@article {pmid41299417,
year = {2025},
author = {Wang, J and Zhu, M and Smith, RD},
title = {Prevalence, incidence and risk factors of syphilis among men who have sex with men in China from 2013 to 2025: a systematic review and meta-analysis.},
journal = {BMC infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12879-025-12176-8},
pmid = {41299417},
issn = {1471-2334},
abstract = {BACKGROUND: Syphilis has re-emerged in China in recent decades, particularly among men who have sex with men (MSM). We aimed to assess the prevalence, incidence, and associated factors of syphilis among MSM in China.

METHODS: We systematically searched major English (MEDLINE via PubMed, Web of Science, Embase, Scopus, Cochrane Library) and Chinese (CNKI, Wanfang, CBM, VIP, Airiti Library) databases for studies on syphilis prevalence or incidence among MSM in China published from January 1, 2013 to March 1, 2025. Study qualities were evaluated using the Hoy et al.'s risk-of-bias tool and the Newcastle-Ottawa Scale. Random-effects meta-analysis models were used to estimate pooled syphilis prevalence (%) and incidence (per 100 person-years, PYs) with 95% confidence intervals (CIs). Meta-regression analyses were performed to assess differences across subgroups.

RESULTS: A total of 441 studies (429 prevalence and 33 incidence) were included. The pooled syphilis prevalence among general MSM was 8.8% (95% CI: 8.3-9.4). Study location (R²=0.13) and study year (R²=0.11) each contributed significantly to the high heterogeneity observed (I² = 98.5%) among the general MSM prevalence studies. MSM with high-risk sexual behaviors or related risk factors exhibited higher prevalence. The pooled incidence among all MSM was 7.8 per 100 PYs (95% CI: 6.0-9.8), with similarly high heterogeneity (I² = 96.4%). Both syphilis prevalence and incidence declined over time.

CONCLUSION: Syphilis prevalence and incidence remain high among high-risk MSM subgroups in China. More rigorous studies and targeted interventions are needed to obtain more accurate estimates and to further reduce syphilis infection rates.},
}

@article {pmid41298695,
year = {2025},
author = {Almaguer-Mederos, LE and Key, J and Sen, NE and Canet-Pons, J and Döring, C and Meierhofer, D and Gispert-Sánchez, S and Cuello-Almarales, D and Almaguer-Gotay, D and Osorio-González, LM and Aguilera-Rodríguez, R and Medrano-Montero, J and Auburger, G},
title = {Multiomics approach identifies SERPINB1 as candidate biomarker for spinocerebellar ataxia type 2.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-29070-7},
pmid = {41298695},
issn = {2045-2322},
abstract = {Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers in the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. The aim of this study was to define novel molecular biomarker candidates for SCA2. Using cerebellar and cervicothoracic spinal cord RNA/protein from Atxn2-CAG100-KnockIn (KIN) and wildtype mice, a multi-omics study was conducted based on the integration of global transcriptomic, proteomic, and phosphoproteomic data, followed by validation in mice and humans. Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a-transcript, SERPINB1A-protein and -phosphopeptides were consistently downregulated at terminal stage in 14-month-old KIN mice. Expression studies in cerebellum and spinal cord from 10 weeks (pre-manifest), 6-month-old (early ataxic), and 14-month-old (late ataxic stage) mice confirmed this progressive decrease at mRNA and protein level. SERPINB1 plasma levels were significantly lower in early-stage SCA2 patients, and displayed a significant association with the CAG repeat length at expanded ATXN2 alleles, the age at onset and INAS count. However, these human data from this SCA2 founder population were not robust, so reappraisal in large international studies and at later disease stages of SCA2 is needed. SERPINB1 was identified as novel candidate progression biomarker for SCA2 pathomechanisms.},
}

@article {pmid41298366,
year = {2025},
author = {Rizuan, A and Shenoy, J and Mohanty, P and Dos Passos, PM and Mercado Ortiz, JF and Bai, L and Viswanathan, R and Zaborowksy, J and Wang, SH and Johnson, V and Mamede, LD and Titus, AR and Ayala, YM and Ghirlando, R and Mittal, J and Fawzi, NL},
title = {Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {10528},
pmid = {41298366},
issn = {2041-1723},
support = {R01NS116176//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS114289//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Molecular Dynamics Simulation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Domains ; *Protein Multimerization ; Magnetic Resonance Spectroscopy ; Mutation ; Conserved Sequence ; Protein Conformation, alpha-Helical ; },
abstract = {Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.},
}

*DNA-Binding Proteins/chemistry/metabolism/genetics
Humans
Molecular Dynamics Simulation
Amyotrophic Lateral Sclerosis/genetics/metabolism
Protein Domains
*Protein Multimerization
Magnetic Resonance Spectroscopy
Mutation
Conserved Sequence
Protein Conformation, alpha-Helical

@article {pmid41298223,
year = {2025},
author = {Lin, CY and Lee, BC and Zhang, PH and Lu, SC and Chang, WZ and Wang, CC and Tsai, HJ},
title = {A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00806},
doi = {10.1016/j.neurot.2025.e00806},
pmid = {41298223},
issn = {1878-7479},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.},
}

@article {pmid41297670,
year = {2025},
author = {Matsumoto, C and Kabuta, T and Sano, T and Murayama, S and Saito, Y and Takahashi, Y},
title = {ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106093},
doi = {10.1016/j.neuint.2025.106093},
pmid = {41297670},
issn = {1872-9754},
abstract = {The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.},
}

@article {pmid41296954,
year = {2025},
author = {Lu, Z and Kong, D and Zhou, H and Zhou, S and Chen, L and Tao, Y and Yang, G},
title = {A Unified Contrastive Learning Framework for Neurological Disease Diagnosis from VGRF and IMU Gait Data.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3637054},
pmid = {41296954},
issn = {2168-2208},
abstract = {Accurate early diagnosis of neurological diseases (NDs) can effectively facilitate intervention and help with neural healthcare. While wearable informatics like Vertical Ground Reaction Force (VGRF) and Inertial Measurement Unit(IMU) offer complementary gait insights, a key challenge is fusing these heterogeneous modalities, especially when the data are unaligned and scarce. In this study, our primary contribution lies in proposing a novel contrastive learning framework designed specifically to unify VGRF and IMU gait data for ND classification. This framework learns a shared representation space during training, enabling the final trained model to perform accurate diagnosis from data streams of either a single VGRF or a single IMU modality. We evaluated this approach on the classification of four NDs-Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke-against healthy controls using two public VGRF datasets and one real-world IMU dataset. As a key result, our model achieved 98.21% accuracy in the binary task (disease vs. healthy) and 96.99% accuracy in the multi-class classification. The high performance demonstrates the potential of our method to advance neural health diagnostics, providing a robust approach for gait-based neurological assessment using heterogeneous wearable sensors.},
}

@article {pmid41296103,
year = {2025},
author = {Ge, TQ and Ma, XY and Guan, PP and Wang, P},
title = {Aspirin Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Inhibiting the Activities of Microglia in a NF-κB-dependent Complement System-deactivating Mechanism.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {180},
pmid = {41296103},
issn = {1559-1182},
support = {JYTMS20230628//Liaoning Provincial Department of Education Funding/ ; D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; Animals ; *Aspirin/pharmacology/therapeutic use ; Mice ; *Complement System Proteins/metabolism ; Apoptosis/drug effects ; Cell Line ; Lipopolysaccharides/pharmacology ; Signal Transduction/drug effects ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which is pathologically characterized by impairing the motor neurons, leading to the disorders of motor function. Aspirin (ASP) has the ability to increase the survival time of SOD1[G93A] mice via concurrently reducing the activation of glial cells and restoring the number of neurons. Meanwhile, ASP treatment inhibited the activities of NF-κB pathway, which resulted in regulating the expression of complement system (CS), including C3, C1qb, and C4b in vivo. To reveal the inherent mechanisms, the in vitro experiments were carried out in SOD1[G93A] protein- and lipopolysaccharide (LPS)-treated BV2 cells. The results demonstrated that SOD1[G93A] protein or LPS induces the activation of NF-κB in BV2 cells, whose conditional medium induces the apoptosis of NSC34 cells. By blocking the activities of NF-κB by ASP, Bay 11-7082 or si NF-κB, the synthesis of CS molecules was suppressed, which results in alleviating the apoptosis of NSC34 cells. More importantly, Terminal complement complex (TCC) was identified to be the critical component of CS for mediating the effects of SOD1[G93A] protein or LPS on inducing the apoptosis of neurons, which was inhibited by the ASP or Bay 11-7082. On the basis of these observations, our findings novelly revealed that ASP delayed the progression of ALS via inhibiting the activities of microglia in a NF-κB-dependent CS-deactivating mechanisms.},
}

*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism
*NF-kappa B/metabolism
*Microglia/drug effects/metabolism/pathology
Animals
*Aspirin/pharmacology/therapeutic use
Mice
*Complement System Proteins/metabolism
Apoptosis/drug effects
Cell Line
Lipopolysaccharides/pharmacology
Signal Transduction/drug effects

@article {pmid41295911,
year = {2025},
author = {Warren, J and Bosson, N and Tolles, J and Wilhelm, K and Avakoff, E and Arase, M and Toy, J and Kim, M and Nulty, J and Roel, A and Mendoza, L and Cohen, M and Gausche-Hill, M and Whitfield, D},
title = {A Live Human Model Comparison Evaluating ThoraSite® Accuracy for Needle Thoracostomy.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/10903127.2025.2592880},
pmid = {41295911},
issn = {1545-0066},
abstract = {OBJECTIVES: Needle thoracostomy (NT) is a time-sensitive procedure infrequently performed by EMS clinicians with variable success rates. Our primary objective was to evaluate the accuracy of NT site selection by paramedics using ThoraSite® compared to traditional anatomic landmarks (ALs). Secondarily, we assessed paramedic-rated confidence and ease of ThoraSite® use.

