Harmonized Testing Tool, and political and operational constraints. Variations in targeting methods, reliance on under-resourced community health actors, and delays in biometric registration contributed to partial enrolment, limited access, exclusion errors, and mistrust. Although some counties reported increased service utilization, this was limited by unregistered dependents and lack of beneficiary awareness. Stakeholders expressed concern over SHA&#x2019;s use of proxy means testing for identifying the poor, citing risks of exclusion, manipulation, and failure to capture locally constructed definitions of poverty.<br><br>CONCLUSION: Kenya&#x2019;s experience demostrates the need to align national targeting frameworks with local realities, invest in policy capacity across stakeholders, and prioritize community validation and communication in subsidy programs. As SHA rolls out a new indigent program, these lessons offer critical guidance for enhancing fidelity, equity, and accountability.}, }
@article {pmid41612406, year = {2026}, author = {Bigi, A and Chiti, F}, title = {Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.}, journal = {Genome biology}, volume = {27}, number = {1}, pages = {}, pmid = {41612406}, issn = {1474-760X}, support = {#NEXTGENERATIONEU (NGEU) - National Recovery and Resilience Plan (NRRP), Investment PE8&#x2500;Project Age-It: "Ageing Well in an Ageing Society" (D.R. 1557 11.10.2022).//Ministero dell'Universit&#xe0; e della Ricerca/ ; Fondi di Ateneo RICATEN 2024 and RICATEN 2025//Universit&#xe0; degli Studi di Firenze/ ; Fondi di Ateneo RICATEN 2023, RICATEN 2024 and RICATEN 2025//Universit&#xe0; degli Studi di Firenze/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *Inclusion Bodies/metabolism ; Neurodegenerative Diseases/metabolism ; Organelles/metabolism ; Cell Compartmentation ; Animals ; Liquid-Liquid Extraction ; Phase Separation ; }, abstract = {Phase separation is an important process in biology associated with formation of membraneless organelles but possibly related to the emergence of solid inclusions. TDP-43 is a largely studied paradigmatic case, as it forms neuronal cytoplasmic inclusions in neurodegenerative diseases and is an essential component of many membraneless organelles. Here, we review the physicochemical fundamentals of liquid-liquid phase separation (LLPS) of TDP-43 and its fragments in vitro, showing that full-length TDP-43 requires RNA or chaperones to form stable liquid droplets. We describe TDP-43-containing membraneless organelles and the debate on whether these assemblies represent reservoirs for pathological solid inclusion formation.}, }
@article {pmid41612503, year = {2026}, author = {Takahashi, K and Kato, C and Ueda, K and Nakamura, S and Ozawa, F and Moritoki, N and Shibata, S and Takahashi, S and Morimoto, S and Okano, H}, title = {Diagnostic potential of cryptic exon-derived peptides in serum extracellular vesicles for sporadic amyotrophic lateral sclerosis.}, journal = {Inflammation and regeneration}, volume = {46}, number = {1}, pages = {}, pmid = {41612503}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP25H00007//Japan Society for the Promotion of Science/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP25wm0625519//Japan Agency for Medical Research and Development/ ; 2024A04//Japan Intractable Diseases&#xff08;Nanbyo&#xff09;Research Foundation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration and loss of upper and lower motor neurons, with approximately 90% of cases being sporadic (sporadic ALS, SALS). A reliable diagnostic biomarker remains an unmet clinical need in SALS, with misdiagnosis and diagnostic delay hindering early management. The mislocalization of the RNA-binding protein TDP-43 (encoded by TARDBP), a pathological hallmark of SALS, could lead to aberrant splicing that produces transcripts with cryptic exons and, consequently, cryptic peptides. This study proposes cryptic peptides in serum extracellular vesicles as a novel candidate diagnostic biomarker of SALS. We included 10 healthy controls and 20 patients with SALS and quantified cryptic peptides predicted from cryptic exon sequences using mass spectrometry-based proteomics. Cryptic peptides from four proteins (RANBP1, IGLON5, ACTN1, ALPK2) were detected in participants, with the IGLON5 cryptic peptide detected significantly more frequently in SALS than in HC (adjusted P = 0.044). The number of detected cryptic peptides classified SALS and healthy controls with acceptable performance (area under the curve = 0.82). In conclusion, cryptic peptides could have diagnostic performance for SALS, warranting further validation.}, }
@article {pmid41613186, year = {2025}, author = {An, W and Jin, Z and Li, Y}, title = {Dual role of exosomes in neurodegenerative diseases: a molecular bridge between neuroinflammation and transmission of pathological proteins.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1708655}, pmid = {41613186}, issn = {1664-2295}, abstract = {Neurodegenerative diseases (NDDs) are complex disorders characterized by the progressive loss of neuronal function. Their pathological mechanisms involve multiple levels, including neuroinflammation, abnormal protein aggregation, and disrupted cell signaling. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis (MS), and prion diseases not only severely impact patients' quality of life but also pose significant challenges for medical research due to their complex pathogenesis and the lack of effective treatments. In recent years, extracellular vesicles (EVs), particularly exosomes, have garnered increasing attention for their critical role in cell-to-cell communication. Exosomes are membrane-enclosed nanovesicles approximately 30-150 nm in diameter that can carry proteins, lipids, nucleic acids, and other bioactive molecules, influencing recipient cells through paracrine or distant signaling. This review aims to summarize the roles of exosomes as mediators of neuroinflammation and as vehicles for intercellular transmission of pathogenic proteins in neurodegenerative diseases.}, }
@article {pmid41613245, year = {2026}, author = {Aronsen, J}, title = {You have ALS: a nurse's revolt against despair.}, journal = {Journal of research in nursing : JRN}, volume = {}, number = {}, pages = {17449871251407834}, doi = {10.1177/17449871251407834}, pmid = {41613245}, issn = {1744-988X}, }
@article {pmid41613680, year = {2025}, author = {Yamazaki, J and Hideyama, T and Teramoto, S and Kato, H and Aizawa, H and Kwak, S and Terashi, H}, title = {Age-Related Changes in Matrix Metalloproteinase-9 Expression in Spinal Motor Neurons of Normal Mice.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100305}, pmid = {41613680}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving the degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs). Although the cause of motor neuron (MN) degeneration in patients with ALS remains unknown, certain MN types (such as oculomotor neurons) and MNs within the Onuf (Onuf-Mannen) nucleus are preserved until the terminal stage. We previously generated mice with a selective knockout of adenosine deaminase acting on RNA 2 (ADAR2) in cholinergic neurons (ADAR2[flox/flox] /vesicular acetylcholine transporter (VAChT)-Cre.Fast; AR2). AR2 mice exhibit slow progressive loss of LMNs accompanied by TAR DNA-binding protein 43 (TDP-43) pathology against a background of insufficient editing at the GluA2 glutamine/arginine (Q/R) site due to ADAR2 deficiency. This model confirmed that insufficient editing at the GluA2 Q/R site, due to reduced ADAR2 activity, contributes to the pathogenesis of ALS. Furthermore, in AR2 mice, more frequent death of fast-fatigable motor neurons (FF MNs) was observed owing to differences in vulnerability under ADAR2-deficient conditions. Similar changes were observed during normal aging in the control mice. These findings suggest that investigating the characteristics of FF MNs may be useful for analyzing neuronal death in ALS. Recently, matrix metalloproteinase-9 (MMP-9), a marker of FF MNs, was reported to induce neurodegeneration. However, the distribution of MMP-9 in normal spinal MNs and its age-related changes remain unclear. Therefore, we investigated the MMP-9 expression patterns in normal mice at six and 12 months of age. In the present study, the number of MNs in the anterior horn (AH) decreased with age, as did the number of MMP-9-positive MNs. Furthermore, as aging has been shown to induce the abnormal localization of TDP-43 in MMP-9-positive MNs, these MNs were considered vulnerable to degeneration. These findings suggest that MMP-9 not only functions as a marker for FF MNs but may also act as a potentially useful marker for MNs prone to degeneration with TDP-43 pathology, or for early degeneration in both physiological aging and age-related diseases, including ALS. Future investigations of MMP-9 expression in patients with ALS and in ALS mouse models are considered useful for elucidating ALS pathogenesis.}, }
@article {pmid41614057, year = {2025}, author = {Subramani, NK and Venugopal, S and Rajan, AP}, title = {An integrated subtractive genomics and immunoinformatic approach for designing a multi-epitope peptide vaccine against methicillin-resistant Staphylococcus aureus.}, journal = {Frontiers in bioinformatics}, volume = {5}, number = {}, pages = {1745495}, pmid = {41614057}, issn = {2673-7647}, abstract = {INTRODUCTION: MRSA is a multi-drug-resistant bacteria responsible for severe infections that has become a major health concern. Due to constraints of traditional methods, there is a need for developing a new approach to prevent the MRSA-related infections by targeting key pathogens.<br><br>METHODS: Initially, the subtractive genomics was applied to the MRSA proteome to identify non-homologous, essential, and virulence targets using comparative BLAST-based screening. Further, immunoinformatic tools were employed for B- and T-cell epitope prediction and vaccine construction with appropriate adjuvants and linkers, followed by immune simulation and molecular docking with immune receptors.<br><br>RESULTS: Comparative metabolic pathway analysis identified 294 MRSA pathway proteins, with acetolactate synthase (ALS) as a non-homologous, essential, and virulent protein that is involved in the branched amino acid biosynthesis pathway. The constructed ALS vaccine consists of 3 B-cell and 19 T-cell epitopes exhibited stable immunological features with 97.55% global population coverage. Molecular docking revealed that ALS exhibited a superior binding affinity with the TLR4 receptor (-1,438.7 kcal/mol) than the TLR2 receptor (-1,103.5 kcal/mol), which was further confirmed by high structural stability and compactness analysis. Immune simulations also exhibited elevated IgM, IgG subtypes, and cytokine productions, suggesting a robust humoral and cellular immunity.<br><br>DISCUSSION: Identified ALS highlights its biological relevance in MRSA survival. The stability predictions with TLR4 suggested effective activation of innate immunity that may enhance antigen presentation and downstream adaptive immunity. The validation of the ALS vaccine's safety and immunogenicity further requires comprehensive in vitro and in vivo examinations.<br><br>CONCLUSION: Thus, ALS is recognized as a promising MRSA vaccine candidate and has the potential to activate immune responses effectively.}, }
@article {pmid41614607, year = {2026}, author = {Combe, P and Subecz, C and Le Goff, G and Plamont, MA and Bohl, D and Gueroui, Z}, title = {Concentration-dependent cytoplasmic phase separation of TDP-43 drives aggregation and proteinopathy.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70429}, pmid = {41614607}, issn = {1742-4658}, support = {MND202003011470//Fondation pour la Recherche M&#xe9;dicale/ ; }, abstract = {TDP-43 mislocalization and aggregation are common features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the mechanisms underlying the transition of nuclear TDP-43 to cytoplasmic aggregates, and their contribution to disease pathogenesis, remain poorly understood. To address this gap, we present a methodology to chemically control the assembly and disassembly of cytoplasmic TDP-43 condensates. By fusing TDP-43 to a phase separation-prone protein scaffold, we can induce the formation of cytoplasmic TDP-43 condensates or, conversely, promote nuclear localization upon addition of a disassembly molecule. TDP-43 accumulates into various assemblies, ranging from submicrometric puncta to larger aggregate-like structures that display hallmarks of proteinopathy in a concentration-dependent manner. Furthermore, oxidative stress drives the maturation of TDP-43 assemblies from puncta into aggregates through interactions with stress granule components. Finally, we show that cytoplasmic TDP-43 aggregates deplete nuclear endogenous TDP-43 and induce cytotoxicity. Collectively, these findings highlight the local cytoplasmic concentration of TDP-43 and stress exposure as key determinants in the onset of TDP-43 proteinopathy, providing a relevant model to study pathological TDP-43 aggregation.}, }
@article {pmid41615807, year = {2026}, author = {Azizzadeh, M and Pirker-Kees, A and Wouters, EFM and Janssen, DJA and Spaetgens, B and Breyer-Kohansal, R and Breyer, MK}, title = {Association of allostatic load with frailty trajectories and the mediating role of depressive symptoms.}, journal = {The Journal of frailty &amp; aging}, volume = {15}, number = {2}, pages = {100132}, pmid = {41615807}, issn = {2260-1341}, abstract = {BACKGROUND: Frailty is a dynamic, age-related condition marked by progressive loss of resilience. Its risk factors include socioeconomic status and physiological stress burden, such as allostatic load score (ALS), remain unclear. This study aims to examine the role of depression in the association between ALS and frailty trajectories.<br><br>METHODS: We analyzed data from 5885 LEAD cohort participants aged 25-82 years at baseline and from 3564 participants with follow-up data. Frailty status (robust, pre-frail, frail) was defined using the Fried phenotype, and transitions between visits were assessed. ALS was calculated from 14 parameters spanning cardiovascular, metabolic, and body composition measures. Associations of ALS with frailty status at baseline and with frailty transitions at follow-up were examined, and depressive symptoms were tested as a mediator.<br><br>RESULTS: At baseline, 62.3% of participants were robust, 36.2% pre-frail, and 1.5% frail. Between visits, 16.3% transitioned to a worse frailty stage, while 17.7% improved. Higher ALS was linked to increased odds of being pre-frail/frail at baseline (OR 1.11; 95% CI: 1.08-1.15), and to a higher risk of transitioning from robust to pre-frail/frail (RRR 1.06; 95% CI: 1.02-1.09). Depressive symptoms mediated 35% (95% CI: 25-47%) of the cross-sectional and 17% (95% CI: 6.6-43%) of the longitudinal association between ALS and frailty.<br><br>CONCLUSIONS: Socioeconomic factors influenced frailty onset but not its progression, whereas depressive symptoms mediated approximately 17% of the effect of ALS on frailty development over time. These findings highlight the importance of exploring the effect of interventions for depression on frailty progression.}, }
@article {pmid41616079, year = {2026}, author = {Steenkjaer, CH and Storgaard, JH and Levison, L and Blicher, JU}, title = {A national survey of pseudobulbar affect and symptomatic treatment in Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2026.2620448}, pmid = {41616079}, issn = {2167-9223}, abstract = {OBJECTIVE: We aimed to determine diagnostic prevalence and symptom burden of pseudobulbar affect (PBA) in patients with Amyotrophic Lateral Sclerosis (ALS) in Denmark and differences in ongoing symptomatic treatment.<br><br>METHODS: In this national cross-sectional survey study, participants with ALS completed an online survey regarding PBA and PBA symptoms, which were quantified through the Center for Neurologic Study Lability Scale (CNS-LS). A CNS-LS score &#x2265; 13 served as a threshold indicative of PBA.<br><br>RESULTS: 157 participants with ALS were recruited. 12.1% were diagnosed with PBA and were more likely to receive antidepressant medication compared to those not diagnosed with PBA (47.4% compared to 15.2%, p&#x2009;=&#x2009;0.002). 30.6% scored &#x2265;13 in the CNS-LS; however, the proportion of participants treated with antidepressants was similar compared to those scoring below the &#x2265;13 threshold (25% compared to 16.5%, p&#x2009;=&#x2009;0.27). Of those not diagnosed with PBA, 23.2% scored &#x2265;13 in the CNS-LS. This PBA symptomatic, but undiagnosed group was less likely to receive symptomatic treatment compared to patients with diagnosed PBA (12.5% compared to 47.4%, p&#x2009;=&#x2009;0.009). No differences were seen in CNS-LS score between these groups.<br><br>CONCLUSIONS: The proportion of diagnosed PBA among the study population was low compared to previous studies; however, the proportion of patients with symptoms of possible PBA was markedly higher. Patients with known PBA were more likely to receive recommended symptomatic treatment compared to patients not diagnosed with PBA, despite symptoms indicative of PBA. These findings highlight the potential underrecognition of PBA in ALS and concurrent absence of symptomatic treatment.}, }
@article {pmid41616251, year = {2026}, author = {Sang, Y and Ren, J and Aballay, A}, title = {A gut-activated NHR-86-CYP pathway mediates the neuroprotective effects of Enterococcus faecium probiotics in a nematode model of amyotrophic lateral sclerosis.}, journal = {PLoS biology}, volume = {24}, number = {1}, pages = {e3003627}, pmid = {41616251}, issn = {1545-7885}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AI117911/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/metabolism/genetics/microbiology ; *Amyotrophic Lateral Sclerosis/metabolism/prevention &amp; control ; *Probiotics/pharmacology ; *Enterococcus faecium/physiology ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Disease Models, Animal ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; Oxidative Stress ; *Neuroprotective Agents/pharmacology ; *Receptors, Cytoplasmic and Nuclear/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Motor Neurons/metabolism ; Animals, Genetically Modified ; Neuroprotection ; Signal Transduction ; }, abstract = {Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen species (ROS) levels. We identified the conserved nuclear hormone receptor NHR-86 as a key regulator of cyp gene expression and neuroprotection. Loss of nhr-86 abolished the probiotic's protective benefits, while transgenic expression of nhr-86 restored cyp induction and neuronal resilience. Importantly, intestinal expression of NHR-86 was sufficient to restore CYP induction and neuronal resilience, whereas neuronal knockdown had no effect, indicating that gut NHR-86 activity is essential for this protective pathway. These findings reveal a previously uncharacterized NHR-CYP regulatory axis activated by an intestinal probiotic, highlighting a mechanistic link between microbial signals and host neuroprotection.}, }
@article {pmid41617608, year = {2026}, author = {Tankéré, P and Bernard, E and Herquelot, E and Denis, H and Sfeir, L and Saint-Raymond, C and Mallaret, M and Lavergne, F and Baillieul, S and Peter-Derex, L and Tamisier, R and Pépin, JL}, title = {Health trajectories of patients with amyotrophic lateral sclerosis before and after initiation of non-invasive ventilation: a French nationwide database analysis.}, journal = {Thorax}, volume = {}, number = {}, pages = {}, doi = {10.1136/thorax-2025-223974}, pmid = {41617608}, issn = {1468-3296}, abstract = {BACKGROUND: Management of amyotrophic lateral sclerosis (ALS) is complicated by heterogeneous presentation and unpredictable disease course. This study described disease trajectories before and after initiation of non-invasive ventilation (NIV) therapy in individuals with ALS, examined the relationship between NIV initiation timing and survival and analysed health trajectory clusters.<br><br>METHODS: Data were extracted from the French national health insurance reimbursement system database for individuals with &#x2265;1 reimbursement for NIV from January 2015 to December 2019, and &#x2265;1 ALS disease code. Health trajectory clusters were determined using time sequence analysis through K-clustering.<br><br>RESULTS: We analysed data from 3443 individuals with ALS (58% male, median age 67 years). The median (IQR) time from ALS diagnosis to NIV initiation was 10.8 (4.5-22.2) months and death occurred 21.5 (12.8-33.9) months after diagnosis. Tracheostomy/gastrostomy was performed in 3.9%/33.4% of patients, respectively. Unsupervised machine learning clustering identified four distinct patient groups. NIV initiation was late in two Clusters (A and B); these individuals were younger, had fewer comorbidities and more physiotherapy sessions before/after NIV. Survival after NIV initiation was longer in Clusters B and C; these individuals had lower rates of depression/anxiety, more prescription of mechanical in/exsufflation therapy and fewer home and emergency hospitalisations. Cluster B was unique, showing late NIV initiation and long post-NIV survival. This cluster was more likely to have spinal onset, a higher rate of obstructive sleep apnoea and fewer comorbidities.<br><br>CONCLUSIONS: There was marked heterogeneity between patients with ALS and their care trajectories. Our data do not support a universal benefit for early initiation of NIV therapy.}, }
@article {pmid41618346, year = {2026}, author = {Öijerstedt, L and Mravinacová, S and Olofsson, J and Azizi, L and Bergström, S and Yazdani, S and De Vita, N and Aksoylu, IS and Foucher, J and Juto, A and Kläppe, U and Nilsson, P and Månberg, A and Ingre, C}, title = {Ratios of CSF proteins reflect cognitive function in ALS.}, journal = {Alzheimer's research &amp; therapy}, volume = {18}, number = {1}, pages = {}, pmid = {41618346}, issn = {1758-9193}, abstract = {BACKGROUND: Cognitive impairment is a recognised feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Despite advances in understanding cognitive impairment in ALS, no fluid biomarkers reliably predict these changes. Prior research in Alzheimer disease (AD) has demonstrated that CSF protein ratios enhance biomarker accuracy by mitigating inter-individual variability, improving diagnostic precision. In AD, ratios involving synaptic markers have shown stronger associations with cognitive outcomes than single proteins, motivating evaluation of a similar ratio-based approach in ALS.<br><br>METHODS: Building on findings from the AD field, we analysed 47 CSF proteins, suggested to be associated to neurodegeneration, in 66 patients with ALS and explored protein ratios to evaluate their utility in detecting cognitive impairment, hypothesising shared mechanisms between neurodegenerative diseases. Elastic net regression identified the most predictive protein pairs associated with cognitive impairment, assessed with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).<br><br>RESULTS: Elastic net identified seven single proteins (NEFM, NPTX2, GAP43, IGFBP4, IGFBP7, SPP1, CDH8) and eight protein pairs associated with ECAS total score. Ratios were generally more informative than individual proteins, with PTPRN2/GAP43 showing the strongest association with ECAS scores, indicating an enhanced ability to capture cognitive changes. Several of the proteins in the most predictive pairs have previously been implicated to associate to cognitive impairment in AD.<br><br>CONCLUSION: Our findings indicate that protein ratios outperform single-protein analyses in detecting associations with cognitive impairment, aligning with advancements in AD research. By extending the concept of CSF protein ratios from AD to ALS, this study highlights shared pathological mechanisms and suggests that similar proteins are linked to cognitive dysfunction in both diseases.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01976-y.}, }
@article {pmid41618385, year = {2026}, author = {Koyama, T and Tsumura, H and Okita, R and Yamazaki, K and Hasegawa, A and Imamura, K and Kato, T and Iwata, H and Kojima, R and Inoue, H and Matsumoto, S and Okuno, Y}, title = {Chemical genomics language model toward reliable and explainable compound-protein interaction exploration.}, journal = {Journal of cheminformatics}, volume = {18}, number = {1}, pages = {29}, pmid = {41618385}, issn = {1758-2946}, support = {JP24KJ1510//Japan Society for the Promotion of Science/ ; 22K06112//Japan Society for the Promotion of Science/ ; JP24H01771//Grant-in-Aid for Transformative Research Areas (A) "Latent Chemical Space"/ ; JP22bm0804034//Japan Agency for Medical Research and Development/ ; }, abstract = {Accurate prediction of compound-protein interactions (CPIs) is crucial for chemical biology and drug discovery. Despite recent advancements, existing deep learning (DL)-based CPI models often struggle to simultaneously achieve high generalization performance, quantify prediction confidence, and ensure explainability. Here, we propose ChemGLaM, a chemical genomics language model designed to address these three crucial challenges, thereby enabling reliable and explainable CPI predictions. ChemGLaM integrates independently pre-trained chemical and protein language models through an interaction block with a cross-attention mechanism, achieving near state-of-the-art performance in predicting novel CPIs at a low computational cost. Incorporating uncertainty estimation and attention visualization enables ChemGLaM to enhance the success rate of virtual screening and to provide molecular insights into CPIs. To demonstrate the practical impact of ChemGLaM, we constructed a publicly available database containing large-scale CPI predictions for every possible pairing between all 20,434 human proteins and all 11,455 drugs and validated its practical applicability in a case study on amyotrophic lateral sclerosis. ChemGLaM marks an important step forward in addressing the challenges of AI-driven CPI exploration and drug discovery.Scientific ContributionThis study established a unified CPI prediction framework that simultaneously achieves high generalization performance, confidence quantification, and explainability. We leveraged this framework to create a community resource by constructing a comprehensive CPI database and demonstrated its practical utility by successfully prioritizing hit compounds and deconvoluting their targets in a phenotypic screening for amyotrophic lateral sclerosis.}, }
@article {pmid41618386, year = {2026}, author = {Omranikhoo, H and Rezaee, M and Verdizadeh, A and Goudarzi, Z and Jafari, M and Gholami, A and Poursadeghfard, M and Keshavarz, K}, title = {Cost-utility analysis of Edaravone compared to Riluzole in patients with amyotrophic lateral sclerosis (ALS) in Iran.}, journal = {Cost effectiveness and resource allocation : C/E}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12962-025-00697-7}, pmid = {41618386}, issn = {1478-7547}, }
@article {pmid41618645, year = {2026}, author = {Verhoeff, MC and van Selms, MKA and Lobbezoo, F}, title = {A Personal Exploration of Oral Health in Amyotrophic Lateral Sclerosis (ALS) Through the Eyes of a Multifaceted Authority.}, journal = {Journal of oral rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1111/joor.70157}, pmid = {41618645}, issn = {1365-2842}, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that impairs motor function, including oral musculature, complicating oral hygiene and care. Despite its impact, oral health in ALS patients remains under-addressed. This personal scoping review explores oral health in ALS through the dual lens of Dr. Maurits K.A. van Selms-a dental researcher and ALS patient-highlighting care, research, and education priorities.<br><br>METHODS: Semi-structured interviews were conducted via email with Dr. van Selms, using a topic guide adapted from a prior personal scoping review. The interview covered personal experiences and professional insights into oral health care, research, and education in ALS. Responses were analysed and synthesised into thematic agendas.<br><br>RESULTS: Dr. van Selms emphasised the neglect of oral hygiene in ALS care. He advocated for patient-informed, tailored guidelines based on functional capacity, interdisciplinary collaboration, and improved accessibility to dental services. In research, he called for ethically sensitive, patient-centered studies that reduce the burden of oral care. Educationally, he stressed the need for inclusive training across disciplines and stakeholder levels, promoting self-advocacy and awareness. Instructional materials, such as videos, were recommended to support caregivers and patients.<br><br>CONCLUSION: This personal scoping review underscores the importance of integrating oral health into ALS management. Dr. van Selms' unique perspective reveals gaps in care delivery, research ethics, and education, advocating for interdisciplinary collaboration and proactive guideline development. His insights offer a roadmap for improving oral health outcomes and quality of life in ALS and similar neurodegenerative conditions.}, }
@article {pmid41619021, year = {2026}, author = {Dressler, D and Frevert, J and Johnson, EA and Fink, K and Pellett, S and Pandey, S and Walter, U and Tacik, P and Kanovsky, P and Shahidi, GA and Brüggemann, N and Rosales, RL and Relja, M and Jin, L and Rodriguez, JAS and Pan, L and Francisco, GE and Shang, H and Bai, X and Adib Saberi, F}, title = {Iatrogenic botulism: a risk for botulinum toxin's medical use?.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {41619021}, issn = {1435-1463}, abstract = {Botulinum toxin (BT) is infamous for its extreme toxicity. If it enters the bloodstream, it can cause botulism presenting with a typical pattern of motor and autonomic dysfunction. An international expert panel organised by IAB-Interdisciplinary Working Group for Movement Disorders explored iatrogenic botulism after BT's medical use (IB), reached conclusions and formulated recommendations. When injected into its target tissue, BT binds to gangliosides on cholinergic nerve terminals before it is internalised permanently. Small amounts of BT, however, are circulating within the bloodstream. When BT type B is applied, IB-B occurs frequently, typically affecting the autonomic nervous system. When BT type A is applied, IB-A only occurs in special circumstances, even when high doses are used. We identified 236 patients with IB-A in the literature. All IB-A was mild or moderate and fully reversible. In 212 patients, it occurred with unapproved BT use. In 116 of them, unapproved BT preparations were used, in 81, unapproved indications were treated and in 15, underlying neuromuscular impairment including myasthenia gravis, Lambert-Eaton myasthenic syndrome, amyotrophic lateral sclerosis and spinal muscle atrophy were contraindications for BT use. In 24 patients, IB-A occurred in approved BT use. Their evaluation was frequently incomplete, so that causes for IB-A often remain unclear. They may include presence of differential diagnosis, subclinical neuromuscular impairment and interference with additional diseases. When IB is suspected, proper evaluation is necessary to verify it and to identify its causes. Off-label use is common in BT therapy. However, it should be performed with caution, especially in children and when high doses are applied. High BT doses should not be applied to low volumes of target tissues, in order not to exceed the BT binding capacity.}, }
@article {pmid41619170, year = {2026}, author = {Steffke, C and Brenner, D and Catanese, A}, title = {Reply to "Extending the Interpretation of Biomarker Dynamics in SOD1-ALS Proteomics".}, journal = {Annals of neurology}, volume = {99}, number = {2}, pages = {546-547}, pmid = {41619170}, issn = {1531-8249}, }
@article {pmid41619791, year = {2026}, author = {Yazdani, S and Seitz, C and Andersson, J and Ingre, C and Fang, F and Lovik, A}, title = {Methodological considerations in the analysis of survival data in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2615111}, pmid = {41619791}, issn = {2167-9223}, abstract = {Survival outcomes are commonly analyzed in studies with data from patients with progressive, neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Given the fast progression of ALS, survival analyses are, however, often difficult to perform and interpret. In this methodological article we demonstrate on real-world data how the choices we make in the study design, data collection, and analysis could influence the results. The factors we consider in this study are length of follow-up, sample size, timing of sample collection, and choice of covariables adjusted for in the models. We further discuss the importance of each of these contributing factors and about how to avoid mistakes in interpreting and reporting survival data in ALS and other rare, progressive diseases.}, }
@article {pmid41620396, year = {2026}, author = {Carroll, E and Scaber, J and Pasniceanu, IS and Dafinca, R and Gordon, D and Candalija, A and Talbot, K}, title = {Mutant TDP-43 drives impairments in axonal transport and glycolysis in a mouse stem-cell-derived motor neuron model of amyotrophic lateral sclerosis (ALS).}, journal = {Cell death &amp; disease}, volume = {17}, number = {1}, pages = {193}, pmid = {41620396}, issn = {2041-4889}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; Mice ; *Axonal Transport/genetics ; *Glycolysis/genetics ; Humans ; *Mutation/genetics ; Disease Models, Animal ; Mouse Embryonic Stem Cells/metabolism ; }, abstract = {TDP-43 dysfunction is thought to be central to ALS pathogenesis. Studying mutations in the gene which encodes TDP-43, TARDBP, provides a valuable opportunity to gain insight into how TDP-43 dysfunction alters cellular homoeostasis. Our group has previously developed a TDP-43[M337V] mouse embryonic stem cell-derived motor neuron (mESC-MN) model, which expresses a single copy of the human TARDBP gene expressing the pathogenic M337V mutation at low levels. Here, we perform extensive phenotypic characterisation of this model, and show that TDP-43[M337V] leads to reduced MN viability, impaired axonal transport and reduced basal glycolysis compared to TDP-43[WT] controls. Altered neuronal viability and function occurs in the absence of TDP-43 mislocalisation or aggregation, suggesting 'proteinopathy' is downstream of these ALS-relevant phenotypes. These findings provide further support for a link between TDP-43 dyshomeostasis, cellular bioenergetics and axonal transport and suggest these pathways warrant further investigation as targets for therapeutic intervention.}, }