METHODS: We conducted a randomized, two-arm crossover study including fire-based paramedics. Emergency physician investigators determined a NT placement zone for live human models in three size groups, confirming with ultrasound and demarcating the zone with "invisible" ultraviolet ink. Following training, paramedics performed NT site selection on the models using ThoraSite® and ALs by placing a sticker at the selected insertion site. Accuracy of placement was confirmed with ultraviolet flashlight. If placement was outside the demarcated zone (DZ), we identified underlying structures with ultrasound. We evaluated the effect of approach on placement accuracy and time-to-NT placement using linear models with covariates of paramedic, approach, and model size. For the outcome of accuracy, we used a log link function. For time-to-NT, we log-transformed the values for the parametric analysis allowing interpretation of the coefficients as percent differences. We compared paramedic confidence in performing the NT procedure and perceived ease of procedure using a 5-point Likert scale.

RESULTS: There were 112 paramedics that performed 223 ThoraSite® and 223 landmark attempts with 383 correct placements within the DZ: 198 attempts using ThoraSite® compared to 185 with ALs, odds ratio (OR) 1.91 (95%CI 1.01-3.62), p = 0.04. Placement accuracy by model size followed similar trends. Incorrect placement over critical structures occurred in 1 ThoraSite® and 3 AL attempts. The mean time for NT site selection was 14.3s (SD = 7.11) using ThoraSite® and 18.7s (SD = 7.40) using ALs (p < 0.01). Overall procedural confidence improved with training. However, there was no statistically significant difference in the change in confidence with ThoraSite® as compared to ALs (OR = 1.55 95%CI = 0.89-2.72). Paramedics rated ease of NT placement significantly higher using ThoraSite® (median = 5, IQR = 4-5) compared to ALs (median = 4, IQR = 4-5; p < 0.01).

CONCLUSIONS: ThoraSite® was associated with increased odds of NT site selection in the DZ, reduced time-to-NT site selection, and increased self-rated ease reported by paramedics.},
}

@article {pmid41295428,
year = {2025},
author = {Lozano, JH and Embretson, SE and Revuelta, J},
title = {An Analysis of Individual Differences in Within-Test Practice Effects in Progressive Matrices.},
journal = {Journal of Intelligence},
volume = {13},
number = {11},
pages = {},
pmid = {41295428},
issn = {2079-3200},
support = {PID2021-124885NB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; },
abstract = {The present study aimed to investigate individual differences in practice effects during progressive matrices based on Carpenter et al.'s taxonomy of abstract rules. To this end, data from a non-verbal reasoning test, the Abstract Reasoning Test (ART), were used. Because the ART was developed from Carpenter et al.'s theory, the impact of extraneous factors unrelated to the theoretical model is minimized, thereby allowing for a more precise identification of practice effects. The sample consisted of 765 military recruits who responded to 34 items on the ART. Analyses were conducted using a random weights operation-specific learning model (RWOSLM), in which practice parameters were treated as random effects allowed to vary across individuals. The model measures within-test practice effects specific to each examinee, allowing the hypothesis of rule learning during the ART to be assessed at the individual level. Correlations between practice effects and external measures associated with intelligence were examined to investigate the nature of the practice effects. The results suggest individual differences in rule learning within the ART. Decreases in difficulty were observed for both pairwise progression and figure addition or subtraction, although between-person variability was evident only for the latter. Additionally, the results revealed between-person variability in decreases in difficulty associated with one of the items' figural properties, which suggests the existence of individual differences in the process of increasing familiarity with this feature throughout the test. Individual differences in practice effects during the ART significantly correlated with external measures of abilities and intellect, suggesting that practice effects during progressive matrices are conceptually tied to intelligence.},
}

@article {pmid41295414,
year = {2025},
author = {Favari, E and Parolini, C},
title = {Marine Bioactive Components and Chronic Neuroinflammation: Focus on Neurodegenerative Disease.},
journal = {Marine drugs},
volume = {23},
number = {11},
pages = {},
pmid = {41295414},
issn = {1660-3397},
support = {NA//MUR Progetto Eccellenza/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroinflammatory Diseases/drug therapy ; *Aquatic Organisms/chemistry ; Oxidative Stress/drug effects ; Inflammation/drug therapy ; },
abstract = {Advances in neuroscience, immunology, and neuroimmunology have revealed that the nervous and immune systems form a bidirectional integrated network, ranging from regulating inflammation to directing stress responses, pivotal for the maintenance of the brain-body physiology. Like peripheral inflammation, neuroinflammation is a conserved process aimed at activating innate/adaptive immune and non-immune cells to effectively deal with bacteria, viruses, toxins, and injuries, and eventually at removing the microbial pathogens and supporting tissue repair and recovery. A failure of this process or the permanent release of pro-inflammatory mediators causes a condition called "chronic low-grade neuroinflammation" resulting in tissue damage and an increased risk of developing neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Marine-derived bioactive components are able to modulate lipid and glucose metabolism as well as inflammation and oxidative stress. In this review, we describe the neuroinflammatory process and its involvement in the pathogenesis and progression of AD, PD, MS, and ALS. Then, we discuss the potential therapeutic efficacy of select marine-derived bioactive components.},
}

Humans
*Neurodegenerative Diseases/drug therapy
Animals
*Neuroinflammatory Diseases/drug therapy
*Aquatic Organisms/chemistry
Oxidative Stress/drug effects
Inflammation/drug therapy

@article {pmid41294911,
year = {2025},
author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG},
title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {41294911},
issn = {2079-9721},
abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

METHODS: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT[2]). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain-Eyelid Thermoregulatory Tunnel. CBIT[2] induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function.

CASE PRESENTATION: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT[2], resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming.

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.},
}

@article {pmid41294873,
year = {2025},
author = {Wang, S and Feng, Z and Wu, H and Wang, S and Qin, S and Wang, X and Zhou, F and Zheng, K and Huang, X and Liu, X},
title = {The m[6]A Modification in Neurodegenerative Disease: A Cellular Perspective.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
pmid = {41294873},
issn = {2073-4409},
support = {BK20231347//Natural Science Foundation of Jiangsu Province/ ; 81971179//National Natural Science Foundation of China/ ; Z2019035//Jiangsu Commission of Health/ ; 20KJA320004//Jiangsu Provincial Department of Education/ ; KC23242//Technology Innovation Foundation of Xuzhou City/ ; JBGS202202//Open Competition Grant of Xuzhou Medical University/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Adenosine/analogs & derivatives/metabolism/genetics ; Animals ; Neurons/metabolism ; },
abstract = {N6-methyladenosine (m[6]A) is the most abundant internal RNA modification in eukaryotes and plays a critical role in gene expression regulation by influencing RNA stability, splicing, nuclear export, and translation. Emerging evidence suggests that dysregulation of m[6]A contributes to neuroinflammation, neurotoxicity, and synaptic dysfunction-key features of neurodegenerative diseases. This review aims to examine the role of m6A modification in neurodegenerative diseases from a cell-type-specific perspective. We systematically reviewed recent studies investigating m[6]A modifications in neurons and glial cells. Data from transcriptomic, epitranscriptomic, and functional studies were analyzed to understand how m[6]A dynamics influence disease-related processes. Findings indicate that m[6]A modifications regulate neuroinflammation and immune responses in microglia, modulate astrocytic support functions, affect myelination through oligodendrocytes, and alter m[6]A patterns in neurons, impacting synaptic plasticity, stress responses, and neuronal survival. These cell-type-specific roles of m[6]A contribute to the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). Understanding m[6]A-modulated mechanisms in specific neural cell types may facilitate the development of targeted interventions for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/genetics/metabolism/pathology
*Adenosine/analogs & derivatives/metabolism/genetics
Animals
Neurons/metabolism

@article {pmid41294820,
year = {2025},
author = {Sironi, F and Parlanti, P and Margotta, C and Cassarà, J and Bonetto, V and Bendotti, C and Tortarolo, M and Cappello, V},
title = {C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
pmid = {41294820},
issn = {2073-4409},
support = {1157625//Regione Lombardia, Italy/ ; },
mesh = {Animals ; *Muscle, Skeletal/metabolism/ultrastructure/pathology ; Mice ; *C9orf72 Protein/metabolism/genetics ; *Proteostasis ; Mice, Knockout ; Mitochondria/metabolism/ultrastructure ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Autophagy ; Mitophagy ; *Homeostasis ; Male ; Ubiquitin-Protein Ligases/metabolism ; Mice, Inbred C57BL ; },
abstract = {The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.},
}

Animals
*Muscle, Skeletal/metabolism/ultrastructure/pathology
Mice
*C9orf72 Protein/metabolism/genetics
*Proteostasis
Mice, Knockout
Mitochondria/metabolism/ultrastructure
Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
Autophagy
Mitophagy
*Homeostasis
Male
Ubiquitin-Protein Ligases/metabolism
Mice, Inbred C57BL

@article {pmid41294805,
year = {2025},
author = {Xu, H and Zhou, K and Xia, L and Ren, K and Xu, Y},
title = {In-Depth Study of Low-Complexity Domains: From Structural Diversity to Disease Mechanisms.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
pmid = {41294805},
issn = {2073-4409},
support = {31972537//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Protein Domains ; Animals ; Neurodegenerative Diseases/metabolism ; Intrinsically Disordered Proteins/chemistry/metabolism ; },
abstract = {Low-complexity domains (LCDs) are protein regions characterized by a simple amino acid composition and low sequence complexity, as they are typically composed of repeats or a limited set of a few amino acids. Historically dismissed as "garbage sequences", these regions are now acknowledged as critical functional elements. This review systematically explores the structural characteristics, biological functions, pathological roles, and research methodologies associated with LCDs. Structurally, LCDs are marked by intrinsic disorder and conformational dynamics, with their amino acid composition (e.g., G/Y-rich, Q-rich, S/R-rich, P-rich) dictating structural tendencies (e.g., β-sheet formation, phase separation ability). Functionally, LCDs mediate protein-protein interactions, drive liquid-liquid phase separation (LLPS) to form biomolecular condensates, and play roles in signal transduction, transcriptional regulation, cytoskeletal organization, and nuclear pore transportation. Pathologically, LCD dysfunction-such as aberrant phase separation or aggregation-is implicated in neurodegenerative diseases (e.g., ALS, AD), cancer (e.g., Ewing sarcoma), and prion diseases. We also summarize the methodological advances in LCD research, including biochemical (CD, NMR), structural (cryo-EM, HDX-MS), cellular (fluorescence microscopy), and computational (MD simulations, AI prediction) approaches. Finally, we highlight current challenges (e.g., structural heterogeneity, causal ambiguity of phase separation) and future directions (e.g., single-molecule techniques, AI-driven LCD design, targeted therapies). This review provides a comprehensive perspective on LCDs, illuminating their pivotal roles in cellular physiology and disease, and offering insights for future research and therapeutic development.},
}