@article {pmid41621017, year = {2026}, author = {Aynaashe, A and Kursula, P}, title = {Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.}, journal = {Amino acids}, volume = {58}, number = {1}, pages = {8}, pmid = {41621017}, issn = {1438-2199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; Mutation ; Axonal Transport/genetics ; Mitochondria/genetics/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT) are two distinct neurodegenerative disorders. While ALS is characterised by rapidly progressive motor neuron degeneration, leading to severe complications and death, CMT as a peripheral neuropathy is less severe, and patients have a longer life span, although with a compromised quality of life. Despite their clinical differences, current knowledge suggests that familial ALS (fALS) and CMT may share common genetic and molecular mechanisms. We aimed to identify shared genes mutations and molecular pathways between fALS and CMT through a literature and database search. Thirteen genes were identified, involved in distinct cellular processes: axonal transport (DYNC1H1, KIF5A, SPG11, DCTN1), protein homeostasis (NEFH, VCP, SOD1), RNA metabolism (GARS, SETX), cellular stress response (HSPB1, FIG4), and mitochondrial function (MFN2, CHCHD10). While these linkages to the two diseases are rare for each gene, understanding possible mechanistic commonalities at the molecular level can initiate new research directions, help in identifying additional common genes between neurodegenerative disorders, and improve diagnostics.}, }
@article {pmid41621376, year = {2026}, author = {Luthfiyah, S and Triwiyanto, T and Rusyadi, L and Ismath, M}, title = {Letter to Editor: Correlation between MRI-derived and biopsy-confirmed liver iron concentration in patients with chronic liver disease.}, journal = {European journal of radiology}, volume = {196}, number = {}, pages = {112701}, doi = {10.1016/j.ejrad.2026.112701}, pmid = {41621376}, issn = {1872-7727}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Iron/metabolism/analysis ; *Liver/pathology/metabolism/diagnostic imaging ; Biopsy ; Chronic Disease ; *Liver Diseases/metabolism/pathology ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {We comment on Ba-Ssalamah et al.'s study comparing MRI-derived and biopsy-confirmed liver iron concentration in chronic liver disease. The strong agreement between two R2*-based methods supports the robustness of relaxometry-based LIC estimation in the low-mild iron range. We discuss physics-related considerations, including R2* nonlinearity, spatial sampling, signal modeling, and calibration dependence, and outline future directions toward volumetric mapping and cross-platform harmonization for quantitative liver MRI.}, }
@article {pmid41621673, year = {2026}, author = {Dev, A and Mehta, H and Vinay, K}, title = {Response to Gao et al's "Can we navigate the pitfalls of tofacitinib RCTs in vitiligo? Addressing long-term safety and generalizability for enhanced clinical translation".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2026.01.059}, pmid = {41621673}, issn = {1097-6787}, }
@article {pmid41621861, year = {2026}, author = {Loan, A and D'Mello, R and Li, Y and Nurkan, T and Minic, Z and Wang, J and Man Chan, H}, title = {Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.}, journal = {The Journal of toxicological sciences}, volume = {51}, number = {2}, pages = {89-100}, doi = {10.2131/jts.51.89}, pmid = {41621861}, issn = {1880-3989}, mesh = {Animals ; *Methylmercury Compounds/toxicity/administration &amp; dosage ; Female ; Pregnancy ; Mice, Inbred C57BL ; *Cerebellum/metabolism/drug effects/pathology ; *Prenatal Exposure Delayed Effects/genetics/metabolism/chemically induced ; *Transcriptome/drug effects ; Proteomics ; *Neurodegenerative Diseases/genetics/chemically induced/metabolism ; Male ; Oxidative Stress/drug effects ; Mice ; }, abstract = {Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.}, }
@article {pmid41622338, year = {2026}, author = {Salehcheh, M and Nikravesh, M and Aghebat-Bekheir, S and Matin, M}, title = {Manganese concentrations in biological matrices and amyotrophic lateral sclerosis (ALS): a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {2}, pages = {216}, pmid = {41622338}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/blood ; Humans ; *Manganese/blood/metabolism/analysis ; }, abstract = {BACKGROUND: Manganese (Mn) is an essential but neurotoxic trace element implicated in neurodegenerative disorders. Its association with amyotrophic lateral sclerosis (ALS) remains uncertain. We conducted a systematic review and meta-analysis to evaluate whether Mn concentrations differ between ALS patients and healthy controls.<br><br>METHODS: We systematically searched PubMed, EMBASE, Web of Science, and Scopus for observational studies comparing Mn concentrations between ALS patients and healthy controls. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Heterogeneity was assessed with the I&#xb2; statistic, and publication bias was evaluated by Egger's test.<br><br>RESULTS: Twelve studies (446 ALS cases, 652 controls) measuring Mn in blood, serum, cerebrospinal fluid (CSF), hair, urine, toenail, plasma, or tissue were included. The pooled SMD was 0.05 (95% CI: -&#x2009;0.20 to 0.30; p&#x2009;=&#x2009;0.68; I&#xb2; = 71.7%), indicating no significant difference in Mn concentrations. Subgroup analyses by biological matrix and analytical method showed no consistent pattern; meta-regression identified analytical method as a significant source of heterogeneity.<br><br>CONCLUSION: No publication bias was detected (Egger's p&#x2009;=&#x2009;0.53). Peripheral Mn concentrations do not differ significantly between ALS patients and controls. Future research should employ longitudinal and CNS-targeted approaches, incorporating occupational exposure assessment and standardized analytical protocols.}, }
@article {pmid41622459, year = {2026}, author = {Diaz, G and Hetz, C}, title = {Protein disulfide isomerases in amyotrophic lateral sclerosis: Endoplasmic reticulum proteostasis and neuromuscular function.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01874}, pmid = {41622459}, issn = {1673-5374}, }
@article {pmid41622476, year = {2026}, author = {Liu, J and Zhou, L and Deng, Y and Xu, R}, title = {Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00221}, pmid = {41622476}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease that targets motor neurons in the cerebral cortex, medulla oblongata, and spinal cord. This review focuses on the current concepts in the aetiopathogenesis and diagnosis of amyotrophic lateral sclerosis, aiming to explore potential neural repair strategies (curative and/or progression-retarding therapeutics). Recent studies have highlighted that the complex pathogenesis of amyotrophic lateral sclerosis is related to its multifactorial aetiology, including proteostasis disruption, impaired RNA metabolism and DNA repair, cytoskeletal and axonal transport defects, excitotoxicity, neuroinflammation, mitochondrial dysfunction, oligodendrocyte dysfunction, nucleocytoplasmic transport deficits, lipid dyshomeostasis, and autophagy. Several approved drugs are currently used to treat patients with amyotrophic lateral sclerosis; however, their curative efficacy is limited. Thus, the search for effective therapeutic strategies for amyotrophic lateral sclerosis requires a comprehensive understanding of its pathogenesis. Current evidence indicates that a single drug cannot provide a satisfactory therapeutic effect. Additionally, multiple pathophysiological processes and related targets are involved in the pathogenesis of amyotrophic lateral sclerosis. Therefore, research on multi-target synchronous interventions may be the path forward for discovering and developing potential neural repair strategies.}, }
@article {pmid41623487, year = {2026}, author = {Lian, L and Robinson, H and Daniels, N and Prieto, GA and Poplawski, GHD and Lopez-Gonzalez, R}, title = {Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD.}, journal = {iScience}, volume = {29}, number = {2}, pages = {114596}, pmid = {41623487}, issn = {2589-0042}, abstract = {The C9orf72 hexanucleotide repeat expansion (G4C2) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet targeted therapies remain unavailable. Here, we show that induced pluripotent stem cell (iPSC)-derived post-mitotic neurons from C9orf72 carriers exhibit age-dependent cell-cycle reentry, increased S-phase entry, and elevated cyclin and CDK expression. Mechanistically, arginine-containing dipeptide repeat proteins (poly-GR and poly-PR) translated from G4C2 repeats drive this aberrant activation through stimulation of the CDK4/6 pathway, whereas poly-GP and C9orf72 loss-of-function show no effect. Importantly, the FDA-approved CDK4/6 inhibitor palbociclib normalizes cell-cycle progression, reduces S-phase entry, decreases motor neuron death, and restores synaptic proteins PSD95 and synapsin-1. Single-nucleus RNA sequencing from C9orf72 patient cortex reveals cell-cycle activation within excitatory neuron subclusters and alterations in DNA repair and cell-cycle regulation pathways, supporting our in vitro findings. These findings establish cell-cycle dysregulation as a central pathogenic mechanism in C9orf72 ALS/FTD and highlight CDK4/6 signaling as a promising therapeutic target.}, }
@article {pmid41623730, year = {2026}, author = {Surtees, JE and Lambert, CV}, title = {Maintenance of competence in rarely performed clinical skills by advanced life support providers in Gauteng, South Africa: A mixed-methods study.}, journal = {African journal of emergency medicine : Revue africaine de la medecine d'urgence}, volume = {16}, number = {1}, pages = {100932}, pmid = {41623730}, issn = {2211-4203}, abstract = {INTRODUCTION: Advanced Life Support (ALS) providers are highly trained emergency care professionals with a broad range of clinical skills. Confidence and competence to perform a clinical skill or intervention has been linked to frequency of application. Differences in training, caseloads, and the context in which ALS providers operate can influence how often they get to perform different skills. Although the Health Professions Council of South Africa (HPCSA) mandates Continuing Professional Development (CPD), there is no requirement for ALS providers to demonstrate maintenance of procedural competence. In this study we investigated approaches to the maintenance of competency in rarely performed clinical skills among a sample of Gauteng-based ALS providers.<br><br>METHODS: An exploratory, descriptive mixed-methods design was employed. A quantitative survey of 41 ALS providers assessed frequency of performance and self-reported confidence across 55 clinical skills was performed in March 2023. This was followed by two focus group discussions to explore in greater depth participant's experiences with regard to maintenance of clinical skills.<br><br>RESULTS: More than half of the 55 skills we assessed were reported to be "rarely" performed. Confidence to perform a particular skill generally mirrored the frequency with which the skill was performed. Focus group participants identified valuable strategies for maintaining skills that included clinical rotations across diverse work environments, peer discussions, instructional videos, and CPD-accredited courses that included a practical component. Limitations were identified in the current CPD system with regard to maintenance of clinical skills.<br><br>CONCLUSION: Skill decay and a reduction in confidence among ALS providers can be linked to infrequent performance of certain clinical skills and interventions. A more purposeful coordinated strategy involving education and training providers, employers and practitioners is required to better support the maintenance of clinical skills that are infrequently performed.}, }
@article {pmid41624110, year = {2026}, author = {Debernard, S and Gassias, E and Aguilar, P and Maria, A and Fuentes, A and Couzi, P and Bozzolan, F and Durand, N and Force, E}, title = {Involvement of Taiman in juvenile hormone signaling controlling sexual maturation in a male moth.}, journal = {Current research in insect science}, volume = {9}, number = {}, pages = {100122}, pmid = {41624110}, issn = {2666-5158}, abstract = {In insects, juvenile hormone (JH) is essential for orchestrating reproductive events. For example, in the male moth Agrotis ipsilon, the behavioral response to female sex pheromone is linked to neuronal sensitivity in the primary olfactory centers (antennal lobes, ALs), and the maturation of accessory sex glands (ASGs) are known to be age- and JH-dependent. The molecular basis of this regulatory action of JH is not fully deciphered, and we show here that the heterodimerizing partner of Methoprene-tolerant called Taiman (Tai) is essential for the sexual maturation of male A. ipsilon. Tai expression in ALs and ASGs is elevated from the third day of adult life and is responsible for the acquisition of behavioral responsiveness to the sex pheromone and ASG maturation. Tai-deficient old males exhibited altered sexual behavior and delayed ASG maturation. Moreover, the expression levels of Tai and Krüppel homolog 1 (Kr-h1), an early JH-induced transcription factor, were reduced in ALs and ASGs of JH-deprived and Tai-deficient old males, respectively. Exogenous JH injection into young males resulted in precocious sexual maturation and this JH induction was suppressed by Tai silencing. Our results demonstrate that Tai is an actor of the JH signaling pathway that operates in ALs and ASGs to promote pheromone information processing and consequently the display of sexual behavior in synchrony with ASG maturation, ultimately optimizing male reproductive success. Thus, this study provides additional insights into the molecular mechanisms underlying hormonal regulation of sexual maturation in insects.}, }
@article {pmid41625181, year = {2026}, author = {Zhen, J and Liu, Q and Xue, X and Hao, F and Zhang, S and Liu, N and Li, Z and Chen, J and Cheng, J}, title = {The Application Value of Nursing Interventions Based on the Chronic Illness Trajectory Framework in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology research international}, volume = {2026}, number = {}, pages = {1280057}, pmid = {41625181}, issn = {2090-1852}, abstract = {This prospective study evaluated the impact of nursing interventions based on the Chronic Illness Trajectory Framework (CITF) on anxiety, depression, mental toughness, sleep quality, and ALSFRS-R scores in amyotrophic lateral sclerosis (ALS) patients to enhance care strategies. Eighty ALS patients were enrolled from the Department of Neurology at the First Hospital of Shanxi Medical University between February 2023 and March 2024. Participants were randomly assigned to an intervention group (CITF-based nursing interventions) or a control group (standard care). Over an 8-week period, the intervention group demonstrated significantly lower anxiety and depression scores, higher mental toughness, and improved sleep quality compared to the control group (p < 0.05). Additionally, the intervention group achieved higher ALSFRS-R scores (31.63 ± 3.54 vs. 29.58 ± 3.38) (p < 0.05). These findings indicate that CITF-based nursing interventions effectively reduce negative emotional states, enhance mental resilience, improve sleep quality, and boost overall quality of life in ALS patients. Based on this study, nurses can integrate CITF-based interventions into standard ALS care to enhance patients' emotional well-being and functional outcomes. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2500108691.}, }
@article {pmid41625544, year = {2025}, author = {Douglas, H and Di Vincenzo, M and Dossa, RFJ and Nunziante, L and Sujit, S and Arulkumaran, K}, title = {Levels of shared autonomy in brain-robot interfaces: enabling multi-robot multi-human collaboration for activities of daily living.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1718713}, pmid = {41625544}, issn = {1662-5161}, abstract = {Individuals with ALS and other severe motor impairments often rely on caregivers for daily tasks, which limits their independence and sense of control. Brain-robot interfaces (BRIs) have the potential to restore autonomy, but many existing systems are task-specific and highly automated, which reduces the users' sense of empowerment and limits opportunities to exercise autonomy. In particular, shared autonomy approaches hold promise for overcoming current BRI limitations, by balancing user control with increased robot capabilities. In this work, we introduce a collaborative BRI that integrates non-invasive EEG, EMG, and eye tracking to enable multi-user, multi-robot interaction in a shared kitchen environment with mobile manipulators. Our system modulates assistance through three levels of autonomy-Assisted Teleoperation, Shared Autonomy, and Full Automation-allowing users to retain meaningful control over task execution while reducing effort for routine operations. We conducted a controlled user study comparing autonomy conditions, evaluating performance, workload, ease of use, and agency. Our results show that, while Full Automation was generally preferred by users due to lower workload and higher usability, Shared Autonomy provided higher reliability and preserved user agency, especially in the presence of noisy EEG decoding. Although there was significant individual variability in EEG decoding performance, our post-hoc analysis revealed the potential benefits of customizing pipelines for each user. Finally, we note that our findings are specific to the multi-modal configuration tested and should not be interpreted as a universal claim about the superiority of any autonomy level, and, furthermore, our user study was limited by the use of healthy adults rather than target population (e.g., individuals with ALS), gender imbalance, and a relatively small sample size, which may affect generalizability. Project website: https://coopopen.github.io/.}, }