Humans
Protein Domains
Animals
Neurodegenerative Diseases/metabolism
Intrinsically Disordered Proteins/chemistry/metabolism

@article {pmid41294799,
year = {2025},
author = {Medigovic, G and Rachamala, HK and Dutta, SK and Pal, K},
title = {Structural and Functional Perspectives of Optineurin in Autophagy, Immune Signaling, and Cancer.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
pmid = {41294799},
issn = {2073-4409},
support = {W81XWH-21-1-0678//Department of Defense Congressionally Directed Medical Research Program/ ; R56HL160545//The National Heart, Lung, and Blood Institute/ ; },
mesh = {Humans ; *Autophagy ; *Neoplasms/immunology/metabolism/pathology ; *Membrane Transport Proteins/chemistry/metabolism ; *Signal Transduction ; *Cell Cycle Proteins/chemistry/metabolism ; Animals ; *Transcription Factor TFIIIA/metabolism/chemistry/genetics ; },
abstract = {Optineurin (OPTN) is a multifunctional adaptor protein that regulates diverse cellular processes, including inflammatory signaling, autophagy, vesicular trafficking, and immune responses. This multifaceted role of OPTN is made possible by the presence of a complex structure comprising multiple domains that interact with different proteins to exert various functions important for modulating key signaling processes. Mutations in OPTN are linked with several human pathologies including glaucoma, Paget's disease of bone, Crohn's disease, and neurodegenerative diseases such as amyotrophic lateral sclerosis, and dementia. Emerging evidence suggests that OPTN has a complex and context-dependent role in cancer biology as well. It is upregulated in pancreatic ductal adenocarcinoma and hepatocellular carcinoma but downregulated in lung and colorectal cancers, indicating its dual role as a potential oncogene or tumor suppressor depending on the cellular environment. Additionally, OPTN plays a critical role in preventing immune evasion in colorectal cancer by maintaining interferon-gamma receptor 1 (IFNGR1) expression and supporting dendritic cell-mediated T-cell priming, thereby enhancing antitumor immune responses. Despite its significance in oncogenic pathways and immune regulation, the therapeutic potential of targeting OPTN in cancer remains largely unexplored. This review aims to provide a comprehensive understanding of OPTN's pleiotropic functions, highlighting its role in autophagy, inflammation, immune surveillance, and cancer progression. By elucidating its diverse regulatory mechanisms, we seek to encourage further research into the therapeutic implications of OPTN in cancer treatment and immunotherapy.},
}

Humans
*Autophagy
*Neoplasms/immunology/metabolism/pathology
*Membrane Transport Proteins/chemistry/metabolism
*Signal Transduction
*Cell Cycle Proteins/chemistry/metabolism
Animals
*Transcription Factor TFIIIA/metabolism/chemistry/genetics

@article {pmid41294352,
year = {2025},
author = {Aradhye, PD and Mandal, S and Gray, RD and Campbell, CJ},
title = {Adaptive Physics-Aware Raman Baseline Correction with Machine Learning Predicted Parameters.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c05185},
pmid = {41294352},
issn = {1520-6882},
abstract = {Accurate baseline correction is critical for reliable Raman spectral interpretation. Traditional algorithmic methods often require manual tuning of regularization parameters, while recent machine learning and neural network approaches automate correction but lack generalizability and user control. We have developed a new approach to baseline correction which adaptively resolves baseline distortions without manual intervention - DIRAS (Dynamic Iterative Reweighted Autoregressive Spectral baseline correction). DIRAS uses a fixed regularization parameter (λ), which performs robust batch correction by iteratively reweighting residuals. We further used Structural Similarity Index Measure (SSIM) as an objective for λ optimization and trained a deep learning model to learn the nonlinear mapping between raw spectral features and optimal regularization. The resulting framework (DIRAS+) was capable of real-time spectrum-specific λ prediction. Applied to two SERS data sets, DIRAS+ outperformed ALS and SEALS in preserving peak fidelity, reducing intraclass variability and minimizing baseline distortion. Importantly, in downstream chemometric workflows, DIRAS improved calibration and model performance, yielding lower errors and enhancing analytical sensitivity. DIRAS and DIRAS+ together provide robust, scalable, and user-adaptable solutions for high-throughput Raman spectroscopy applications.},
}

@article {pmid41294071,
year = {2025},
author = {Khan, H and Khan, MM},
title = {Extending the Interpretation of Biomarker Dynamics in SOD1-ALS Proteomics.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78089},
pmid = {41294071},
issn = {1531-8249},
}

@article {pmid41293946,
year = {2025},
author = {Xue, X and Xu, X and Lin, X and Wang, G and Dong, H},
title = {Optimizing the Diagnostic Assessment of Left Ventricular Noncompaction Cardiomyopathy: The Clinical Value of Cardiac Magnetic Resonance Imaging.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056440144251119065016},
pmid = {41293946},
issn = {1573-4056},
abstract = {INTRODUCTION: The current diagnostic criteria for noncompaction of the ventricular myocardium (NVM) remain inconsistent, and comprehensive cardiac magnetic resonance (CMR) imaging data on the disease are limited. Therefore, the purpose of this study is to evaluate the clinical utility of CMR imaging in the diagnosis and functional assessment of patients with NVM.

MATERIALS AND METHODS: Twenty patients with NVM and twenty age- and sex-matched healthy controls (HC) underwent comprehensive CMR imaging. Postprocessing software was used to quantify left ventricular longitudinal strain, both global longitudinal strain (GLS) and strain in the basal, middle, and apical segments (BLS, MLS, and ALS, respectively). Statistical analyses were performed to assess group differences.

RESULTS: Compared with the HC group, patients with NVM presented significantly increased left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), and myocardial mass index (LVMI) and a significantly reduced left ventricular ejection fraction (LVEF) (all P < 0.001). All NVM patients presented prominent trabeculations and deep intertrabecular recesses in the left ventricle during diastole. Cine imaging revealed direct blood flow communication between the recesses and the ventricular cavity. The myocardium exhibited a thin compacted outer layer (C) and a thickened noncompacted inner layer (NC), with an average NC/C ratio of 2.8 ± 0.5. For these patients, NVM primarily involved the apical and adjacent mid-ventricular free wall segments; in five patients, it also involved the basal segment. Right ventricular noncompaction was observed in five patients, and apical ventricular aneurysms were identified in two patients. Compared with the HC group, the NVM group presented a significantly lower ALS (P < 0.05); however, the BLS, MLS, and GLS values were not significantly different between the groups (P > 0.05).

DISCUSSION: Our study demonstrated the feasibility of using CMR imaging to quantitatively assess left ventricular systolic function in NVM patients. The choice of longitudinal strain as a primary parameter was driven by the fact that NVM predominantly affects the endocardial myocardium, particularly the subendocardial fibers, which are primarily longitudinal. As such, longitudinal strain is particularly sensitive for detecting myocardial contractile dysfunction in NVM. Our results indicated that ALS apical longitudinal strain is a more significant marker of contractile dysfunction in NVM than MLS, which was not significantly altered in NVM patients relative to HCs.

CONCLUSION: CMR imaging offers robust diagnostic capabilities for patients with NVM and, when combined with feature tracking, allows the quantitative assessment of left ventricular systolic function. The ALS may serve as a sensitive marker of early myocardial dysfunction and may be clinically important in guiding timely diagnosis and intervention.},
}

@article {pmid41293411,
year = {2025},
author = {Yang, D and Zhou, J and Zhao, Y and Nasb, M},
title = {Tuina combined with Riluzole in amyotrophic lateral sclerosis: protocol for a randomized controlled trial with clinical outcomes and synaptic PET biomarkers.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1705466},
pmid = {41293411},
issn = {1664-2295},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration, leading to severe functional decline and limited therapeutic options. While current pharmacological interventions such as Riluzole offer only modest benefits, there is a growing imperative to explore complementary rehabilitation strategies. Preclinical and neuroimaging evidence suggests that Tuina, a traditional Chinese manual therapy, may influence synaptic plasticity and integrity, offering a biologically reasonable mechanism for therapeutic benefit.

METHODS: This randomized controlled trial, approved by the Ethics Committee of Hubei Provincial Hospital of Traditional Chinese Medicine (Approval No. HBZY2022-C42-01), will use a 1:1:1 allocation to enroll 135 participants. Participants will be assigned to: (i) Tuina therapy plus oral Riluzole, (ii) sham Tuina plus oral Riluzole, or (iii) Riluzole alone. Interventions will last for 1 year. The primary outcome is the change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Secondary outcomes include manual muscle test (MMT), modified Ashworth scale (MAS), forced vital capacity (FVC), vital capacity (VC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio, peak expiratory flow (PEF), maximal voluntary ventilation (MVV), and ALS Assessment Questionnaire (ALSAQ-40). Outcomes will be assessed at baseline, 4 weeks, and every 6 months up to 24 months. A mechanistic substudy will employ presynaptic Synaptic vesicle protein 2A (SV2A) PET imaging to quantify synaptic changes associated with Tuina intervention.

DISCUSSION: This study is designed to evaluate the clinical efficacy of Tuina therapy combined with Riluzole and to investigate its potential to modulate synaptic integrity in patients with ALS. The findings are expected to provide evidence for integrating Tuina as an adjunctive, non-pharmacological therapy into comprehensive ALS management, linking functional improvements to underlying synaptic mechanisms.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn, identifier ChiCTR2300068650.},
}

@article {pmid41292965,
year = {2025},
author = {Zhang, Q and Liu, M and Fan, X and Chin, N and Xu, Y and Suh, J and Amniouel, S and Linask, K and Zou, J and Hafner, M and Ma, L and Zheng, W and Ye, Y},
title = {A human forebrain organoid model phenocopies dysregulated RNA and protein homeostasis in ALS/FTD-associated TDP-43 proteinopathies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.09.687455},
pmid = {41292965},
issn = {2692-8205},
abstract = {BACKGROUND: TAR DNA-binding protein 43 (TDP-43) proteinopathy is a central hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet current experimental models fail to reproduce the full pathological spectrum without external stress or TDP-43 overexpression. This study aims to establish a human induced pluripotent stem cells (iPSC)-derived system that spontaneously manifests TDP-43 pathology driven by an ALS-associated TDP-43 mutation.