@article {pmid41625676, year = {2025}, author = {Ghasemi, S and Imani, B and Torabi, M and Ayubi, E}, title = {The effects of team-based and mastery-based learning on the student's clinical competence and the results of clinical evaluation: A quasi-experimental study among operating room nursing students.}, journal = {Journal of education and health promotion}, volume = {14}, number = {}, pages = {537}, pmid = {41625676}, issn = {2277-9531}, abstract = {BACKGROUND: Clinical education is a crucial component of the medical education system, providing essential opportunities to enhance students' clinical competence and skills. In light of the numerous challenges in the clinical environment of the operating room, this study was conducted to compare the impact of team-based and mastery-based learning methods on the student's clinical competence and their evaluation.<br><br>MATERIALS AND METHODS: This quasi-experimental study was conducted on 6[th]-semester operating room technology students at Hamadan University of Medical Sciences in 2023. In this study, students were selected by the convenience sampling method and were placed in two educational groups (team-based and mastery-based) of 31 people by the matching method. After implementing the training process in the operating room environment, the data related to the study were collected from Liu et al.'s clinical competence questionnaire and clinical assessment checklist of operating room nursing students.<br><br>RESULTS: Findings showed that implementing the team-based learning method significantly affected students' clinical competence (P value = 0.012). Also, utilizing a mastery-based learning method compared to a team-based one had a significantly greater impact on the level of clinical skills and evaluation of students (P value = 0.007).<br><br>CONCLUSION: The results of this study have practical implications for clinical instructors and higher education institutions. Clinical instructors are advised to adopt a team-based learning method to enhance the student's clinical competence in the operating room. Furthermore, higher education institutions are encouraged to provide adequate resources and make essential efforts to modernize educational methods in clinical environments, thereby empowering students and improving the quality of healthcare.}, }
@article {pmid41625796, year = {2025}, author = {Jagannathan, A and Al-Bayati, R and Clarke, KM and Micallef, J and Willett, T and Wattie, N and Dubrowski, A}, title = {Developing and Validating a Competency Framework for Non-clinical Simulation Operations Specialists.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e100408}, pmid = {41625796}, issn = {2168-8184}, abstract = {BACKGROUND: Simulation-based education (SBE) is essential for developing and maintaining clinical skills, yet its effectiveness is partially contingent on simulation operations specialists (SOS) who provide technical, pedagogical, and safety support. Traditionally, SOS roles have been filled by clinicians, but healthcare workforce shortages have prompted simulation centres to rely on informal, on-the-job pathways to train non-clinicians as SOS. This approach has raised concerns regarding workforce readiness and highlights the absence of structured training pathways. To address this gap, we developed and validated a competency framework explicitly tailored to entry-level, non-clinical SOS to inform the development of structured training pathways.<br><br>METHODS: A mixed-methods design guided by participatory action research (PAR) was used to guide this work. This study followed Batt et al.'s six-step model to develop and validate the competency framework. Methods included a narrative review, artificial intelligence (AI)-supported competency generation, semi-structured interviews, a card-sorting exercise, survey-based validation, and focus groups.&#xa0; Results: This study produced a validated competency framework for non-clinical SOS training consisting of 36 competencies across three technical pillars: (i) Simulation Technology (SIMTECH); (ii) Educational Principles (EDUPRI); and (iii) Safety (SAFE), plus a General Competencies (GEN) pillar aligned with transferable knowledge, skills, and attitudes (KSAs).&#xa0; Conclusion: This study provides the first validated competency framework tailored for entry-level, non-clinical SOS, grounded in both theory and real-world perspectives. The final framework offers a foundation for curriculum developers, employers, and certification bodies, and informs the development of accessible training pathways for non-clinicians entering the simulation operations field.}, }
@article {pmid41626035, year = {2025}, author = {Jackson, MC and Azarraga, RB and Fraix, MP and Agrawal, DK}, title = {Stage-Based Communication Rehabilitation in Amyotrophic Lateral Sclerosis (ALS): A Review of Strategies for Enhancing Quality of Life.}, journal = {Archives of internal medicine research}, volume = {8}, number = {4}, pages = {359-371}, pmid = {41626035}, issn = {2688-5654}, support = {R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable progressive degenerative neuromuscular disease. One way ALS affects patients is through dysarthria significantly impacting a patient's quality of life by affecting their ability to communicate. This makes maintaining relationships, identity and autonomy difficult, all of which affect psychological wellbeing - a determinant of the quality of life. Dysarthria makes communication difficult, and because the regions affected by ALS first are different for each patient, creating strategies for rehabilitating communication can be challenging. In this review we explore the different communication rehabilitation options available and organize them based on if they are usable based on the onset of intelligibility and locked in state. Interventions before the onset of intelligibility in the early stage are proactive measures such as voice banking and education which empower patient autonomy and a sense of control. Interventions between onset of intelligibility and the locked-in state in the middle stage are alternative and augmentative communication strategies varied in accessibility and usability in patients based on their preferences and functional ability. Late-stage interventions which work after a patient with ALS has entered a locked-in state, are the most technologically advanced alternative and augmentative communication devices and rehabilitate function inaccessible by other methods in this disease stage. While assessing patient values and recommending interventions which meet patient needs is most important in rehabilitation of communication in patient with ALS, using a stage-based approach to evaluate and recommend the treatment of dysarthria and communication rehabilitation will optimize quality of life throughout the progression of disease.}, }
@article {pmid41626491, year = {2026}, author = {Akimoto, Y and Miyamae, Y and Shigemori, H}, title = {Effects of Cyanidin Derivatives for the Aggregation of Cu/Zn Superoxide Dismutase 1.}, journal = {ACS omega}, volume = {11}, number = {3}, pages = {3849-3865}, pmid = {41626491}, issn = {2470-1343}, abstract = {Cu/Zn superoxide dismutase 1 (SOD1), whose aggregation is considered cytotoxic, is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Therefore, inhibiting SOD1 aggregation may represent a promising strategy for the treatment and prevention of this disease. We first screened seven polyphenols using an optimized thioflavin T (Th-T) assay and found that cyanidin exhibited the strongest inhibitory activity among the seven polyphenols. We then compared cyanidin with its derivatives(?)delphinidin, petunidin, malvidin, and cyanidin-3-glucoside (C3G). In this study, we concluded that delphinidin had the strongest antifibrillation activity among the five cyanidin derivatives. Turbidity, transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), circular dichroism (CD) spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy indicated that the inhibitory activity was influenced by the number of phenolic hydroxyl groups on the B-ring of the cyanidin derivatives. Based on the LDH assay, delphinidin was the most effective compound in preventing the formation of cytotoxic SOD1 aggregates in the cells. Furthermore, we found that the compounds also interfered with the SOD1 cross-linking. Finally, we transfected GFP-SOD1A4 V into Neuro2a cells and observed that the compounds' inhibitory activity on intracellular aggregation was limited.}, }
@article {pmid41628199, year = {2026}, author = {Hasan, MM and Mostaid, MS and Bepari, AK and Reza, HM and Hossain, M}, title = {Discovery of a novel Keap1 inhibitor for neurodegeneration through virtual screening and molecular dynamics simulations.}, journal = {PloS one}, volume = {21}, number = {2}, pages = {e0341965}, pmid = {41628199}, issn = {1932-6203}, mesh = {*Kelch-Like ECH-Associated Protein 1/antagonists &amp; inhibitors/metabolism/chemistry ; Molecular Dynamics Simulation ; Humans ; NF-E2-Related Factor 2/metabolism/chemistry/antagonists &amp; inhibitors ; Molecular Docking Simulation ; Protein Binding ; Drug Discovery ; Drug Evaluation, Preclinical ; *Neurodegenerative Diseases/drug therapy/metabolism ; Biological Products/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/chemistry ; }, abstract = {Oxidative stress is a key feature of Alzheimer's disease (AD) and other neurodegenerative disorders. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway controls redox balance, and disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has become a promising therapeutic approach. Marine natural products (MNPs), because of their structural diversity and bioactivity, are an underexplored source of potential neuroprotective compounds. This study aimed to identify novel marine-derived inhibitors of the Keap1-Nrf2 interaction using a comprehensive in silico pipeline. A total of 14,492 compounds from an open-access MNP database were virtually screened against the Keap1 Kelch domain through molecular docking. The top 1,329 candidates exhibited strong binding affinities, with several reaching scores comparable to the co-crystallized reference ligand L5F. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling was employed to assess pharmacokinetic properties, brain penetration, and safety, leading to the identification of compound 145398-61-4 as the most promising hit. Molecular dynamics (MD) simulations verified the structural stability of the Keap1-145398-61-4 complex, while binding free energy calculations indicated energetically favorable interactions. Additional validation using principal component analysis (PCA) and highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy analysis further confirmed the stability of this interaction. Overall, our in silico study identified compound 145398-61-4 as a novel Keap1-Nrf2 inhibitor, highlighting its potential as a lead candidate for developing treatments for Alzheimer's disease and other neurodegenerative disorders, such as amyotrophic lateral sclerosis and multiple sclerosis.}, }
@article {pmid41628987, year = {2026}, author = {Xue, X and Cui, H and Hu, S and Ma, H and Wei, S and Huang, H and Li, X and Huang, Z}, title = {Both target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Silene conoidea L.}, journal = {Pesticide biochemistry and physiology}, volume = {218}, number = {}, pages = {106905}, doi = {10.1016/j.pestbp.2025.106905}, pmid = {41628987}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; Acetolactate Synthase/genetics/metabolism/antagonists &amp; inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Silene/drug effects/genetics ; Plant Proteins/genetics/metabolism ; Molecular Docking Simulation ; Mutation ; }, abstract = {Silene conoidea L., a common weed in wheat fields, is mainly controlled by acetolactate synthase (ALS)-inhibiting herbicides such as mesosulfuron-methyl. In this study, we investigated a mesosulfuron-methyl resistant population to elucidate the resistance mechanisms. The resistant (R) population displayed a high level of resistance to mesosulfuron-methyl, with the resistance index (RI) of 18.87. It also exhibited cross-resistance to halosulfuron-methyl, florasulam, flumetsulam, and flucarbazone‑sodium. In vitro ALS enzyme activity in the R population was 22.85-fold higher than in the susceptible (S) population. A W574L mutation (leucine replaced tryptophan) was identified in the ALS gene of the R population. Through molecular docking, this substitution of amino acid weakened the π-π stacking interaction between mesosulfuron-methyl molecule and the non-mutated ALS enzyme. The R population also showed significantly higher ALS expression than the S population, while the ALS gene copy number did not differ between the two populations. Pretreatment with malathion (cytochrome P450 inhibitor) and NBD-Cl (glutathione S-transferases inhibitor) reduced mesosulfuron-methyl resistance by 43.92 % and 29.20 %, respectively. Indicating that CYP450s and GSTs are involved in resistance. Transcriptome and qPCR analyses identified significant upregulation of three ABC transporter genes, three CYP450 genes, and one GST gene in the R population. Meanwhile, KEGG pathway analysis indicated that the photosynthetic pathways were significantly affected after mesosulfuron-methyl treatment. This is the first report of mesosulfuron-methyl resistance in S. conoidea, involves both target site resistance and non-target site resistance mechanisms.}, }
@article {pmid41629112, year = {2026}, author = {Kuzmanova, BR and Kuzmanova, MR and Elgizouli, M and Tatrai, B and Möller, JC}, title = {Novel KIF5A variant in a patient with early-onset levodopa-responsive Parkinson's syndrome.}, journal = {BMJ case reports}, volume = {19}, number = {2}, pages = {}, doi = {10.1136/bcr-2025-267762}, pmid = {41629112}, issn = {1757-790X}, mesh = {Humans ; Male ; *Kinesins/genetics ; *Levodopa/therapeutic use ; Adult ; *Parkinson Disease/genetics/drug therapy ; Mutation ; *Parkinsonian Disorders/genetics/drug therapy ; Antiparkinson Agents/therapeutic use ; }, abstract = {We present the case of a male in his mid-30s with a progressive complex neurological phenotype primarily characterised by levodopa-responsive parkinsonism with motor fluctuations as well as gait ataxia, peripheral neuropathy and finally also spastic paraplegia. Genetic analysis identified a novel heterozygous variant in the KIF5A gene: c.937G>A (p.Glu313Lys). This variant is genetically classified as likely pathogenic. Other pathogenic mutations in the KIF5A gene are associated with hereditary spastic paraplegia type 10, Charcot-Marie-Tooth disease type 2 and amyotrophic lateral sclerosis. We discuss the clinical, genetic and prognostic implications of this finding.}, }
@article {pmid41629165, year = {2026}, author = {Zermeño, NA and Godde, K}, title = {Patterns in the Phenice (1969) and Klales et al. (2012) methods of sex estimation using forensic casework from the United States.}, journal = {Journal of forensic sciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/1556-4029.70279}, pmid = {41629165}, issn = {1556-4029}, abstract = {Sex estimation methods from the pelvis have been well-studied in research settings to estimate accuracy, error, and bias. However, patterns in casework are minimally described. We uniquely examine forensic anthropology casework in the United States retrospectively for the Phenice and Klales et al.'s sex estimation methods. Our hypothesis is that casework patterns will reflect the greater literature derived from research settings that show Phenice's method is more accurate and has lower error and sex bias. We use the publicly available Forensic Anthropology Database for Assessing Methods Accuracy. A sample of 229 cases from the United States reported the outcomes of applying these methods. McNemar's tests evaluate whether estimated sex is consistent with documented sex, and a Fisher's exact test compared the performance of the two methods. We further calculated accuracy, error, and sex biases of the methods. The McNemar's and Fisher's exact tests were not statistically significant, which indicates that both methods estimated sex at a rate close to the documented sex and to each other. Phenice's method displayed an accuracy of 99.4%, an error of 0.6%, and a sex bias of -2.4%. Alternatively, the Klales et al.'s method performed slightly lower with a 97.5% accuracy, 2.5% error, and 3.5% sex bias. Forensic anthropology casework in the United States reflects broader patterns in accuracy, error, and bias in the research setting literature, where Phenice outperforms the Klales et al.'s method, despite the values from casework probably reflecting practitioners using information beyond the method reported to make a final sex estimate.}, }
@article {pmid41629214, year = {2026}, author = {Malard, F}, title = {Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {27}, number = {2}, pages = {e202500774}, pmid = {41629214}, issn = {1439-7633}, mesh = {Humans ; *N-Acetylglucosaminyltransferases/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy ; *Aging/metabolism/genetics ; RNA, Messenger/metabolism/genetics ; RNA Splicing ; Animals ; }, abstract = {The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.}, }