METHODS: We generated forebrain 3-D organoid cultures from iPSC carrying the TDP-43 K181E patient mutation. Single-cell RNA sequencing was used to define transcriptional alterations across cell types, and enhanced crosslinking immunoprecipitation (eCLIP) was applied to examine the global RNA binding and splicing defects in mutant organoids. We further used immunostaining, RT-PCR and biochemical assays to confirm TDP-43 proteinopathy and validate findings from the multi-omics analyses.

RESULTS: The TDP-43 K181E organoids recapitulated key disease features, including cytoplasmic p-TDP-43 accumulation, RNA dysregulation, and cryptic exon inclusion. Single-cell analysis revealed a population of immature neurons with enhanced neuroinflammation and altered translation capacity. Comparative transcriptomics showed that the ALS mutation-induced transcriptional changes strongly overlap with those in ALS patient-derived brains. eCLIP analysis showed that mutant TDP-43 exhibited altered RNA-binding specificity, resulting in widespread RNA mis-splicing and cryptic exon inclusion. RT-PCR confirmed PRDM2 , a gene regulating cell senescence, is mis-spliced in mutant cells. These defects collectively disrupt neuronal homeostasis and cell-cell communications.

CONCLUSIONS: Our iPSC-derived forebrain organoid model displays spontaneous TDP-43 proteinopathies and associated molecular dysfunctions without artificial manipulation. The model offers a robust platform for dissecting the mechanisms of TDP-43-mediated neurodegeneration and advancing therapeutic discovery in ALS and FTD.},
}

@article {pmid41292773,
year = {2025},
author = {Linsenmeier, M and Shinn, MK and Mumford, TR and Liu, V and Bugaj, LJ and Pappu, RV and Shorter, J},
title = {Nuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.14.688546},
pmid = {41292773},
issn = {2692-8205},
abstract = {RNA-binding proteins (RBPs) with prion-like domains, including FUS, hnRNPA1, and hnRNPA2, assemble into functional, metastable condensates that organize ribostasis, but can also transition into self-templating fibrils implicated in neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS). How nuclear-import receptors (NIRs) antagonize this pathological transition has remained unresolved. Here, we establish that NIRs regulate the phase behavior of prion-like cargos by remodeling the dilute phase. Quantitative analyses across length scales reveal that Karyopherin-β2 (Kapβ2) preferentially binds cargo in the dilute phase to lower the effective concentration of free RBPs thereby elevating the saturation concentration for phase separation and suppressing mesoscale clustering. ALS-linked FUS [P525L] , which binds Kapβ2 weakly, evades this regulation to form pathogenic assemblies. Thus, NIRs harness polyphasic linkage, the thermodynamic relationship between ligand binding and phase equilibria, to reshape the landscape of prion-like RBP assembly states, establishing a paradigm for how ATP-independent chaperones regulate phase behavior to prevent disease-linked aggregation.},
}

@article {pmid41292721,
year = {2025},
author = {Buchholz, HE and Martin, SA and Dorweiler, JE and Prosser, DC and Sontag, EM and Manogaran, AL},
title = {Stress granules and protein aggregates reveal intracellular resource competition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.08.687377},
pmid = {41292721},
issn = {2692-8205},
abstract = {Stress granules are biomolecular condensates that form in response to environmental stress and disassemble once normal conditions are restored. However, when disassembly fails, stress granules can persist and solidify. While stress granule solidification has been well documented, the cellular mechanisms underlying the transition from reversible to persistent stress granules remain unclear. Persistent stress granules can seed the formation of pathological aggregates, such as TDP-43 in amyotrophic lateral sclerosis [1, 2] . Although amyloid and tau aggregates are hallmarks of Alzheimer's disease, a subset of patients also develop TDP-43 deposits, suggesting a possible role for stress granule solidification in Alzheimer's disease progression [3-5] . Despite theoretical models explaining why persistence and ensuing solidification occurs, strong in vivo evidence is lacking [6] . Here we show that competition for limited chaperone resources drive stress granule persistence. In the presence of TDP-43 aggregates or yeast amyloid proteins called prions, stress granule disassembly is slowed or halted disassembly. Using yeast prions as a model, we show that the addition of chaperones, specifically the AAA+ ATPase molecular chaperone, Hsp104, resulted in resumption of stress granule disassembly. Our results demonstrate that the competition for shared resources, such as molecular chaperones, can limit stress granule disassembly. We suspect that the presence of pathological aggregates results in resource competition within the aging brain, contributing to the persistence of stress granules and their subsequent solidification and aggregation.},
}

@article {pmid41292426,
year = {2025},
author = {Menta, BW and Schueddig, E and Ranjan, A and Li, Y and Andrews, SJ and Wilkins, HM and Pei, D and Swerdlow, RH},
title = {MtDNA-depleted neuronal cell transcriptomes reveal Alzheimer's disease-related changes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70929},
doi = {10.1002/alz.70929},
pmid = {41292426},
issn = {1552-5279},
support = {P30AG072973//The University of Kansas Alzheimer's Disease Research Center/ ; P30 GM122731/GM/NIGMS NIH HHS/United States ; S10OD021743//An NIH S10 High End Instrumentation award/ ; UL1TR002366//The KUMC Frontiers CTSA/ ; P30 CA168524/CA/NCI NIH HHS/United States ; P20 GM130423/GM/NIGMS NIH HHS/United States ; //The KUMC Neurological & Rehabilitation Sciences Training Program: NIHCHD T32HD057850/ ; //The Institute for Neurological Discoveries Mabel A. Woodyard Memorial Fellowship Fund/ ; //The KU Institute for Neurologic Discoveries/ ; //The Clune Family Foundation/ ; //The Ruble Family Foundation/ ; //The Snyder Family Foundation/ ; //The Stop Alzheimer's Now Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *DNA, Mitochondrial/genetics ; *Transcriptome/genetics ; *Neurons/metabolism ; Sequence Analysis, RNA ; Cell Line, Tumor ; },
abstract = {INTRODUCTION: We determined whether mitochondrial DNA (mtDNA) depletion induced Alzheimer's disease (AD)-relevant transcription changes.

METHODS: Following RNA sequencing (RNA-seq), we identified differentially expressed genes (DEGs) between SH-SY5Y or NT2 mtDNA-depleted (ρ0) and intact (ρ+) cell lines and quantified concordant DEG changes. Gene set enrichment analysis and over-representation analysis were used to determine the impact on the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD and other neurodegenerative disease pathways, ascertain pathway and term enrichment in the Reactome and Gene Ontology databases, and generate Ingenuity Pathway Analysis z-scores.

RESULTS: Relative to their ρ+ comparators, ρ0 lines differentially expressed >75% of their genes. The KEGG AD pathway was significantly enriched, and equivalently altered genes ranked the AD, Parkinson's disease, ALS, and Huntington's disease KEGG pathways among the most enriched gene sets. AD-related enriched pathways and terms reflected lipid, insulin signaling, synapse, inflammation/immune response, endosome/endocytosis, RNA, and proteostasis biology.

CONCLUSION: MtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena.

HIGHLIGHTS: MtDNA-depleted neuronal cell lines reshuffle nuclear gene expression. The KEGG AD pathway is enriched with DEGs. Transcription-defined pathways and terms relating to AD biology broadly change.},
}

Humans
*Alzheimer Disease/genetics/metabolism
*DNA, Mitochondrial/genetics
*Transcriptome/genetics
*Neurons/metabolism
Sequence Analysis, RNA
Cell Line, Tumor

@article {pmid41291690,
year = {2025},
author = {Mac Conghail, L and Parker, S and Matthews, A and Burke, S},
title = {Examining the roles, relationships and power dynamics shaping universal health system policy processes in high- and upper-middle-income countries: a scoping review.},
journal = {BMC health services research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12913-025-13773-8},
pmid = {41291690},
issn = {1472-6963},
support = {SPHeRE/2018/1/HRBI_/Health Research Board/Ireland ; },
abstract = {BACKGROUND: Policies for universal health systems aim to provide equitable access to quality healthcare. However, achieving this remains a complex goal in high and upper-middle-income countries. Despite widespread efforts, universal health system reforms vary significantly, shaped by historical, political, and economic contexts. Understanding the policy process, including the roles of various actors and institutions, is essential to improving policy effectiveness and achieving equitable health systems. This scoping review examines the literature on policy processes, stakeholder influences, and contextual factors shaping policies for universal health system reforms.

METHODS: A systematic search of peer-reviewed and grey literature from 2014 to 2024 was conducted using five academic databases and Google Scholar. Seventy-four studies focused on policies for universal health systems in high and upper-middle-income countries. Data was examined in two phases. First, a descriptive analysis explored the geographic and economic contexts of the studies and their representation across stages of the policy cycle, including agenda-setting, formulation, adoption implementation, and evaluation. Topp et al.'s framework was then used to examine the influence of key actors, focusing on their relationships, power sources, and societal expressions of power.

RESULTS: The review revealed significant geographical disparities, representing only 30% of eligible countries. Most studies focused on early policy stages, with limited attention to implementation and evaluation. A predominance of qualitative research facilitated contextual insights, yet the underrepresentation of quantitative and mixed methods approaches restricted opportunities for integrated analysis. Crises and ideological shifts were drivers of policy momentum, catalysing changes in universal health system reforms. Governments played a central role, supported or contested by civic groups, professional associations, and academia. Media often influenced public discourse and policy perceptions, amplifying or challenging reform narratives. Persistent challenges included fragmented systems, equity-efficiency tensions, and definitional ambiguities, undermining policy coherence and sustainability.