@article {pmid41630787, year = {2026}, author = {Mukai, T and Kanbayashi, T and Kobayashi, M and Okano, MP and Tachiyama, K and Miyaji, Y and Hatanaka, Y and Kobayashi, S and Sonoo, M}, title = {Discrimination of spontaneous activity in needle EMG based on the quantitative assessment of the discharge rhythm using "Random Index".}, journal = {Clinical neurophysiology practice}, volume = {11}, number = {}, pages = {65-71}, pmid = {41630787}, issn = {2467-981X}, abstract = {OBJECTIVE: Discrimination between EMG activity such as fibrillation potentials/positive sharp waves (Fib/PSW), end plate spikes (EPS), fasciculation potentials (FP), and contaminating voluntary motor unit potentials (MUP) is mandatory for EMG diagnosis. Discharge rhythm is the key for discrimination. We devised a new parameter, Random Index (RI), which quantifies the rhythm and takes a value from 0 to 1, smaller for regular trains of discharges. This study evaluated the utility of RI as well as modified versions of the regularity indices proposed in past reports.<br><br>METHODS: EMG records of patients with amyotrophic lateral sclerosis were retrospectively reviewed. EPS were collected also from a healthy volunteer. The EMG activity was classified by an expert. RI and other regularity indices as well as the median instantaneous firing rate (IFRm) were calculated.<br><br>RESULTS: Analyzed sequences were 73 Fib/PSW, 27 EPS, 24 FP, and 36 MUP. The four types were clearly separated over the 2-dimensional plots of regularity indices vs. IFRm. Especially, Fib/PSW and EPS were far separated in these plots. RI achieved significantly better discrimination between Fib/PSW and MUP than other indices.<br><br>CONCLUSION: RI is a robust tool for discriminating EMG activity.<br><br>SIGNIFICANCE: RI and other regularity indices would be useful for educational purpose.}, }
@article {pmid41630851, year = {2026}, author = {Appel, M and Jubel, A and Antoni, M}, title = {Interobserver reliability of the AO/OTA and Luo three-column classification systems for tibial plateau fractures and their impact on surgical approach selection.}, journal = {Journal of orthopaedics}, volume = {74}, number = {}, pages = {234-238}, pmid = {41630851}, issn = {0972-978X}, abstract = {PURPOSE: This study aims to compare the interobserver reliability of the traditional two-dimensional AO/OTA classification with the more recent three-dimensional Luo three-column classification for tibial plateau fractures. Furthermore, it evaluates the impact of both systems on the surgical approach selection, particularly examining Luo et al.'s hypothesis that the three-column classification encourages increased consideration of the posterior column during preoperative planning. However, this hypothesis has not been evaluated yet, leaving a research gap regarding its influence in practice on surgical approach selection.<br><br>METHODS: Fifteen cases of tibial plateau fractures were retrospectively analyzed by nine trauma surgeons using radiographs and CT scans. Fractures were classified according to the AO/OTA and Luo classifications, and preferred surgical approaches for definitive fixation were determined. Interobserver reliability was assessed using Fleiss' kappa and interpreted according to the categorical rating by Landis and Koch. Additionally, a chi-square test was performed to evaluate statistical significance in the surgical approach selection.<br><br>RESULTS: Both classification systems showed overall substantial reliability (kAO&#xa0;=&#xa0;0.63; kLuo&#xa0;=&#xa0;0.67). The difference in agreement for surgical approach groups between the two classifications was 0.11 (kAO_approach&#xa0;=&#xa0;0.37; kLuo_approach&#xa0;=&#xa0;0.48). The posterior approach group was not selected significantly more often using the Luo three-column classification compared to the AO/OTA classification (p&#xa0;=&#xa0;0.543).<br><br>CONCLUSION: No significant difference in interobserver reliability or in the choice of surgical approach was observed between the AO/OTA and Luo classifications.}, }
@article {pmid41630926, year = {2026}, author = {Saucier, J and Al-Qadi, M and Allain, EP and Robichaud, PP and Chamard-Witkowski, L and Alvarez, M and Dion-Côté, AM and Richard, L and Crapoulet, N and Ben Amor, M}, title = {Expanding the Genetic Landscape of ATXN2 Variants: Insights From a Biallelic Trinucleotide Repeat Expansion in an Acadian Family.}, journal = {Neurology. Genetics}, volume = {12}, number = {1}, pages = {e200345}, pmid = {41630926}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Spinocerebellar ataxias are a diverse group of autosomal dominant cerebellar ataxias. SCA2 is a complex ataxia with various extracerebellar symptoms, including parkinsonism, dystonia, hyporeflexia, and cognitive impairment. ATXN2 is a modulator of neurologic disease: Expansions of at least 37 CAG (glutamine) repeats are pathogenic for SCA2, while expansions in the intermediate range (30-32) convey risk for the development of neurodegenerative disorders including Parkinson disease and amyotrophic lateral sclerosis. Homozygous variants are exceedingly rare. This study describes a novel ATXN2 presentation identified in an Acadian family from New Brunswick, Canada: a CAG repeat expansion within the fully penetrant range of SCA2, asymptomatic in the heterozygous state and resulting in a neurodegenerative disorder in homozygous patients.<br><br>METHODS: Three individuals, 2 siblings and their cousin, were investigated for a neurodegenerative disorder with overlapping phenotypes. The affected individuals and their 5 immediate family members underwent whole-genome sequencing analyzed by ExpansionHunter, repeat-primed PCR and Sanger sequencing.<br><br>RESULTS: Sequencing revealed a homozygous 39/39 CAG repeat expansion with 4 CAA interruptions in ATXN2 across all 3 affected individuals. After experiencing childhood intellectual or learning difficulties, the patients developed a pyramidal syndrome with spastic gait and a major neurocognitive disorder characterized by prominent frontal signs during their late twenties. Within a decade, all patients completely lost their autonomy. Shared phenotypic features included ataxia, spasticity, aphasia, dysphagia, myoclonus, atypical parkinsonism, incontinence, diffuse cortical atrophy with frontal predominance, and cerebellar atrophy. The same 39 CAG repeat allele with 4 CAA interruptions was identified in heterozygous state in 4 asymptomatic parents (age 65+) and 1 sibling in their thirties. Three carriers consented to further investigation with a neurologic examination, neuropsychological assessment, and cerebral MRI. Clinical and radiologic signs of disease were absent, despite the carriers' ages and their heterozygous expansion in the fully penetrant range of SCA2.<br><br>DISCUSSION: This study describes a novel ATXN2 expansion within the classic pathogenic range for SCA2 that manifests as an early-onset neurodegenerative disorder in the homozygous state, while being asymptomatic into late adulthood in the heterozygous state.}, }
@article {pmid41631638, year = {2026}, author = {Allen, S and Howard, J and McDermott, CJ and Boardman, F and McNeill, A}, title = {Limited data capture on reproductive medicine use in amyotrophic lateral sclerosis: implications for monitoring access.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2618124}, pmid = {41631638}, issn = {2167-9223}, abstract = {There is very limited evidence around the use of reproductive genetic testing in individuals with amyotrophic lateral sclerosis (ALS)-linked gene variants. This study aimed to identify the use of reproductive genetic testing in these individuals to understand patterns of (under)utilization and to identify barriers to equitable access. Freedom of information requests were sent in January 2025 to the 22 regional clinical genetics centers across the UK around reproductive services for individuals with, or at risk for, ALS and Huntington's disease. Limited data were available with only six trusts answering in full. The data that our study yielded raises significant concerns and inconsistencies regarding clinical recording and reporting of reproductive genetic counseling and testing. The absence of standardized retrievable data limits the ability to assess utilization and may point toward a systemic issue in data capture of reproductive genetic services for individuals at risk of ALS, and by extension, those affected by other genetic conditions.}, }
@article {pmid41633321, year = {2026}, author = {Di Gennaro, G and Grammaldo, LG and Tomasini, A}, title = {Toward a multidimensional understanding of internalized epilepsy stigma.}, journal = {Epilepsy &amp; behavior : E&amp;B}, volume = {177}, number = {}, pages = {110899}, doi = {10.1016/j.yebeh.2026.110899}, pmid = {41633321}, issn = {1525-5069}, mesh = {Humans ; *Epilepsy/psychology ; *Social Stigma ; Emotions ; }, abstract = {This letter responds to Prieto et al.'s discussion of our article Rethinking epilepsy stigma: the uncanny, the emotional, and the structural. We clarify that our original framework was primarily theoretical, aiming to illuminate the multifaceted mechanisms sustaining internalized epilepsy stigma, including the "uncanny" experience of seizures, ambivalent emotional responses, and structural inequities. We highlight how third-generation psychotherapeutic approaches, emphasizing psychological flexibility, mindfulness, and emotional acceptance, complement cognitive-behavioral strategies by enhancing individuals' capacity to relate adaptively to stigma-related distress. We propose that integrating behavioural, emotional, and structural perspectives offers a multidimensional framework to better understand and address internalized epilepsy stigma, guiding interventions that promote psychological well-being, social inclusion, and empowerment for people living with epilepsy.}, }
@article {pmid41633359, year = {2026}, author = {Xie, X and Liu, J and Liang, W and Zhang, Y and Gong, X and Yuan, S and Qi, C and Huang, M and Shi, L and Hou, M and Zhang, M and Liu, W and Sun, W and Wu, Y and Li, C and Cao, Z and Jing, H and Qian, L and Liu, J and Yuan, S and Wang, Q and Shen, Y and Liu, Z and Li, Y and Pan, H and Zhu, B and Shan, B and He, K and Wang, W and Zou, C and Li, Y and Chou, JJ and Yuan, J}, title = {Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors.}, journal = {Immunity}, volume = {59}, number = {2}, pages = {419-437.e11}, doi = {10.1016/j.immuni.2026.01.014}, pmid = {41633359}, issn = {1097-4180}, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; Animals ; Humans ; *Microglia/metabolism ; Mice ; Risk Factors ; *Phosphoric Monoester Hydrolases/metabolism/genetics ; *Inflammation Mediators/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Inflammation ; Signal Transduction ; }, abstract = {Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer's disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complements, and ROS mediators, as well as proinflammatory signaling mediators such as Toll-like receptors (TLRs), MyD88, Nlrp3, gasdermin D, and Zbp1. RIPK1-regulated microglial transcriptomic signatures were found in microglial subtypes implicated in human Alzheimer's disease (AD) pathogenesis. Furthermore, microglial INPP5D deficiency promoted aging-dependent RIPK1-mediated development of neuronal TDP-43 pathology, neuronal loss, and motor dysfunction in a non-cell-autonomous manner. Our data suggest that INPP5D functions as an intracellular rheostat in regulating RIPK1-mediated neuroinflammation for promoting aging-related neurodegenerative diseases, including LOAD and AD-amyotrophic lateral sclerosis comorbidity.}, }
@article {pmid41633603, year = {2026}, author = {Tian, X and Song, Z and Huang, Y and Yao, W}, title = {[Analysis of early complications and risk factors in patients with amyotrophic lateral sclerosis after percutaneous endoscopic gastrostomy].}, journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences}, volume = {58}, number = {1}, pages = {190-195}, pmid = {41633603}, issn = {1671-167X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/surgery ; *Gastrostomy/adverse effects/methods ; Male ; Middle Aged ; Risk Factors ; Female ; Retrospective Studies ; *Postoperative Complications/etiology/epidemiology ; Aged ; Adult ; Enteral Nutrition/adverse effects/methods ; *Gastroscopy/adverse effects ; }, abstract = {OBJECTIVE: To explore risk factors of early complications (≤14 days) and the clinical characteristics in patients with amyotrophic lateral sclerosis (ALS) after percutaneous endoscopic gastrostomy (PEG).<br><br>METHODS: Patients diagnosed with ALS who underwent first PEG insertion between January 2011 and December 2020 were eligible. Medical records were retrospectively reviewed to determine clinical characteristics and outcomes (&#x2264;14 days) of patients who underwent the pull type PEG. Grouping was performed based on the presence and severity of complications, and SPSS 27.0 statistical software was used for data analysis. Finally, Logistic regression model was applied for multivariate factor analysis of risk factors related to complications.<br><br>RESULTS: In the study, 192 cases of PEG were all successfully completed, with 97 (51%) males, mean age of ALS onset disease (55&#xb1;11) years and 93 (48%) bulbar onset symptoms included. Complications occurred in 40 (21%) cases after PEG within 14 days, all of which had fever, including 16 cases without clear infection focus, 18 cases of respiratory tract infections, and 6 cases of fistula site infections. In the study, 13 (7%) cases had major complications, including 11 cases of respiratory tract infection and 2 cases of stoma infection. Two cases of respiratory tract infection died due to respiratory failure, and the remaining 11 cases recovered after upgraded antibiotic. No complications, such as tube dislodgement, benign pneumoperitoneum, hemorrhage or buried bumper syndrome occurred. The operation time and postoperative hospital stay were longer in the complication group than in the non-complication group [(16&#xb1;5) min vs. (13&#xb1;5) min, P < 0.001; 6 (5, 9) d vs. 5 (3, 7) d, P=0.009]. Compared with the mild complication group, the creatinine and triglyceride in the major complication group were significantly lower [(46.5&#xb1;16.2) &#x3bc;mol/L vs.(66.8&#xb1;16.4) &#x3bc;mol/L, P&#xff1c;0.001; (1.1&#xb1;0.5) mmol/L vs.(1.6&#xb1;0.7) mmol/L, P=0.038], and the operation time was significantly longer [(20&#xb1;5) min vs. (15&#xb1;5) min, P=0.002]. Further, Logistic regression model analysis revealed that the operation time was also independent associated with complications (OR=1.132, 95%CI: 1.051-1.220, P=0.001).<br><br>CONCLUSION: PEG was a reliable method for ALS patients to put nutrition tube. Postoperative fever was the most common complications. Long surgical duration was an independent risk factor for the occurrence of complications (&#x2264;14 d).}, }
@article {pmid41633676, year = {2025}, author = {Šoša, I and Sergi, CM}, title = {Genomics for Sudden Cardiac Death: A Review of the Topic and Call for Increased Professionalism in Clinico-Molecular Autopsy and Forensic Laboratory Sciences.}, journal = {Annals of clinical and laboratory science}, volume = {55}, number = {6}, pages = {859-868}, pmid = {41633676}, issn = {1550-8080}, mesh = {Humans ; *Death, Sudden, Cardiac/pathology ; *Genomics/methods ; Autopsy ; *Professionalism ; Gene Frequency ; *Forensic Genetics ; Genome, Human/genetics ; }, abstract = {In 2001, the first draft sequence of the human genome was released, the culmination of a decade-long, multibillion-dollar effort. Since then, an OMICs platform has been proposed to further evaluate and edit the human genome for diagnostic and therapeutic purposes. The Human Genome Project opened a Pandora's box, expanding the forensic laboratory physicians' toolbox. Kinship analysis has been used extensively for parentage testing and identifying cases of human remains and missing persons. The Combined DNA Index System has played a significant role in forensic DNA databases. Nanopore sequencing and improved genomic tools aid enormously in identifying amplicons from degraded samples. The application of genomics in determining the potential channelopathies of sudden cardiac death (SCD) has been an enormous step forward in recent years in forensic histopathology. We reviewed the literature. Kong et al.'s meta-analysis of the mean allele frequencies of SCN5A, NOS1AP, KCNH2, KCNE1, and KCNQ1 genes across Black, Caucasian, Asian, and Hispanic ethnicities has been pivotal to forensic science in the last decade. The authors used sequenced genomic data from the Exome Aggregation Consortium to compare allele frequencies between different ethnicities. They found that Asians had the highest overall mean allele frequencies for NOS1AP and SCN5A, Caucasians had the highest KCNH2 frequency, and Hispanics had the highest KCNQ1 frequency. In 2026, the call for increased professionalism in clinico-molecular autopsy and forensic laboratory sciences is driven by rapid technological advancements (e.g., forensic molecular genomic autopsies), critical workforce shortages in some geographical areas, and the increasing complexity of death investigations. This professionalization focuses on standardizing molecular protocols, enhancing ethical frameworks, and addressing the need for specialized interdisciplinary expertise.}, }