CONCLUSIONS: The review underscores the need for a broader 'universal' framework for understanding health system reform and prioritising equity, quality, and sustainability. Adaptive health systems, robust institutions, and standardised frameworks to address political, economic, and ideological barriers are crucial. Future research must evaluate equity impacts, refine policy design, and explore mechanisms to align reforms with universal health system principles and goals.},
}

@article {pmid41291238,
year = {2025},
author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y},
title = {Chemical strategies for brain delivery of genomic therapy.},
journal = {Nature reviews. Chemistry},
volume = {},
number = {},
pages = {},
pmid = {41291238},
issn = {2397-3358},
abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.},
}

@article {pmid41290864,
year = {2025},
author = {Kaur, P and Singh, G and Kaur, K and Kaur, N and Kumar, R and Bhullar, MS},
title = {Nanoemulsion of Apium graveolens essential oil as a natural pre-emergent herbicide.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41963},
pmid = {41290864},
issn = {2045-2322},
mesh = {*Oils, Volatile/pharmacology/chemistry ; *Herbicides/pharmacology/chemistry ; Emulsions/chemistry ; *Apium/chemistry ; Germination/drug effects ; Limonene ; },
abstract = {Essential oils (EOs) are recognized for their potential as environmentally compatible alternatives to synthetic herbicides, often associated with a reduced risk of resistance development. However, their practical application faces challenges such as volatility and inconsistent efficacy. To address these limitations and enhance herbicidal potential, nanoemulsions (NEms) of Apium graveolens L. EO (celery) were formulated and assessed for their efficacy against Phalaris minor Retz. biotypes resistant (R) and sensitive (S) to ALS and ACCase-inhibiting herbicides, as well as Avena ludoviciana Durieu. The EO of A. graveolens had 37 compounds, with limonene (76.95%) as the main one. In the Petri plate bioassay emulsion of A. graveolens EO completely inhibited the germination of R and S P. minor biotypes and A. ludoviciana at 0.1%w/w. The individual components, R (+) limonene, S (-) limonene and their binary mixtures were less effective and reduced the germination of R and S P. Minor biotype and A. ludoviciana at comparatively higher concentrations. Individual components at concentration of 3 to 4%w/w were also toxic to Triticum aestivum. NEm of effective EO concentrations were fabricated by high frequency ultrasonic method and a phase diagram was mapped. The physicochemical properties indicated the formation of isotropic oil-in-water NEm. Transmission electron microscopy (TEM) and Dynamic Light scattering (DLS) studies indicated spherical nature of droplets with an average size > 21 nm. The prepared formulations were stable to storage as well as external forces. Emulsion and NEms each prepared at 0.05 and 0.1% w/w. A. graveolens EO concentrations completely inhibited the germination of R and S P. minor biotypes and A. ludoviciana by altering the physiological processes such as reduction in seed imbibition by 20% to 40% and causing up to a 13% increase in membrane leakage, without having adverse effects on T. aestivum.},
}

*Oils, Volatile/pharmacology/chemistry
*Herbicides/pharmacology/chemistry
Emulsions/chemistry
*Apium/chemistry
Germination/drug effects
Limonene

@article {pmid41290422,
year = {2025},
author = {Morena, J and Hiana, J and Naum, R and Juel, V},
title = {Mills' syndrome and myasthenia gravis: a case report.},
journal = {Neuromuscular disorders : NMD},
volume = {},
number = {},
pages = {106280},
doi = {10.1016/j.nmd.2025.106280},
pmid = {41290422},
issn = {1873-2364},
abstract = {A 50-year-old man with hypothyroidism was referred for refractory myasthenia gravis (MG). He developed progressive, painless right-sided shoulder and leg weakness, dysphagia, and fatigable diplopia. Acetylcholine receptor (AChR) antibodies were positive. Immunosuppressive therapies provided only transient improvement in oculo-bulbar symptoms, while hemiparesis progressed. Examination showed fatigable ptosis with curtain sign, vertical gaze limitation, and diplopia localizing to left lateral rectus weakness. Upper motor neuron signs included brisk masseteric reflex, right spastic hemiparesis, and hyperreflexia. EMG demonstrated chronic reinnervation in right cervical and lumbosacral regions. MRI revealed T2 hyperintensity in the left upper cervical cord and adjacent medulla without enhancement. A diagnosis of AChR+ MG and Mills' syndrome was made. While MG has previously been reported to coexist with ALS, this is the first known case associated with Mills' syndrome. This highlights the importance of recognizing overlapping autoimmune and neurodegenerative disorders and the need for further research into shared mechanisms.},
}

@article {pmid41289739,
year = {2025},
author = {Dakroub, F and Awada, B and Abdelhady, S and Shaito, AA and Eid, AH and Walker, J and Mondello, S and Bondi, CO and Moro, F and Elgendy, B and Wang, KK and Zanier, ER and Mechref, Y and Kobeissy, F},
title = {Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action.},
journal = {Pharmacological reviews},
volume = {78},
number = {1},
pages = {100101},
doi = {10.1016/j.pharmr.2025.100101},
pmid = {41289739},
issn = {1521-0081},
abstract = {Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.},
}

@article {pmid41288560,
year = {2025},
author = {Jaecques, V},
title = {[Academische publicatie als toegangsticket tot het beroep: tijd voor een alternatief!].},
journal = {Tijdschrift voor psychiatrie},
volume = {67},
number = {9},
pages = {488-489},
pmid = {41288560},
issn = {0303-7339},
}

@article {pmid41287956,
year = {2025},
author = {Bennetts, SL and Pepin, G and Lucas, JJ},
title = {A Reflexive Narrative of Co-Design Within a Regional Mental Health Service in Victoria, Australia.},
journal = {International journal of mental health nursing},
volume = {34},
number = {6},
pages = {e70178},
doi = {10.1111/inm.70178},
pmid = {41287956},
issn = {1447-0349},
support = {//Deakin University/ ; },
mesh = {Humans ; *Mental Health Services/organization & administration ; Victoria ; Quality Improvement ; },
abstract = {There has been a growing emphasis on co-design practices that enable health service improvement. By centering lived experience and elevating the voices of those directly affected by potential service changes, co-design ensures that meaningful impact is achieved at every stage of the process. This article outlines a reflexive narrative of the co-design processes that involved mental healthcare practitioners and service users, utilised within a regional mental healthcare service from the perspective of the primary author of this paper. Key insights involved discussion around Tindall et al.'s framework of opportunities, challenges and lessons learned of the co-design process documented throughout the first author's doctoral research. This article furthers ongoing critical reflection and quality improvement of co-design processes within regional adult acute mental healthcare services.},
}

Humans
*Mental Health Services/organization & administration
Victoria
Quality Improvement

@article {pmid41287942,
year = {2025},
author = {Kimachi, T and Kowa, H},
title = {Pneumothorax During Mechanical Ventilation in Patients With Amyotrophic Lateral Sclerosis: Incidence, Risk Factors, and Impact on Survival.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70078},
pmid = {41287942},
issn = {1097-4598},
support = {JPMH23FC1008//MHLW Research on Rare and Intractable Diseases Program/ ; },
abstract = {INTRODUCTION/AIMS: Pneumothorax is a complication of mechanical ventilation (MV) in patients with amyotrophic lateral sclerosis (ALS); however, its clinical features and risk factors are not well defined. This study aimed to characterize the incidence, risk factors, and prognostic impact of pneumothorax in patients with ALS undergoing MV.

METHODS: We retrospectively analyzed clinical data from patients with ALS admitted to our center between 2014 and 2024. Patient demographics and baseline characteristics, pneumothorax occurrence, MV details, chest computed tomography (CT) findings, and survival outcomes were reviewed. We analyzed independent risk factors for pneumothorax and evaluated cumulative incidence and survival.

RESULTS: Among the 131 patients with ALS, 95 underwent MV, 19 of whom developed pneumothorax. Only low body mass index (BMI) (< 18.5 kg/m[2]; p = 0.015) was identified as an independent risk factor. The cumulative incidence rates of pneumothorax at 1, 3, 5, and 10 years after MV initiation were 4.5%, 13.4%, 24.3%, and 32.0%, respectively. The median post-pneumothorax survival was 16 months (95% confidence interval [CI]: 6-67), with no significant difference in overall survival from the time of initiation of MV between patients with and without pneumothorax (p = 0.88).

DISCUSSION: This study identified low BMI as a potential risk factor for pneumothorax in ALS patients receiving MV. However, given the limited sample size, these findings should be interpreted with caution. Larger, multicenter studies are warranted to validate this association and to further elucidate long-term pulmonary effects and preventive strategies.},
}

@article {pmid41287286,
year = {2025},
author = {Prema, SS and Shanmugamprema, D},
title = {Empowering Parent-Focused Involvement in Early Detection and Treatment of Eating Disorders.},
journal = {European eating disorders review : the journal of the Eating Disorders Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/erv.70060},
pmid = {41287286},
issn = {1099-0968},
abstract = {OBJECTIVE: To critically appraise Sidari et al.'s pilot evaluation of the Strong Foundations programme - a 6-week pre-treatment, family-centred intervention that reconceptualises the waitlist as an active window for support, and to assess whether scalable caregiver interventions can improve clinical outcomes and treatment engagement.

METHOD: Critical synthesis of the pilot study's design, implementation, and outcomes. The programme delivered structured psychoeducation to parents alongside specialist medical oversight for adolescents during the pre-treatment period. We summarise reported process and clinical indicators, assess methodological strengths and limitations, and explore adaptations such as digital delivery, peer co-facilitation and primary care integration within stepped-care frameworks.

RESULTS: Participating parents reported increased caregiving confidence and understanding of treatment pathways. Adolescents demonstrated preliminary improvements in BMI, affective symptoms and eating-disorder psychopathology. Strengths included focus on an overlooked treatment interval and integrated medical support; limitations included small sample size, absence of a control condition, selection bias, and brief follow-up. Proposed adaptations may increase scalability while preserving family-centred elements.