@article {pmid41634873, year = {2026}, author = {Garrigos, D and Martinez-Morga, M and Pombero, A and García-Lopez, R and Pastor, D and Riquelme, D and Blanquer, M and Iniesta, F and Valdor, R and Geijo-Barrientos, E and Hargus, G and Moraleda, JM and Martínez, S}, title = {Chaperone mediated autophagy is deficient in spinal motoneurons of ALS patients with TDP-43 proteinopathy.}, journal = {Acta neuropathologica communications}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40478-026-02238-6}, pmid = {41634873}, issn = {2051-5960}, support = {Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; Grant Numbers SEV-2017-0723//Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&amp;D/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; SAF2017-83702-R and PID2020-11817RB-I00//Spanish Ministerio de Ciencia e Innovaci&#xf3;n/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; Grant Number 2018/041//Generalitat Valenciana (program Prometeo II)/ ; RD21/0017/0017; RD21/0017/0001//Instituto de Salud Carlos III (ISCIII) through the RICORS Project TERAV/ ; RD21/0017/0017; RD21/0017/0001//Instituto de Salud Carlos III (ISCIII) through the RICORS Project TERAV/ ; RD21/0017/0017; RD21/0017/0001//Instituto de Salud Carlos III (ISCIII) through the RICORS Project TERAV/ ; RD21/0017/0017; RD21/0017/0001//Instituto de Salud Carlos III (ISCIII) through the RICORS Project TERAV/ ; RD21/0017/0017; RD21/0017/0001//Instituto de Salud Carlos III (ISCIII) through the RICORS Project TERAV/ ; Ramon y Cajal (RYC) 2019-027520-I//Ministerio de Ciencia e Innovaci&#xf3;n/ ; }, }
@article {pmid41635116, year = {2026}, author = {Wang, Y and Lipton, SA}, title = {Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.}, journal = {Journal of neurochemistry}, volume = {170}, number = {2}, pages = {e70365}, pmid = {41635116}, issn = {1471-4159}, support = {R56 AG065372/AG/NIA NIH HHS/United States ; R01 AG078756/AG/NIA NIH HHS/United States ; R01 AG056259/AG/NIA NIH HHS/United States ; DP1 DA041722/DA/NIDA NIH HHS/United States ; /NH/NIH HHS/United States ; U01 AG088679/AG/NIA NIH HHS/United States ; R35 AG071734/AG/NIA NIH HHS/United States ; ReMIND-L DISC4 16292//California Institute for Regenerative Medicine/ ; R01 DA048882/DA/NIDA NIH HHS/United States ; RF1 AG057409/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; *Mutation/genetics ; *Protein Processing, Post-Translational/genetics ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.}, }
@article {pmid41635249, year = {2026}, author = {Ponikiewska, K and Strus, W and Cieciuch, J}, title = {The Temperament Metadimensions Model: A Complex Framework for Formal Characteristics of Behavior as Composed of Energetic, Temporal, and Autoregulatory Facets of Reactivity and Activity.}, journal = {Journal of personality}, volume = {}, number = {}, pages = {}, doi = {10.1111/jopy.70054}, pmid = {41635249}, issn = {1467-6494}, abstract = {OBJECTIVE: The paper presents the Temperament Metadimensions Model (TMM), which extends the integrative model of temperament structure proposed by Strus et al. (2022). This extension adds four autoregulatory trait-facets to the originally proposed four energetic and four temporal ones, enhancing the theoretical comprehensiveness of the model in terms of regulatory function of temperament and coverage of crucial constructs postulated in other well-established temperament theories. The autoregulatory trait-facets were conceptually introduced and subsequently empirically tested within the whole expanded 12 trait-facet model of bipolar and orthogonal Reactivity and Activity metadimensions, verifying its synthesizing and predictive potential.<br><br>METHOD: The empirical verification of the TMM model was performed throughout three subsequent studies, with a joint sample of 1756 participants (52.0% females; Mage&#x2009;=&#x2009;34.68). We examined the TMM's: (1) internal structure, (2) relationships with constructs from other established theories of temperament, and (3) predictive capabilities in relation to mental health-related variables.<br><br>RESULTS AND CONCLUSIONS: The obtained results confirmed the validity of the 12-facet TMM as an integrative and comprehensive framework for formal characteristics of behavior, possessing evident functional significance and indicating its superiority over the eight-facet Strus et&#xa0;al.'s (2022) model. Theoretical implications of the TMM were discussed.}, }
@article {pmid41635251, year = {2026}, author = {Li, X and Ding, W and Lu, Y and Sun, M and Xu, E}, title = {Nocturnal Hypoxia and Sleep-Disordered Breathing as Potential Early Biomarkers of Respiratory Progression in Mild ALS.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-6}, doi = {10.1017/cjn.2026.10557}, pmid = {41635251}, issn = {0317-1671}, abstract = {BACKGROUND: Early detection of respiratory decline is crucial in amyotrophic lateral sclerosis (ALS). We tested if nocturnal polysomnography (PSG) predicts dyspnea onset in mild ALS patients with preserved daytime function.<br><br>METHODS: In this study, 41 mild ALS patients (ALS Functional Rating Scale-Revised [ALSFRS-R] &#x2265; 37, sitting forced vital capacity [FVC] &#x2265;80% predicted, no dyspnea) and 41 matched controls underwent baseline assessment, including ALSFRS-R scoring, pulmonary function tests, and overnight PSG. ALS patients were followed for 12 months. Baseline apnea-hypopnea index (AHI) and oxygen saturation (mean SpO2, minimum SpO2) were analyzed as continuous predictors and using exploratory thresholds (AHI &#x2265; 5 events/h, min SpO2 &#x2264; 88%, mean SpO2 &#x2264; 95%) for dyspnea onset (Dyspnea-ALS-15 [DALS-15] > 0).<br><br>RESULTS: Compared to controls, ALS patients had significantly higher AHI (p = 0.004) and lower minimum SpO2 (p = 0.018). The ALSFRS-R orthopnea subscore showed a significant positive correlation with mean and minimum SpO2 (P < 0.05). Cox regression identified baseline AHI (HR 1.08 per event/h; 95% CI 1.01-1.15, p = 0.028) and minimum SpO2 (HR 0.94 per %; 95% CI 0.88-0.99, p = 0.033) as independent predictors of dyspnea onset within 12 months. Thresholds AHI &#x2265; 5 (HR 2.28, p = 0.031) and min SpO2 &#x2264; 88% (HR 2.42, p = 0.027) also predicted increased risk. Patients meeting &#x2265;1 threshold (n = 25/37) showed trends toward greater FVC and ALSFRS-R decline.<br><br>CONCLUSIONS: In patients with mild ALS and normal daytime function, specific nocturnal PSG parameters (AHI, minimum SpO2) predicted the risk of dyspnea within 12 months. This longitudinal study provides novel evidence that PSG could identify early respiratory vulnerability in the incipient stage, earlier than conventional FVC-based monitoring, supporting its potential utility in refining early intervention strategies. Validation in larger cohorts is warranted.}, }
@article {pmid41635876, year = {2025}, author = {Elsawah, HK and Elmarawany, MN}, title = {Letter regarding Pereira et al.'s SAH-VP score: Methodological and statistical considerations.}, journal = {Brain &amp; spine}, volume = {5}, number = {}, pages = {104294}, pmid = {41635876}, issn = {2772-5294}, }
@article {pmid41637622, year = {2026}, author = {Du, C and Li, Y and Wu, R and Shen, Y and Yang, J and Xiao, X and Zhou, Y}, title = {Aberrant Splicing Signatures Underpin Oligodendrocyte Damage in ALS and Neuron Loss in FTD.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e14886}, doi = {10.1002/advs.202514886}, pmid = {41637622}, issn = {2198-3844}, support = {2023YFC2307802//National Key R&amp;D Program of China/ ; 2042022dx0003//Fundamental Research Funds for the Central Universities/ ; 2025AFA051//Hubei Provincial Natural Science Foundation of China/ ; 2023AFB182//Hubei Provincial Natural Science Foundation of China/ ; 2023KFZZ007//Open Project of Hubei Key Laboratory/ ; 32525018//National Natural Science Foundation of China/ ; 82341023//National Natural Science Foundation of China/ ; 324B2009//National Natural Science Foundation of China/ ; 82401650//National Natural Science Foundation of China/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two severe diseases sharing similar genetic, pathological, and clinical features, including TDP-43 pathology. However, differences in molecular changes between ALS and FTD remain elusive. Here, integrating large sets of bulk and single-nucleus RNA-seq from ALS/FTD patients revealed expression and splicing changes indicating more severe oligodendrocyte damage in ALS than FTD, and more significant neuron loss in FTD. Specifically, we identified 31 oligodendrocyte-specific and 507 neuron-specific aberrant splicing junctions as potential biomarkers with robust classification performance, and experimentally validated a novel target in patient tissues. Moreover, we found that abnormally spliced transcripts produced de novo peptides in patients' cerebrospinal fluids. Importantly, we further identified the targets of TDP-43 in glial cells and decoded the differential RNA-binding protein (RBP) contexts of TDP-43-regulated aberrant splicing. These findings uncover that ALS and FTD patients have distinct dysfunctional cell populations harboring specific aberrant splicing signatures, suggesting varying cellular impacts and providing potential biomarkers and insights into molecular mechanisms underlying ALS/FTD.}, }
@article {pmid41638255, year = {2026}, author = {Yeh, CH and Chen, SC}, title = {Comments on Huang et al's "Proteomic profiling reveals distinct inflammatory and neurogenic endotypes in rosacea".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.12.114}, pmid = {41638255}, issn = {1097-6787}, }
@article {pmid41638429, year = {2026}, author = {Madsen, M and Rønne, ME and Petersen, AB and Tandrup, T and Pilgaard, B and Holck, J and Aachmann, FL and Wilkens, C and Klau, LJ and Svensson, B}, title = {Dissecting a two-domain alginate lyase of family PL6 reveals a mechanistic basis for substrate specificity and enzyme activity.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {3}, pages = {111227}, doi = {10.1016/j.jbc.2026.111227}, pmid = {41638429}, issn = {1083-351X}, abstract = {Alginate lyases (ALs) cleave 4-O-glycosidic linkages in alginate, composed of mannuronate (M) and guluronate (G) residues via β-elimination with preference for either one or several M-M, M-G, G-M, G-G linkages. ALs in polysaccharide lyase family 6 (PL6) present different specificities and modes of action and contain either one or two parallel β-helix domains. About half of almost 600 PL6 sequences are of the two-domain type, all located in the phyla Pseudomonadota and Bacteroidota. Here, functional roles are described for the N- and C-terminal domains (NTD and CTD) using BoPL6, a two-domain AL from the human gut bacterium Bacteroides ovatus CP926, which is specific for G in subsite +1. The NTD contains the catalytic site, but BoPL6-NTD markedly preferred the model substrate polyMG and cleaved M-G bonds in endo-mode, whereas the NTD + CTD mixture, similarly to BoPL6, acted with highest activity on model substrate polyG in exo-mode, verified by time-resolved [1]H-NMR. The CTD was not catalytically active but bound polyguluronate and, when mixed with BoPL6-NTD, promoted activity on polyG, yielding products of DP 1‒3, similarly to BoPL6. This defines a crucial role of the CTD in shaping the active site in BoPL6, as validated by substrate docking. The BoPL6 E634A mutant in the conserved CTD DEST loop, interacting with the active site in two-domain PL6 enzymes, was inactive, while the corresponding CTD mutant mixed with the NTD did not form the WT structure and had highly reduced activity on polyG but acted on polyMG in endo-mode with improved rate and conversion.}, }
@article {pmid41638908, year = {2026}, author = {Villarroel-Campos, D and Vargas, JNS and Wallace, M and Sun, K and Sleigh, JN and Fratta, P and Schiavo, G}, title = {TBK1 activity regulates the directionality of axonal transport of signalling endosomes.}, journal = {Life science alliance}, volume = {9}, number = {4}, pages = {}, pmid = {41638908}, issn = {2575-1077}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Protein Serine-Threonine Kinases/metabolism/genetics ; *Endosomes/metabolism ; *Axonal Transport/physiology ; Humans ; Signal Transduction ; Phosphorylation ; Animals ; rab GTP-Binding Proteins/metabolism/genetics ; rab7 GTP-Binding Proteins ; Amyotrophic Lateral Sclerosis/metabolism ; Mice ; Axons/metabolism ; Motor Neurons/metabolism ; Lysosomes/metabolism ; Protein Transport ; Neurons/metabolism ; }, abstract = {The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.}, }
@article {pmid41639167, year = {2026}, author = {Jansén-Storbacka, LR and Honasoge, KS and Molnárová, E and Soboleva, A and Agema, BC and Paats, MS and Moes, DJAR and Veerman, GDM and Barbaro, ABT and Dobbe, R and Grossmann, I and Azimi, S and Mathijssen, RHJ and Dingemans, AC and Staňková, K}, title = {Can evolutionary therapy be applied in non-small cell lung cancer?.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41639167}, issn = {2045-2322}, support = {VI.Vidi.213.139//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 955708//European Commission/ ; }, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/therapy ; *Lung Neoplasms/pathology/drug therapy/therapy ; Erlotinib Hydrochloride/therapeutic use ; Male ; Models, Biological ; }, abstract = {Evolutionary therapy (ET) applies principles of evolutionary biology to steer tumour dynamics and forestall or delay treatment resistance, typically guided by data-driven mathematical models. Our aim is to assess whether ET protocols, and specifically Zhang et al.'s protocol proposed for metastatic castrate-resistant prostate cancer, can be theoretically effective for fast-growing metastatic cancers such as stage IV non-small-cell lung cancer (NSCLC). Using longitudinal tumour-burden data from NSCLC patients treated with erlotinib, we systematically evaluate 26 two-population differential-equation models based on classical tumour-growth dynamics, with varying assumptions about density- and frequency-dependent interactions, pharmacokinetics, and treatment-induced death. Previous work by Yin et al. on the same dataset employed an exponential model that omitted density- and frequency-dependent interactions; although it provided a good fit to tumour-burden data, its structure would theoretically lead to poorer outcomes under ET protocols. In contrast, our analysis identifies the minimal model structure required to reproduce the resistance-driven regrowth observed in NSCLC, with the Gompertzian model featuring log-kill dynamics and both density- and frequency-dependent interactions providing the best fit. In this model, Zhang et al.'s protocol prolonged median time-to-progression to 42.3 months compared with 24.8 months under maximum tolerated dose. These results indicate that ET is theoretically a viable treatment strategy for NSCLC. This study offers a practical framework for assessing ET feasibility using clinical data and supports future clinical translation of ET in NSCLC.}, }
@article {pmid41639245, year = {2026}, author = {Fernandes, AR and Owen, AP and Faroqi, AH and Lee, J and Sachdeva, GS and Morderer, D and Hoffmann, C and Madden, B and Zhang, S and Ren, Y and Boschen, SL and Pandey, A and Rossoll, W and McLean, PJ}, title = {A split biotin ligase approach reveals proteins associated with oligomeric alpha-synuclein during aggregation.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41639245}, issn = {2045-2322}, support = {U01CA271410/BC/NCI NIH HHS/United States ; RF1AG076122/GF/NIH HHS/United States ; A2021615S//BrightFocus Foundation/ ; 23A04//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Grant/ ; 024079//Michael J. Fox Foundation for Parkinson's Research/ ; 24A10//Florida Department of Health Ed and Ethel Moore AD Research Program/ ; U54 NS110435/NS/NINDS NIH HHS/United States ; APDA#11-08//Mayo Clinic American Parkinson's Disease Association Center for Advanced Research/ ; U54 NS110435/NS/NINDS NIH HHS/United States ; }, mesh = {*alpha-Synuclein/metabolism/chemistry/genetics ; Humans ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; *Carbon-Nitrogen Ligases/metabolism/genetics ; Lewy Body Disease/metabolism/pathology ; Protein Binding ; }, abstract = {Lewy pathology can form over decades in patients with Lewy body diseases, but the causal cellular mechanisms associated with this process remain unclear. This project aims to discover proteins that associate with monomeric and/or oligomeric alpha-synuclein during early stages of the aggregation process. To mimic aggregation processes, cells expressing a synuclein-biotin ligase fusion protein were treated with human recombinant pre-formed fibrils and subjected to BioSITe and mass spectrometry. Using a novel split biotin ligase fused to alpha-synuclein facilitated the identification of proteins specifically associated with multimeric alpha-synuclein. A total of 581 proteins were differentiated into potential interactors of monomeric versus multimeric alpha-synuclein in physiological versus aggregated conditions. The data reveal potentially relevant phosphorylation mechanisms, connections to insulin processing, and a potential interaction with ALS/FTD-associated FUS. Interestingly, we propose that loss of specific interactions may contribute to pathology in patients with sporadic onset of Lewy body diseases. Future studies will validate both true interaction of highlighted proteins with alpha-synuclein, and the impact of such proteins on alpha-synuclein aggregation.}, }