CONCLUSIONS: Reframing waitlists as active therapeutic intervals via brief, caregiver-focused interventions are promising for improving early outcomes, uptake and retention. Larger, controlled trials of condensed and digitally enabled formats are needed to establish effectiveness, cost-effectiveness, implementation feasibility and generalisability.},
}

@article {pmid41286450,
year = {2025},
author = {Bye, CR and Qian, E and Lim, K and Daniszewski, M and Garton, FC and Trần-Lê, BC and Liang, HH and Lin, T and Lock, JG and Crombie, DE and Morgan, S and Hu, Y and Barton, SK and Palmer, LM and Djouma, E and Kodikara, S and Lê Cao, KA and Dharmadasa, T and Henders, AK and Ziser, LA and Kiernan, MC and Talbot, K and Needham, M and Fletcher, S and Talman, P and Mathers, S and Wray, NR and Hewitt, AW and Pebay, A and Turner, BJ},
title = {Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41286450},
issn = {1546-1726},
support = {1137024//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 2021//Department of Health | National Health and Medical Research Council (NHMRC)/ ; },
abstract = {Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS.},
}

@article {pmid41286090,
year = {2025},
author = {Ariaei, A and Talebi, S and Ashtiani, BH and Hamblin, MR and Alipour Langouri, M and Ramezani, F},
title = {Distinguishing amyotrophic lateral sclerosis from radiculopathy using machine learning to analyze nerve conduction data.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41633},
pmid = {41286090},
issn = {2045-2322},
support = {1402-4-4-27191//Iran University of Medical Sciences/ ; 43008282 -0//Shahid Beheshti University of Medical Sciences/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Radiculopathy/diagnosis/physiopathology ; *Machine Learning ; Male ; Female ; Middle Aged ; Diagnosis, Differential ; *Neural Conduction/physiology ; Algorithms ; Adult ; Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, fatal, and irreversible disease that shares some key clinical features with radiculopathy, including muscle atrophy, muscle cramps, and fasciculation. The aim of this study was to find a reliable method to differentiate these two diseases. Machine learning was used to discover new clinical biomarkers for the differential diagnosis of ALS from radiculopathy using nerve conduction study (NCS) data from patients. Data preparation and feature selection were performed by a random forest classifier algorithm, as well as a confusion matrix tool for model selection. After selecting the minimum number of features and the best algorithm, grid search cross-validation was used to optimize the hyperparameters of the chosen algorithm. 77 features were ranked according to their importance. The results of 20 algorithms acting on 8 different groups of features showed that the best performance (accuracy, precision, recall, f-1 score) was obtained using 35 important features and the XGB algorithm, particularly for the recall parameter. Using the XGB algorithm, ALS patients could be identified with accuracy = 0.871, precision = 0.923, recall = 0.850, and f-1 score = 0.857. The XGB algorithm using 35 NCS features could differentiate radiculopathy from ALS in patients with high accuracy.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
*Radiculopathy/diagnosis/physiopathology
*Machine Learning
Male
Female
Middle Aged
Diagnosis, Differential
*Neural Conduction/physiology
Algorithms
Adult
Aged

@article {pmid41285384,
year = {2025},
author = {Kılıç Çil, M and Telefon, AH and Afat Turgut, E and Kandemir Gülmez, T and Çelik, Ü},
title = {[Neutrophilen-Lymphozyten-Verhältnis, mittleres Thrombozytenvolumen und Breite der Erythrozytenverteilung als Biomarker für die Diagnose: Welches Verhältnis sollte für die Vorhersage der Diagnose].},
journal = {Klinische Padiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2734-8740},
pmid = {41285384},
issn = {1439-3824},
abstract = {This study aims to evaluate the diagnostic and follow-up utility of complete blood count-derived biomarkers -neutrophil-to-lymphocyte ratio, mean platelet volume, and red cell distribution width - in pediatric tuberculosis. A total of 52 children diagnosed with tuberculosis and 55 healthy controls, followed between 2020 and 2023 at a tertiary pediatric infectious disease clinic, were retrospectively analyzed.Laboratory values were recorded at diagnosis, the second month of treatment, and at least 6 months post-treatment. Receiver operating characteristic analysis was performed to assess diagnostic performance. At diagnosis, the neutrophil-to-lymphocyte ratio and red cell distribution width levels were significantly higher in the tuberculosis group than in control group (p<0.001), while mean platelet volume showed no significant difference (p=0.096). During treatment, the neutrophil-to-lymphocyte ratio and red cell distribution width values progressively decreased. Receiver operating characteristic analysis demonstrated good diagnostic performance with optimal cut-off values of 1.7 for the neutrophil-to-lymphocyte ratio and 15.4 for the red cell distribution width. The neutrophil-to-lymphocyte ratio and red cell distribution width are accessible, cost-effective biomarkers that may support the diagnosis of tuberculosis and monitor treatment responses in children.While promising as supportive tools, the diagnostic specificity of these markers is subject to study limitations, including an age-unmatched control group. Therefore, they should be considered complementary to existing diagnostic methods, especially when microbiological confirmation is challenging in pediatric cases.},
}

@article {pmid41285343,
year = {2025},
author = {Pedde, M and Adar, SD and D'Souza, J and Feldman, EL and Goutman, SA},
title = {Air Pollution and Disease Progression in a University of Michigan Amyotrophic Lateral Sclerosis Cohort.},
journal = {Environmental research},
volume = {},
number = {},
pages = {123398},
doi = {10.1016/j.envres.2025.123398},
pmid = {41285343},
issn = {1096-0953},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, fatal, neurodegenerative disease without effective treatments. Therefore, identifying modifiable risk factors to slow disease progression is important. We aimed to identify whether air pollution may be a modifiable risk factor associated with ALS progression. We recruited patients with ALS from the University of Michigan ALS Clinic from 2009-2022. Patient functional status was assessed at clinic evaluations approximately every three months using the ALS Functional Rating Scale Revised (ALSFRS-R); the change in total ALSFRS-R score over time was used to assess disease progression. The repeated ALSFRS-R overall scores were linked to spatiotemporal prediction model estimates of 3-month and 5-year average residential exposures to fine particulate matter mass (PM2.5) and components (sulfate, nitrate, black carbon), ozone, nitrogen dioxide, and sea salt (negative control expected to be nontoxic) before baseline and each clinical assessment. We used longitudinal linear mixed-effects models to assess associations between air pollution and the rate of disease progression, using the overall ALSFRS-R score, controlling for potential confounders. Among 469 participants with 3,147 valid overall ALSFRS-R scores (44.8% female; 62+11 years at symptom onset; 3.6+2.9 years follow-up) who resided in areas with PM2.5 levels near and below US regulatory standards, average rates of decline were 11.6+24.0 ALSFRS-R points/year. In multi-pollutant models adjusted for potential confounders, one interquartile range (IQR) higher 5-year average black carbon (0.2 μg/m[3]) and nitrate (0.4 μg/m[3]) concentrations were associated with 2.4 (95% CI: -3.4, -1.4) and 1.2 (95% CI: -1.9, -0.5) ALSFRS-R points/year faster rates of decline, respectively. One IQR higher 3-month average ozone concentrations (1.4 ppb) were also associated with a faster rate of decline (-0.3 [95% CI: -0.5, -0.1] ALSFRS-R points/year). Sea salt was not associated with ALS progression. These observed differences between high and low exposure participants reflected 3-21% of the observed average annual ALSFRS-R decline.},
}

@article {pmid41283860,
year = {2025},
author = {Varline, J and Enfinger, M and Kavanaugh, MS},
title = {Mental health treatment of persons with ALS & their families: implementing an intervention to support practitioners.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/21678421.2025.2593304},
pmid = {41283860},
issn = {2167-9223},
abstract = {Objective: Given the limited education available to practitioners who provide mental health care for persons with amyotrophic lateral sclerosis (ALS) and their family members, a partnership between Mental Health America, Global Neuro YCare, and the ALS Association developed a web-based education programme providing discussions addressing ALS background, lived experience, and impact of caregiving, to increase confidence in care and access to resources when serving persons living with ALS and their caregivers. Methods: A pre/post survey was utilized to assess the webinar's impact on provider confidence in their knowledge and experience of ALS, access to ALS information and resources, and the ability to refer persons with ALS to care. The percentage change from pretest to post-test, frequency of knowledge, and qualitative analyses were conducted. Results: The findings indicated a 24% increase in practitioners' confidence in working with people with ALS and their family members, a 19% increase in providing mental health care to a family member, and a 20% increase in assessing resource information about ALS. Qualitative data highlighted several categories of responses, including increases in knowledge from the workshop, the need for individuals to be treated as more than just ALS, and a continuing need for training, and additional emotional support for practitioners. Conclusion: The online training increased confidence in providing mental health care to people living with ALS and their family members, adding to this understudied area. Still, additional research is needed to increase confidence in referring people to care, accessing information, and growing knowledge about ALS.},
}

@article {pmid41283823,
year = {2025},
author = {Alshoshan, A and Aldubaiyan, AAR and Hakami, A and Alolayyan, A and Alqurishi, M and Alhazmi, OM and Abuzinadah, AR and Alshareef, AA and Alqahtani, HM and Alanazy, MH and Bushnag, A and Alkully, H and Beck, AA and Makkawi, S and Maglan, A and Al Hashim, S and Abulaban, AA and Almasood, AA and Alnasser, OI and Alyahya, M and Alsolaihim, A and Alshehri, A and , },
title = {Amyotrophic lateral sclerosis in Saudi Arabia: a multicenter descriptive study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/21678421.2025.2582835},
pmid = {41283823},
issn = {2167-9223},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by the progressive loss of muscle control, leading to paralysis and death. While ALS has been extensively studied globally, little research has focused on ALS in the Middle East, specifically Saudi Arabia. This study aims to investigate the demographic data, clinical characteristics, disease progression, and prognosis of ALS patients in Saudi Arabia to better understand region-specific disease patterns and potential therapeutic strategies.

METHODOLOGY: Retrospective multicenter cohort across five tertiary Saudi centers (2003-2022). The authors identified cases from neurology/neuromuscular clinics and neurophysiology laboratories; diagnoses followed revised El Escorial criteria with EMG confirmation where indicated. ALS variants and cases lacking sufficient longitudinal evidence were excluded. Clinical genetic testing was performed at the clinician's discretion; variants were classified per ACMG and only pathogenic/likely pathogenic results were counted; C9orf72 repeat-expansion testing was not systematically available. Prespecified variables included demographics, family history, initial phenotype, MRI/EMG, genetics, treatments (riluzole, edaravone, SPT, tofersen for SOD1), times to noninvasive ventilation (NIV), gastrostomy and invasive ventilation.

RESULTS: We included 270 patients (57% male). Mean age at first symptom was 51 years. Limb-onset occurred in 169/247 (68%) and bulbar-onset in 78/247 (32%). Among those with documented family history (97/270), 14% reported an affected relative. 37/270 underwent genetic testing; 56.7% were positive-most commonly OPTN (47.6.6% of positives) and SOD1 (38.1%). MRI brain/spine was normal in ∼53%. By 3 years from symptom onset, ∼80% of those who eventually required advanced support (NIV, invasive ventilation, and/or gastrostomy) had received it. Most patients were treated with riluzole.