@article {pmid41639347, year = {2026}, author = {Tosi, M and Favero, F and Zuccalà, M and Visha, E and Caushi, F and Barizzone, N and Pomella, N and Follia, L and Corrado, L and Corà, D and Martignetti, L and Leone, M and D'Alfonso, S}, title = {A multi-omics study on monozygotic twins discordant for amyotrophic lateral sclerosis and literature review underline a potential role for innate immunity and epigenetic dysregulation in disease mechanisms.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {3}, pages = {230}, pmid = {41639347}, issn = {1590-3478}, support = {DIG-ALS//AriSLA/ ; PRIN project GENIALS//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Although genetic contributions to both familial and sporadic ALS (sALS) cases are well established, a substantial portion of ALS heritability remains unexplained, suggesting the involvement of other genetic and epigenetic factors.<br><br>METHODS: To address this gap, we have devised a comprehensive multi-omics approach in a pair of Italian monozygotic twins discordant for ALS, performing DNA methylation, transcriptomic, and whole exome sequencing (WES). We then conducted a structured literature research on ALS-discordant monozygotic twins (n&#x2009;=&#x2009;45) and on case-control sALS (~&#x2009;7000 patients and ~&#x2009;3000 controls), investigated for at least one of the omics approaches.<br><br>RESULTS: Our exploratory analysis reveals distinct transcriptomic and epigenetic profiles underlying the discordant disease phenotypes in genetically identical individuals, particularly implicating immune system functions and brain development pathways. Notably, a comprehensive comparison of our results with existing literature underlined the involvement of pathways related to NK cell activation, chemokine production, and signal transduction, suggesting potential shared disease associated mechanisms across ALS cases.<br><br>CONCLUSIONS: This hypothesis-generating study, although limited by the sample size, demonstrates the utility of multi-omics approaches in uncovering broader pathological insights into ALS, speculating on the possible contribution of innate immunity and epigenetic dysregulation in disease processes. This work provides a foundation for future research aimed at identifying disease-associated processes and biomarkers.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10072-026-08813-y.}, }
@article {pmid41639687, year = {2026}, author = {Zhang, N and Su, WM and Chen, T and Zhang, Q and Cao, B and Wang, Y and Chen, YP}, title = {From pathogenesis to therapy: the emerging role of regulatory T cells in amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {50}, pmid = {41639687}, issn = {1742-2094}, support = {82371422//National Natural Science Fund of China/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023HXFH032//1&#xb7;3&#xb7;5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord, with a pathogenesis that remains incompletely understood. Increasing evidence in recent years has highlighted the pivotal role of neuroinflammation in ALS, in which regulatory T cells (Tregs) emerge as key modulators of the neuroimmune response. This review systematically summarizes recent advances in understanding Treg biology in ALS, including their dynamic alterations across different disease stages and their potential immunoregulatory mechanisms, while also highlighting ongoing clinical trials and emerging cellular therapeutic strategies targeting Tregs. Current evidence suggests that Tregs not only participate in the immunopathology of ALS but also represent a promising target for therapeutic intervention. Nevertheless, there are still significant challenges, including incomplete mechanistic insights, limited clinical validation and obstacles to the implementation of Treg-based therapies. Overall, Treg research in ALS provides valuable directions for elucidating disease mechanisms and developing novel immune-based interventions.<br><br>GRAPHICAL ABSTRACT: [Image: see text]}, }
@article {pmid41639826, year = {2026}, author = {Shoji, H and Ishikawa, Y and Watanabe, J and Takahashi, S and Sawakami, K and Segawa, H and Ohashi, M}, title = {Differential diagnosis of degenerative cervical myelopathy considered in patients spine surgeons referred to neurologists: a retrospective cohort study.}, journal = {BMC musculoskeletal disorders}, volume = {27}, number = {1}, pages = {}, pmid = {41639826}, issn = {1471-2474}, abstract = {BACKGROUND: When patients suspected of degenerative cervical myelopathy present with atypical neurological findings, the spine surgeons generally referred the patients to neurologists preoperatively to distinguish it from non-compressive neurological diseases. This study aimed to elucidate the diseases that should be differentiated from degenerative cervical myelopathy and the differentiation points.<br><br>METHODS: We conducted a retrospective cohort study, and extracted consecutive patients who were suspected of degenerative cervical myelopathy with spinal cord compression and consulted a spine surgeon but were referred to a neurologist from 2011 to 2021 because of atypical findings. The main reason for consultation with a neurologist and the definitive diagnosis were investigated.<br><br>RESULTS: Sixty-eight patients were included (60 men and 8 women; median age [interquartile range], 72 [63&#x2013;76]). The main reasons for consultation with a neurologist were lack of sensory disturbance in 43 patients, lack of upper extremity symptoms and/or atypical gait impairment in 13, and symptoms in the unilateral upper and lower extremities in 3, and others. Definitive diagnoses were degenerative cervical myelopathy in 40 patients, non-compressive neurological diseases in 26, and others in 2. Non-compressive neurological diseases included parkinsonian syndromes in 9 patients, amyotrophic lateral sclerosis in 3, cerebrovascular disease in 3, and others. Regarding paresis of upper extremity in patients with lack of sensory disturbance, bilateral extensive type and no abnormality in upper extremity were related to non-compressive neurological diseases. In patients with lack of upper extremity symptoms and/or atypical gait impairment, 8 of 10 patients with non-spastic gait were diagnosed with non-compressive neurological diseases, and 5 of them with parkinsonian syndromes.<br><br>CONCLUSIONS: Non-compressive neurological disease should be considered in patients with a lack of sensory disturbance who present with bilateral extensive paresis or no neurological abnormality in the upper extremity. Parkinsonian syndromes should be considered as differential diagnosis for patients presenting with non-spastic abnormal gait.}, }
@article {pmid41640102, year = {2026}, author = {Ross, D and Lewis, O and McLean, O and Bhanot, S and Donahue, S and Baker, R and Dias, R and Eagerton, D and Mohanty, V and Mohanty, BK}, title = {Thermally activated history-dependent homogenization of G-quadruplexes in an ALS/FTD-associated gene.}, journal = {Biophysical journal}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bpj.2026.01.054}, pmid = {41640102}, issn = {1542-0086}, abstract = {A significant proportion of familial amyotrophic lateral sclerosis and frontotemporal dementia cases exhibit a substantial copy number expansion of the hexanucleotide GGGGCC/GGCCCC sequence in the C9ORF72 gene. The GGGGCC sequence forms a noncanonical DNA structure called a G-quadruplex (G4), which has been associated with the disease states and with nucleic acid condensate formation. G4s can fold into various topologies, which can differentially impact fidelity of DNA synthesis. However, how G4 conformational heterogeneity and its regulation impact hexanucleotide repeat expansion is unclear, and important clues may lie in the thermodynamic properties of different G4 topologies. Here, we use temperature-swept CD spectroscopy to observe configurational homogenization of an initially heterogeneous population of G4s over a small range of temperatures, demonstrating thermally activated behavior. The G4s adopt the parallel configuration after the temperature sweep, and subsequent temperature sweeps show little to no reversal back to nonparallel topologies, suggesting the homogenization is history-dependent. Finally, we provide an analytical theory based on a two-state thermodynamic model which is compatible with experimental evidence, and we discuss alternate mechanisms for the homogenization transition. These findings suggest that kinetic regulation of noncanonical DNA structures may play a role in cellular homeostasis or disease pathogenesis.}, }
@article {pmid41640104, year = {2026}, author = {Karros, M and DiFulco, M and Nogid, A}, title = {Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {}, number = {}, pages = {10600280251408862}, doi = {10.1177/10600280251408862}, pmid = {41640104}, issn = {1542-6270}, abstract = {OBJECTIVE: This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).<br><br>DATA SOURCES: PubMed, MEDLINE, Google Scholar, and ClinicalTrials.gov were searched using the keywords: Qalsody, BIIB067, antisense oligonucleotides, SOD1, and amyotrophic lateral sclerosis. Articles published from inception to November 2025 were included.<br><br>English-language studies assessing the pharmacokinetics, pharmacology, efficacy, and safety of tofersen were included. Prescribing information and real-world evidence were also reviewed.<br><br>DATA SYNTHESIS: Tofersen is an intrathecally administered antisense oligonucleotide targeting superoxide dismutase 1 (SOD1) mRNA. Early trials demonstrate dose-dependent reductions in cerebrospinal fluid (CSF) SOD1 protein levels of -33% and slower ALS Functional Rating Scale (ALSFRS-R) decline compared to placebo (-1.19 vs -5.63 points). In Phase 3 trials, tofersen reduced CSF SOD1 by 29% and plasma neurofilament light chain (NfL) by 60%, while biomarkers increased in the placebo group. There was no significant difference in ALSFRS-R decline between tofersen and placebo (-6.98 vs -8.14; P = 0.97). Real-world data show favorable patient-related outcomes and improvement in ALSFRS-R. Adverse effects are primarily lumbar puncture related with serious neurologic events documented in 7% of tofersen recipients.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:As the first Food and Drug Administration (FDA)-approved gene-directed therapy for SOD1 ALS, tofersen directly targets the underlying genetic cause. Barriers include the need for genetic confirmation and intrathecal administration.<br><br>CONCLUSION: Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.}, }
@article {pmid41640493, year = {2025}, author = {Li, SC}, title = {Evolving target: A 16-year progressive framework for shifting the rubric of scientific publishing toward transparency, artificial intelligence, and the Economic Impact Factor for impact that matters.}, journal = {World journal of stem cells}, volume = {17}, number = {12}, pages = {111748}, pmid = {41640493}, issn = {1948-0210}, abstract = {Reflecting on 16 years of continuous evolution at the World Journal of Stem Cells, this editorial offers a forward-looking vision for redefining the framework of scientific publishing. With the emergence of artificial intelligence, open science, and the growing need for translational value, we propose shifting from traditional citation-based assessments toward an impact and progress framework, anchored by the Economic Impact Factor. The World Journal of Stem Cells experience, grounded in metrics and milestones, supports this evolution: Among the more than 1200 published articles since inception, our top 10 cited works have collectively accrued over 2475 citations, led by Kyurkchiev et al (398 citations) and Casteilla et al (392 citations). Emerging scholars such as Ann De Becker and Nipha Chaicharoenaudomrung have shaped the next generation of research, as seen in our top 10 junior authors table. Clinically, World Journal of Stem Cells has supported critical translational work, such as Tsang et al's mesenchymal stem cell stroke trial (27 citations), illustrating real-world impact. Thematic breadth remains a cornerstone, with 22 focus areas including artificial intelligence-integrated programming, spatial single-cell biology, CRISPR-based gene editing, and bench-to-bedside translation. As Nature and other leading publishers move toward transparent peer review, World Journal of Stem Cells embraces editorial co-creation, recognizing peer reviewers and editors as contributors with "10000-foot eagle views" by publishing peer-review reports side-by-side with the related manuscripts since its inception. Together, these shifts signify a call to recalibrate what we value in science - not just what is cited, but what truly counts.}, }
@article {pmid41640615, year = {2026}, author = {Wang, G and Pan, SJ}, title = {Integrative acupoint stimulation within enhanced recovery after endoscopic procedures: Harnessing the neuroimmune axis for enhanced gastrointestinal recovery.}, journal = {World journal of gastroenterology}, volume = {32}, number = {3}, pages = {114048}, pmid = {41640615}, issn = {2219-2840}, mesh = {Humans ; *Acupuncture Points ; Recovery of Function ; *Enhanced Recovery After Surgery ; *Gastrointestinal Tract/innervation/surgery/immunology ; Neuroimmunomodulation ; Randomized Controlled Trials as Topic ; *Perioperative Care/methods ; Hypothalamo-Hypophyseal System/immunology ; *Transcutaneous Electric Nerve Stimulation/methods ; Pituitary-Adrenal System ; *Endoscopy, Gastrointestinal/adverse effects ; Treatment Outcome ; }, abstract = {Enhanced recovery after surgery (ERAS) programs have transformed perioperative care, yet delayed gastrointestinal function and excessive neuroendocrine stress remain major obstacles to optimal recovery. Hong et al's randomized controlled trial embedded acupoint-based neuromodulation - meridian-timed acupoint application combined with transcutaneous electrical acupoint stimulation - within an ERAS framework and demonstrated accelerated gastrointestinal recovery accompanied by endocrine attenuation. This article offers a structured critical appraisal of the trial, emphasizing methodological rigor, mechanistic plausibility, and alignment with ERAS core principles of stress mitigation, functional restoration, and patient experience. The observed reductions in norepinephrine, cortisol, and aldosterone suggest modulation of the hypothalamic-pituitary-adrenal axis as a key mediator of benefit. Future research priorities include multicenter, sham-controlled validation; integration of autonomic and inflammatory biomarkers (heart rate variability, interleukin-6, tumor necrosis factor-α, C-reactive protein); and pragmatic evaluation of cost-effectiveness and acceptability. Positioning acupoint stimulation within precision-integrative perioperative care could advance ERAS from a recovery protocol to a system of host-response modulation. Integrative acupoint neuromodulation thus represents a biologically coherent, low-risk, and scalable strategy for enhancing resilience, accelerating gastrointestinal recovery, and improving surgical outcomes worldwide.}, }
@article {pmid41640951, year = {2026}, author = {Cui, X and Yin, BQ and Chen, L}, title = {Remote telerehabilitation for frailty management in liver transplant candidates: A feasible yet underutilized strategy.}, journal = {World journal of hepatology}, volume = {18}, number = {1}, pages = {114880}, pmid = {41640951}, issn = {1948-5182}, abstract = {This letter reviews Loschi et al's study evaluating structured telerehabilitation for frail cirrhotic liver transplant candidates, which fills a critical pre-transplant care gap. The video-based program, using low-cost tools and asynchronous sessions, improved liver frailty index reduction and function in adherent patients (29.8%) although a high attrition rate (70%) highlighted engagement challenges. Limitations include a small, non-randomized sample, mixed frailty subgroups, and unexplored long-term effects. Future directions emphasize hybrid models, patient-centered barrier analysis, and policy-driven frailty screening. This work advances digital health for cirrhosis; however, larger trials are needed to optimize outcomes.}, }
@article {pmid41641215, year = {2026}, author = {Zhang, Y and Wang, JJ and Xing, HY and Yan, J}, title = {Neurofeedback for autism spectrum disorder: Current evidence, challenges, and future directions.}, journal = {World journal of psychiatry}, volume = {16}, number = {2}, pages = {114358}, pmid = {41641215}, issn = {2220-3206}, abstract = {Neurofeedback therapy (NFT) has emerged as a promising noninvasive intervention for autism spectrum disorder (ASD), targeting core symptoms such as social communication deficits and emotional dysregulation. This editorial synthesizes findings from recent studies, including Wang et al's retrospective analysis (2025), which reported improvements in Social Responsiveness Scale and Aberrant Behavior Checklist scores following NFT combined with conventional therapy. Mechanistically, NFT may modulate prefrontal gamma-band activity, enhances neuroplasticity in social brain networks (e.g., default mode network, a brain network involved in social cognition), and optimizes cognitive processing via event-related potential changes (e.g., shortened P300 latency). Emerging trends include hybrid approaches (e.g., NFT with repetitive transcranial magnetic stimulation and artificial intelligence-driven protocols). However, challenges persist in protocol standardization, long-term efficacy validation, and biomarker identification. Future research must prioritize large-scale randomized trials, neuromarker discovery, and individualized protocols to establish NFT as a viable component of precision psychiatry for ASD.}, }