CONCLUSION: This study provides valuable insights into ALS in Saudi Arabia, contributing to a better understanding of the disease in this region. The younger age of onset and the high familial prevalence are notable findings that warrant further investigation. Future studies focusing on genetic and environmental influences in Saudi Arabia may help improve diagnosis and therapeutic approaches.},
}

@article {pmid41283496,
year = {2025},
author = {D'Alatri, L and Marchese, MR and Tizio, A and Galli, J},
title = {Pathophysiology and Etiology of Brainstem-Related Dysphagia.},
journal = {Audiology research},
volume = {15},
number = {6},
pages = {},
pmid = {41283496},
issn = {2039-4330},
abstract = {BACKGROUND: Brainstem-related dysphagia represents a complex and severe form of neurogenic dysphagia (ND) arising from lesions that disrupt the central pattern generator (CPG) for swallowing located in the medulla oblongata.

METHODS: This paper explores the physiological basis of swallowing and its disruption in various brainstem pathologies.

RESULTS: The clinical presentation and electrophysiological evaluation of dysphagia are discussed, with a focus on volitional and spontaneous swallowing (SS) and the use of electromyography (EMG)-based assessment techniques.

CONCLUSIONS: Finally, therapeutic strategies are reviewed, including conventional rehabilitative methods, neuromuscular electrical stimulation, non-invasive brain stimulation, and invasive procedures such as neurobotulinum toxin-A (BoNT-A) injections, balloon dilation, and CP myotomy.},
}

@article {pmid41283495,
year = {2025},
author = {Capobianco, S and Bastiani, L and Forli, F and Fattori, B and Stomeo, F and Russo, M and Barillari, MR and Nacci, A},
title = {Acoustic Vowel Metrics as Correlates of Dysphagia and Dysarthria in Brainstem Neurodegenerative Diseases.},
journal = {Audiology research},
volume = {15},
number = {6},
pages = {},
pmid = {41283495},
issn = {2039-4330},
abstract = {Background/Objectives: Swallowing and speech rely on shared brainstem circuits coordinating oropharyngeal motor functions. In neurodegenerative diseases affecting the brainstem-such as progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA)-bulbar dysfunction often impairs tongue propulsion and motility, affecting both swallowing (dysphagia) and phonation (dysarthria). This study aimed to investigate whether vowel-based acoustic features are associated with swallowing severity in brainstem-related disorders and to explore their potential as surrogate markers of bulbar involvement. Methods: This was a cross-sectional observational study. Thirty-one patients (13 PSP, 12 ALS, 6 MSA) underwent clinical dysarthria assessment, acoustic analysis of the first (F1) and second (F2) formants during sustained phonation of /a/, /i/, /e/, and /u/, and swallowing evaluation using standardized clinical scales (DOSS, FOIS, ASHA-NOMS) and fiberoptic endoscopic evaluation (Pooling Score, Penetration-Aspiration Scale). The vowel space area (tVSA, qVSA) and Formant Centralization Ratio (FCR) were computed. Results: Significant correlations emerged between acoustic vowel metrics and dysphagia severity, especially for liquids. The FCR showed strong correlations with DOSS (ρ = -0.660, p < 0.0001), FOIS (ρ = -0.531, p = 0.002), ASHA-NOMS (ρ = -0.604, p < 0.0001), and instrumental scores for liquids: the Pooling Score (ρ = 0.538, p = 0.002) and PAS (ρ = 0.630, p < 0.0001). VSA measures were also associated significantly with liquid swallowing impairment. F2u correlated with dysarthria severity and all liquid-related dysphagia scores. Conclusions: Vowel-based acoustic parameters, particularly FCR and F2u, reflect the shared neuromotor substrate of articulation and swallowing. Acoustic analysis may support early detection and monitoring of bulbar dysfunction, especially where instrumental assessments are limited.},
}

@article {pmid41283303,
year = {2025},
author = {Bartoshyk, P and O'Caoimh, R},
title = {Update on Disease-Modifying Pharmacological Treatments for Frontotemporal Dementia (FTD): A Scoping Review of Registered Trials.},
journal = {NeuroSci},
volume = {6},
number = {4},
pages = {},
pmid = {41283303},
issn = {2673-4087},
abstract = {Frontotemporal dementia (FTD) represents a cluster of adult-onset neurodegenerative diseases resulting from a combination of genetic and epigenetic factors. Currently, treatment is symptomatic and there are no licensed disease-modifying therapies available. The aim of this review was to provide an overview of ongoing or recently completed clinical studies targeting disease modification in FTD. A structured search of interventional trials of pharmacological compounds was conducted on three clinical trial registries (National Library of Medicine Clinical Trials, European Union Clinical Trials, and the Australian New Zealand Clinical Trials registries) up to September 2025. Twelve interventional trials were found. Half targeted autosomal-dominant progranulin (GRN) mutations (n = 6) and half examined therapies targeting neuroinflammatory-induced sporadic FTD (n = 6). The interim results of the early-phase (1/2) randomized controlled trials (RCTs), comprising three ongoing gene replacement studies (PROCLAIM, ASPIRE-FTD, upliFT-D) and one immune-modulating monoclonal antibody (INFRONT, now in phase 3)-all targeting the FTD-GRN mutation-show safety, tolerability, and effectiveness in restoring progranulin levels. Two recently completed phase 2 RCTs for sporadic FTD targeting neuroinflammation, the PEA-FTD and C9orf72 ALS/FTD trials, show disease-modifying potential. While interim results from six trials suggest clear mechanistic efficacy, prospective high-quality later-phase RCTs are required to ascertain long-term clinical efficacy. Since familial FTD encompasses less than half of the people with this disease, it is important to continue exploring the underlying pathophysiology, neuroimmunology, and treatment of epigenetic-induced sporadic FTD.},
}

@article {pmid41283146,
year = {2025},
author = {Chen, BP and Lee, CC and He, RY and Huang, AC and Huang, JR and Chan, JCC and Huang, JJ},
title = {Amyloidogenic oligomers derived from TDP-43 LCD promote the condensation and phosphorylation of TDP-43.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {41283146},
issn = {2041-6520},
abstract = {The aberrant aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS). While TDP-43 aggregation can occur via both classical amyloidogenesis and phase separation-mediated mechanisms, the role of amyloidogenic oligomers in modulating TDP-43 condensation remains unclear. Herein, we employ a reverse micelle method to prepare uniform oligomers derived from the low-complexity domain of TDP-43, termed D1core oligomers. These amyloidogenic oligomers are toxic, potently induce phase separation of recombinant TDP-43 C-terminal domains, and promote phosphorylation of cytosolic TDP-43 condensates in cells. Compared to monomeric or fibrillar forms, D1core oligomers uniquely enhance the condensation propensity of wild-type TDP-43 and further potentiate aggregation of the ALS-associated A315T mutant. Live-cell studies using fluorescence recovery after photobleaching reveal that oligomer-induced condensates are modulated by HSP70, which preserves their liquid-like properties. These findings provide new insights into the interplay between TDP-43 oligomers, phase separation, and aggregation, advancing our understanding of ALS-related proteinopathy.},
}

@article {pmid41282964,
year = {2025},
author = {Nachammai, KT and Sangavi, P and Sekar, C and Sangeetha, and Kulanthaivel, L},
title = {Targeting the core: C9ORF72 antagonists as pioneers in amyotrophic lateral sclerosis therapy-a computational and machine learning based approach.},
journal = {In silico pharmacology},
volume = {13},
number = {3},
pages = {188},
pmid = {41282964},
issn = {2193-9616},
abstract = {Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is a neurodegenerative condition characterized by the gradual deterioration of motor neurons in the brain and spinal cord, leading to muscle weakness, difficulty swallowing, speaking, and breathing. The normal ageing process has structural and functional effects on motor neurons, which may contribute to motor neuron pathology in ALS, either directly or indirectly. Although there are a few treatments available for ALS, their efficacy is limited. The objective of this study is to identify and screen potential C9ORF72 Agonists using High Throughput Virtual screening and Molecular Dynamics simulations. Using Edaravone and Riluzole as benchmark molecules, the study evaluated various chemical compounds from different databases against the target. Lead compounds from three databases (Specs_1289, Zinc_67912153 and Enamine_785152) showed binding affinity, stability and pharmacokinetic greater activity which is achieved through ML based tool; concluding that they could be used as a potential agonist for ALS-associated C9ORF72. The complexes have the highest docking scores of - 8.21, - 11.06, and - 6.934 kcal/mol with the lowest binding energy which aids the structural stability of the complex. HOMO and LUMO occupancy of the lead compounds deciphers the energy levels of the compounds with the lowest energy gap which was favorable for the chemical reactivity and chemical inertness of the molecule. Furthermore, ADME and Toxicity analysis of the compounds were evaluated through Machine Learning based tool, pkCSM. MD simulation concluded that the lead complexes showed lesser deviation and fluctuations with the higher number of hydrogen bond interactions which favors the structural stability and biological activity of the complex. This study concluded that the resultant leads from three different chemical libraries were considered as the potential therapeutic option for targeting ALS.},
}

@article {pmid41282495,
year = {2025},
author = {Araújo, B and Serrenho, I and Valente da Silva, A and Marceta, BM and Baltazar, G},
title = {Mesenchymal stem cells in neurological disorders: Insights from clinical trials.},
journal = {Regenerative therapy},
volume = {30},
number = {},
pages = {1024-1035},
pmid = {41282495},
issn = {2352-3204},
abstract = {Mesenchymal stem cells (MSCs) exhibit unique properties that make them promising candidates for cell therapy, particularly in neurological disorders. They can be derived from various tissues, with bone marrow, adipose tissue, umbilical cord, and placenta being the most common sources. Evidence suggests that the tissue of origin significantly influences MSC characteristics, including secretome composition, proliferation rate, and adhesion capacity. Clinical trials have demonstrated the safety and therapeutic potential of MSCs in conditions such as spinal cord injury, multiple sclerosis, and stroke. MSC therapy has been associated with improvements in motor, sensory, and cognitive functions, as well as enhanced quality of life. Mechanistically, MSCs promote neuroprotection, reduce inflammation, and modulate immune responses. In spinal cord injury, intrathecal administration of adipose- and bone marrow-derived MSCs has led to significant functional recovery, with single high-dose treatments often yielding better outcomes than multiple lower doses. In amyotrophic lateral sclerosis, bone marrow-derived MSCs have shown potential in slowing disease progression, though higher doses do not always result in greater benefits. In multiple sclerosis, high doses of umbilical cord-derived MSCs improved quality of life and prevented disease progression, whereas lower doses of bone marrow-derived MSCs provided limited functional benefits. While MSC therapy is considered safe, patient responses vary, and a definitive correlation between administered dose and therapeutic effects remains elusive. The small number of studies using comparable protocols impedes comparison of other relevant factor, limits the drawing of conclusions and underscore the importance of developing standardized protocols to optimize MSC-based treatments and maximize their clinical efficacy.},
}