@article {pmid41641779, year = {2026}, author = {Varderidou-Minasian, S and Jakobs, CE and Pasteuning-Vuhman, S and Gal, L and Timmers, A and Altelaar, M and Lorenowicz, MJ and Pasterkamp, RJ}, title = {Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01790}, pmid = {41641779}, issn = {1673-5374}, abstract = {Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell-derived motor neurons carrying amyotrophic lateral sclerosis-associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell-derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell-derived extracellular vesicles as a versatile therapeutic approach.}, }
@article {pmid41641857, year = {2026}, author = {Marcinkowska, K and Wrzesińska-Krupa, B and Obrępalska-Stęplowska, A}, title = {Insights Into Sequences of Viral and Bacterial Origin in the Metatranscriptome of Centaurea cyanus L. Susceptible and Resistant to Acetolactate Synthase (ALS)-Inhibiting Herbicides.}, journal = {Environmental microbiology reports}, volume = {18}, number = {1}, pages = {e70287}, pmid = {41641857}, issn = {1758-2229}, support = {2020/04/X/NZ9/01767//National Science Centre/ ; }, mesh = {*Herbicides/pharmacology ; *Acetolactate Synthase/antagonists &amp; inhibitors ; *Bacteria/genetics/classification/isolation &amp; purification/drug effects ; *Herbicide Resistance ; *Centaurea/microbiology/virology ; Arylsulfonates/pharmacology ; Transcriptome ; Poland ; Plant Weeds/virology/microbiology ; *Plant Viruses/genetics/classification/isolation &amp; purification ; Phylogeny ; }, abstract = {Cornflower (Centaurea cyanus L.) is a widespread weed in cereal crops and is commonly controlled with sulfonylurea herbicides. In Poland, populations of cornflower resistant to acetolactate synthase inhibiting herbicides, such as tribenuron-methyl, have been increasingly reported. Both target-site and non-target-site resistance mechanisms may contribute to this phenomenon. Plant-associated microorganisms are known to play essential roles in alleviating abiotic stress. Moreover, weeds are considered reservoirs of plant pathogenic viruses. Since bacteria and viruses associated with cornflower have not been analysed to date, data mining was undertaken to identify viral and bacterial sequences in metatranscriptome datasets obtained from plant biotypes that are both susceptible and highly resistant to tribenuron-methyl. Using MEGAN6 and Kraken2, taxonomic classification revealed the presence of sequences of two double-stranded RNA viruses belonging to the family Partitiviridae, which have not been described before. For bacterial sequences, 19 genera were identified, including Bacillus, Mesorhizobium and Acinetobacter, some of which are associated with plant growth promotion or xenobiotic degradation. Although the presence of partitiviruses was unrelated to herbicide resistance status, some bacterial genera (e.g., Rothia) were more abundant in resistant than in susceptible plants. These results suggest that those bacterial genera present in weeds may be involved in counteracting ALS-inhibiting herbicides.}, }
@article {pmid41642424, year = {2026}, author = {Sun, Y and Huang, C and Pan, Y and Zhang, H and He, X}, title = {Correction: Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {418}, doi = {10.1007/s12035-026-05721-2}, pmid = {41642424}, issn = {1559-1182}, }
@article {pmid41642483, year = {2026}, author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS}, title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.}, journal = {Cellular and molecular neurobiology}, volume = {46}, number = {1}, pages = {43}, pmid = {41642483}, issn = {1573-6830}, mesh = {Humans ; *Neuroglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Gonadal Steroid Hormones/metabolism ; Animals ; }, abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.}, }
@article {pmid41642988, year = {2026}, author = {Wells, TL and Galani, M and Popoli, R and Zagoraiou, L and Akay, T}, title = {Compensatory scaling of modulatory neural populations in response to motor challenges.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {6}, pages = {e2519741123}, pmid = {41642988}, issn = {1091-6490}, mesh = {Animals ; Mice ; *Motor Neurons/physiology/metabolism ; *Interneurons/physiology/metabolism ; Spinal Cord/physiology/metabolism ; Serotonin/metabolism ; Brain Stem/physiology/metabolism ; Muscle, Skeletal/physiology ; Locomotion/physiology ; Cholinergic Neurons/physiology/metabolism ; Male ; Electromyography ; }, abstract = {Precise and adaptable movements are achieved by well-regulated muscle contractions, which are mainly governed by the excitability of motor neurons. Several neuromodulatory systems originating in the motor cortex, brainstem, and spinal cord regulate motor neuron excitability via the release of neurotransmitters such as acetylcholine and serotonin. However, these systems can have seemingly similar effects on motor neuron output, raising questions about interaction during movement. To address this, we investigated two modulatory systems in mice: the cholinergic V0c interneurons in the spinal cord and the serotonergic system in the brainstem. Electromyographic and behavioral recordings revealed that, when compared to control mice, mice whose V0c interneuron cholinergic output was genetically inactivated failed to display speed-dependent modulation of the gastrocnemius muscle, and exhibited lower amplitude bursting in the gastrocnemius muscle during swimming. c-Fos expression in this population during locomotion also indicated that they are active in a speed-dependent manner. Relative to control mice, those mice whose V0c interneurons had their cholinergic output inactivated showed upregulated activity in motor-related serotonergic populations while trotting at higher speeds but not while walking at lower speeds, indicating that serotonin plays a compensatory role in the absence of functional V0c interneurons. Last, we observed a progressive recruitment of these two populations in mice with amyotrophic lateral sclerosis, and the recruitment of serotonergic neurons is hastened in those mice whose V0c interneurons had their cholinergic output inactivated. These findings highlight that modulatory systems scale their activity to match motor demand across various circumstances.}, }
@article {pmid41643021, year = {2026}, author = {Jiang, X and Schaeffer, L and Patni, D and Russo, T and Lee, CZ and Aguilar, C and Marques, C and Jansen-West, K and Hruska-Plochan, M and Ray-Soni, A and Lim, SM and Held, A and Yue, M and Castellanos Otero, P and Aryal, S and Beaussant, HDAM and Basu, H and Takakuwa, H and Daughrity, LM and Ramesh, N and Da Costa, P and A A Quadros, AR and Nolan, M and Reyes, CJF and Wheeler, H and Moran, LC and Griesman, G and Wymann, B and Trombetta, BA and Lopez-De-Silanes, ES and Canori, M and Krishnan, G and Vieira Souza Da Silva, Y and Eriani, G and Albers, MW and Arnold, SE and Song, Y and Jain, A and Chiu, IM and Zhang, YJ and Gao, FB and Wainger, BJ and Polymenidou, M and Petrucelli, L and Martin, F and Lagier-Tourenne, C}, title = {Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes.}, journal = {Science (New York, N.Y.)}, volume = {391}, number = {6785}, pages = {eadv2600}, doi = {10.1126/science.adv2600}, pmid = {41643021}, issn = {1095-9203}, support = {R01 NS057553/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; *C9orf72 Protein/genetics ; Codon ; Dipeptides/genetics ; Disease Models, Animal ; *DNA Repeat Expansion ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics/pathology/therapy ; Induced Pluripotent Stem Cells ; Motor Neurons/pathology ; Mutation ; Phenotype ; *Protein Biosynthesis ; *ran GTP-Binding Protein/genetics ; *RNA/genetics/metabolism ; HEK293 Cells ; Male ; Female ; Mice, Inbred C57BL ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell-derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.}, }
@article {pmid41643078, year = {2026}, author = {Fernandez, R and Sívori, M}, title = {[Clinical scale of ventilatory failure risk in patients with amyotrophic lateral sclerosis].}, journal = {Medicina}, volume = {86}, number = {1}, pages = {60-72}, pmid = {41643078}, issn = {1669-9106}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/mortality/physiopathology ; Male ; Retrospective Studies ; Female ; Middle Aged ; *Hypercapnia/etiology ; *Respiratory Insufficiency/etiology/mortality ; Aged ; Risk Factors ; Risk Assessment/methods ; Prognosis ; Respiration, Artificial ; Dyspnea/etiology ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes atrophy and paralysis of skeletal muscles, including respiratory muscles. The development of ventilatory failure determines the prognosis. The primary outcome was to determine which common clinical variables can be predictors of daytime hypercapnia and develop a risk model of ventilatory failure. Secondary outcome was to determinate the survival rate of high-risk patients with and without hypercapnia.<br><br>MATERIALS AND METHODS: Retrospective study. Patients with ALS without mechanical ventilation were selected and followed from June 2015 to May 2024. They underwent arterial blood carbon dioxide measurement and classified into two groups: hypercapnic (pCO2 &#x2265;45 mmHg) and normocapnic (pCO2 <45 mmHg). Different predictive models for hypercapnia were constructed.<br><br>RESULTS: An association between orthopnea (p=0.0001), dyspnea (p=0.02) and FVC <50% (p=0.04) was found. The predictive model constructed with the following variables: orthopnea, dyspnea and ALSFRS-R score &#x2264;21, presented a good performance on the detection hypercapnia risk. A score > 23 points had a sensitivity of 80.6% and a specificity of 72.8% for detecting patients at high risk of hypercapnia. Normocapnic patients at high risk who start mechanical ventilation before developing hypercapnia improve their survival rate by 6 months (p=0.17).<br><br>DISCUSSION: The risk score includes easily obtained clinical variables and is effective in detecting patients at risk for hypercapnia. Initiating mechanical ventilation in at-risk patients who have not yet developed hypercapnia has a clinically significant impact on survival.}, }
@article {pmid41643564, year = {2026}, author = {Ma, Z and Zheng, J and Wang, H and Chen, C and Yue, J and Duan, X and Jiang, H}, title = {A Novel Classification of Esophageal Anastomotic Leaks and Its Impact on Healing Time After Esophagogastrostomy.}, journal = {Cancer research and treatment}, volume = {}, number = {}, pages = {}, doi = {10.4143/crt.2025.1029}, pmid = {41643564}, issn = {2005-9256}, abstract = {PURPOSE: Anastomotic leakage (AL) is a severe complication after esophagogastrostomy, yet the classifications of AL and their associated healing times are poorly understood.<br><br>MATERIALS AND METHODS: This study retrospectively analyzed 117 cases of AL among 2,728 patients who underwent esophagectomy with circular stapled esophagogastric anastomosis at Tianjin Medical University Cancer Institute and Hospital from January 1, 2019, to March 31, 2024. AL cases were categorized into four types based on the direction of leakage (anterior, right, posterior, and left). The differences in healing times among these four types were analyzed using the log-rank test. A multivariable Cox model was used to identify factors associated with healing time.<br><br>RESULTS: The incidence of AL was 4.3% (117/2728), with a median occurrence time of 9 days (Interquartile Range[IQR]: 5) and a median healing time of 56 days (IQR:64). Single cervical ALs accounted for 17.5%, with significantly shorter healing times compared to intrathoracic leaks (33 days vs. 61 days, p=0.018). Right-sided leaks were the most common (49.6%), while left-sided leaks healed faster than right- and posterior-sided leaks (42 days vs. 63 days vs. 70 days, p<0.05). Body Mass Index (BMI), diabetes, and neoadjuvant therapy did not influence healing time. In 117 AL patients, the occurrence of tracheoesophageal fistula (p=0.004) and the placement of trans-fistula reverse drainage tubes (p=0.002) were associated with healing time.<br><br>CONCLUSION: These findings provide valuable insights for clinicians to better understand the mechanisms of AL development and predict the healing times.}, }
@article {pmid41643607, year = {2026}, author = {Cásedas, G and Rojas-Márquez, H and Ventura, L and Moliner, C and Maggi, F and Rubio-Castellanos, A and López, V}, title = {Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {196}, number = {}, pages = {119048}, doi = {10.1016/j.biopha.2026.119048}, pmid = {41643607}, issn = {1950-6007}, mesh = {Humans ; *Cannabis/chemistry ; *NF-E2-Related Factor 2/metabolism ; *Polyphenols/pharmacology/isolation &amp; purification ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Antioxidants/pharmacology/metabolism ; Oxidative Stress/drug effects ; Cell Line, Tumor ; *Neurons/drug effects/metabolism/pathology ; Molecular Docking Simulation ; Neuroprotective Agents/pharmacology ; Plant Extracts/pharmacology ; *Cytoprotection/drug effects ; Signal Transduction/drug effects ; }, abstract = {Oxidative stress (OS) is widely recognized as a central promoter to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Cannabis sativa L. synthesizes a complex array of bioactive compounds that extends well beyond the well-known cannabinoids to include a diverse suite of polyphenols, terpenes, fatty acids, tocopherols, and proteins. The non-cannabinoid polyphenolic fraction is composed primarily of flavonoids, stilbenoids, lignans, and lignanamides, which contribute substantially to the plant's antioxidant, anti-inflammatory, and neuroprotective properties. This study investigates the redox-modulating and cytoprotective properties of a polyphenolic fraction derived from Cannabis sativa L. in SH-SY5Y neuroblastoma cells. Neurons were treated with various concentrations of the aqueous polyphenolic cannabis extract and exposed to oxidative stress using hydrogen peroxide (100 µM). Protein and gene expression related to redox signalling were analyzed via Western blot and qPCR, and molecular docking studies were performed in silico. Furthermore, antioxidant enzymes activity was measured by spectrophotometry. Results revealed that the phenolic fraction significantly activated the Keap1/Nrf2 pathway, increased expression of PRDX1 and PRDX3, and enhanced endogenous antioxidant defences. Simultaneously, it reduced endoplasmic reticulum stress-induced apoptosis (via Bax/Bcl-2 modulation) and attenuated inflammatory markers, including NO, NF-κB2, IL-6, and IL-8. In silico docking studies identified Leu583 as a key residue in Nrf2-ligand interactions. These findings suggest that Cannabis sativa L. polyphenols are key bioactive compounds modulating redox homeostasis and inflammation, and offering neuroprotective benefits with potential relevance in diseases involving mitochondrial dysfunction and oxidative damage.}, }
@article {pmid41643661, year = {2026}, author = {Liu, H and Liu, M and Liu, Y and Gui, G and Paul, T and Lu, YN and Huang, Z and Wang, H and Xiao, Y and Zheng, Z and Periz, G and Shi, Y and Ichida, JK and Myong, S and Ji, H and Wang, J}, title = {C9orf72 hexanucleotide repeat RNA drives transcriptional dysregulation through genome-wide DNA:RNA hybrid G-quadruplexes.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.12.005}, pmid = {41643661}, issn = {1097-4199}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.}, }
@article {pmid41645155, year = {2026}, author = {McDonald, DW and Chugh, N and Sava, R and Duennwald, ML}, title = {FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.}, journal = {BMC biology}, volume = {24}, number = {1}, pages = {}, pmid = {41645155}, issn = {1741-7007}, support = {RGPIN-2024-05867//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Saccharomyces cerevisiae/genetics/metabolism/physiology ; *Protein Aggregates ; *Aging/metabolism ; Humans ; Proteostasis ; }, abstract = {BACKGROUND: Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models.<br><br>RESULTS: Using optimized low-expression FUS and TDP-43 yeast models, we demonstrate that chronological ageing antagonizes proteostasis, the steady state levels and solubility of molecular chaperones, and aggregation of FUS and TDP-43. In addition, mistranslation caused by tRNA variants further antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity.<br><br>CONCLUSIONS: Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.}, }
@article {pmid41645941, year = {2026}, author = {Iammeechai, W and Srikulmontri, T and White, BAA}, title = {Emotional intelligence development in medical education: A scoping review of educational interventions.}, journal = {Medical teacher}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/0142159X.2026.2621214}, pmid = {41645941}, issn = {1466-187X}, abstract = {Background and aims: Emotional intelligence (EI) is an essential competency for physicians. Medical educators seek educational interventions to cultivate EI in their learners. This scoping review aimed to conceptualize current knowledge about educational interventions for developing EI in medical education. Methods: This study adopted the first five stages of Levac et al.'s scoping review framework, which builds on Arksey and O'Malley's scoping review methodology. The authors accessed three databases-PubMed, CINAHL, and PsycINFO-to review the literature from 2014 to February 2025. Two authors (WI and TS) independently screened the literature for eligibility. A third author (BAAW) resolved any discrepancies. Two authors (WI and BAAW) charted the eligible articles. Results: Of the 638 studies, 64 were eligible. Approximately one-third of eligible studies focused on interventions for medical students. Stress management, leadership, communication, and professionalism w