@article {pmid41282267,
year = {2025},
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 to Revealing Proteins Associated with Oligomeric Alpha-Synuclein During Aggregation.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7697442/v1},
pmid = {41282267},
issn = {2693-5015},
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 the aggregation processes, cells expressing a synuclein-biotin ligase fusion protein were treated 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 important phosphorylation mechanisms, connections to insulin processing, and a potential interaction with ALS-associated FUS. Interestingly, we identified 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 {pmid41281542,
year = {2025},
author = {Wang, X},
title = {Childhood trauma and parenting in at-risk mental state: Clarifying pathways and expanding perspectives.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {112624},
pmid = {41281542},
issn = {2220-3206},
abstract = {Jovani et al's study contributes important evidence linking childhood trauma (CT) and parental socialization with at-risk mental state (ARMS) in non-clinical adolescents, demonstrating the mediating role of low levels of parental affection and communication in this relationship. This letter commends the study's strengths while also identifying key issues that warrant further attention, including the limitations of cross-sectional design, potential perceptual biases, conceptual overlap between CT and parenting, and limited cultural generalizability. We advocate for longitudinal, culturally sensitive, and multi-informant approaches to further refine ARMS risk models, strengthen theoretical distinctions between CT and parenting, and inform targeted prevention strategies across diverse populations. We also extend the discussion by highlighting promising directions for future research.},
}

@article {pmid41281507,
year = {2025},
author = {Lucke-Wold, B and Salam, HD and Karayi, G},
title = {Behavioral analysis of insomnia sufferers to acupuncture treatment.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {108630},
pmid = {41281507},
issn = {2220-3206},
abstract = {In this commentary, we respond to Zhao et al's recent paper which focuses on mechanisms underlying insomnia sufferers' engagement with acupuncture. Insomnia, a prevalent condition characterized by difficulty falling asleep and poor sleep quality, is associated with increased risk of cardiovascular disease, diabetes, and psychiatric illness. Acupuncture, a method involving the therapeutic placement of needles, has been widely accepted as a treatment for insomnia with minimal side effects. In fact, clinical trials suggest auricular acupuncture may improve sleep duration more than cognitive behavioral therapy. However, responses to acupuncture vary. Some patients find it extremely beneficial, while others view it as a routine treatment-or avoid it altogether due to needle phobia. Patient engagement is influenced by cultural beliefs, encouragement, motivation, prior experiences, and recommendations from peers or clinicians. Trust in the physician and testimonials from recovered patients are particularly important facilitators. Looking ahead, a holistic approach - integrating acupuncture with meditation, pranayama, yoga, and other restorative practices - may enhance treatment effectiveness and help patients achieve restorative sleep.},
}

@article {pmid41281478,
year = {2025},
author = {Kumar, S},
title = {Artificial intelligence powered radiomics model for the assessment of colorectal tumor immune microenvironment.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {11},
pages = {108576},
pmid = {41281478},
issn = {1948-5204},
abstract = {Zhou et al's investigation on the creation of a non-invasive deep learning (DL) method for colorectal tumor immune microenvironment evaluation using preoperative computed tomography (CT) radiomics published in the World Journal of Gastrointestinal Oncology is thorough and scientific. The study analyzed preoperative CT images of 315 confirmed colorectal cancer patients, using manual regions of interest to extract DL features. The study developed a DL model using CT images and histopathological images to predict immune-related indicators in colorectal cancer patients. Pathological (tumor-stroma ratio, tumor-infiltrating lymphocytes infiltration, immunohistochemistry, tumor immune microenvironment and immune score) parameters and radiomics (CT imaging and model construction) data were combined to generate artificial intelligence-powered models. Clinical benefit and goodness of fit of the models were assessed using receiver operating characteristic, area under curve and decision curve analysis. The developed DL-based radiomics prediction model for non-invasive evaluation of tumor markers demonstrated potential for personalized treatment planning and immunotherapy strategies in colorectal cancer patients. The study, involving a small group from a single medical center, lacks inclusion/exclusion criteria and should include clinicopathological features for valuable therapeutic practice insights in colorectal cancer patients.},
}

@article {pmid41280089,
year = {2025},
author = {Rotunno, MS and Fowler-Magaw, M and Zhong, J and O'Hara, K and Wiggin, EA and Cameron, D and Stallworth, K and Bouley, J and McEachern, H and Anadolu, MN and Nickerson, JA and Tapper, AR and Molas, S and Massi, F and Henninger, N and King, OD and Bosco, DA},
title = {TDP-43 dysfunction leads to impaired proteostasis and predisposes mice to worse neurological outcomes after brain injury.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.20.683438},
pmid = {41280089},
issn = {2692-8205},
abstract = {BACKGROUND: Pathological TAR DNA-binding protein 43 (TDP-43) dysfunction is associated with multiple neurodegenerative disorders. However, the mechanistic link between TDP-43 dysfunction and neurodegeneration is poorly understood and likely involves a combination of genetic and environmental risk factors. A major risk factor for neurodegenerative disease is exposure to traumatic brain injury (TBI). Here, we investigated the synergistic interplay between TDP-43 dysfunction and TBI in a murine model of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD).

METHODS: A model of TDP-43 dysfunction caused by a knock-in Q331K mutation in Tardbp was combined with a mild model of TBI. Control conditions included both WT mice and mice with sham surgery. Animals were evaluated for behavioral deficits at timepoints pre- and post-surgery. Additionally, post-mortem brain tissues were examined using RNA sequencing and mass spectrometry-based quantitative proteomics together with histological and biochemical analyses.

RESULTS: Expression of dysfunctional TDP-43 in vivo caused deficits in multiple branches of the proteostasis network, including protein folding, protein synthesis, and protein turnover. Examples include mis-expression of chaperones and genes within the ubiquitin-proteosome pathway in mutant TDP-43 versus WT mice. Further, mutant TDP-43 expression correlated with reduced thermostability of proteins associated with the ribosome and the chaperonin containing TCP-1 complex. In response to TBI, mutant TDP-43 mice exhibited significantly worse neurological outcomes relative to WT animals. Heightened neurological deficits in mutant TDP-43 mice following TBI coincided with a robust upregulation of proteostasis- and stress-related genes at the transcript level. However, this upregulation was not detected at the protein level.

CONCLUSIONS: Our data demonstrate that expression of dysfunctional TDP-43 leads to deficits within the proteostasis network in vivo at baseline. Despite an upregulation of proteostasis-related genes at the transcript level in mutant TDP-43 mice after TBI, mutant TDP-43 mice exhibit an impaired response to, and recovery from, brain trauma relative to their WT counterparts. Restoring proteostasis is expected to protect against the detrimental effects of TDP-43 dysfunction, especially under stress conditions that promote neurodegenerative disease.},
}

@article {pmid41280004,
year = {2025},
author = {Rao, PP and Herbert, C and Azeem, SM and Gary, E and Ho, G and Munira, R and Askarifirouzja, H and Haimovitz-Friedman, A and Mahajan, SS},
title = {Riluzole as a Dual-Targeted Radiosensitizer for Osteosarcoma: Targeting Tumor Cells and Angiogenic Vasculature to Enhance Single High Dose Radiotherapy Efficacy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.07.681036},
pmid = {41280004},
issn = {2692-8205},
abstract = {UNLABELLED: Osteosarcoma is a highly aggressive bone malignancy primarily affecting children and young adults. It presents significant treatment challenges due to its inherent resistance to conventional fractionated radiotherapy (CFRT). Single high dose radiation therapy (SDRT) has promise for the treatment of radioresistant sarcomas, especially those characterized with extensive vascularity. However, its clinical application is severely constrained by toxicity to adjacent critical tissues. Radiosensitizers can enhance tumor cell susceptibility to radiation-induced DNA damage, improving therapeutic efficacy and potentially reducing collateral toxicity. Monotherapies targeting tumor vasculature alone in solid tumors have shown limited success as radiosensitizers in clinical settings. This highlights the importance of compounds that can simultaneously target both tumor cells and its associated microvasculature to maximize the therapeutic outcome to SDRT. Riluzole, the FDA-approved drug for Amyotrophic Lateral Sclerosis, is currently under investigation as a therapeutic agent for osteosarcoma. Riluzole acts to inhibit glutamate release, reduce glutathione levels in cancer cells, and mitigate tumor angiogenesis, positioning it as a potent radiosensitizing agent for the treatment of osteosarcoma. We hypothesize that Riluzole enhances osteosarcoma radiosensitivity to SDRT by simultaneously targeting intrinsic tumor radioresistance and pro-angiogenic signaling. Our findings demonstrate that Riluzole radiosensitizes osteosarcoma cells in vitro by reducing clonogenic survival and enhancing apoptosis. Mechanistically, Riluzole potentiates irradiation-induced reactive oxygen species (ROS) production, induces G2/M phase cell cycle arrest, inhibits DNA repair, and thereby amplifies radiation-induced DNA damage. Additionally, Riluzole suppresses radiation-induced Vascular Endothelial growth factor A (VEGFA) expression indicating its ability to overcome endothelial cell mediated radioresistance. Collectively, these results establish Riluzole as a promising radiosensitizer for osteosarcoma, with the potential to improve SDRT efficacy by overcoming both tumor-intrinsic and microvasculature-mediated radioresistance.

GRAPHICAL ABSTRACT: This schematic illustrates the proposed mechanism by which Riluzole enhances SDRT efficacy in osteosarcoma by targeting both tumor cells and VEGFA-mediated pro-survival signaling in endothelial cells. Riluzole increases radiation-induced ROS levels, induces G2/M cell cycle arrest, and inhibits DNA repair in osteosarcoma cells, thereby overcoming intrinsic tumor radioresistance. It also suppresses tumor cell VEGFA expression, which may contribute to reduced pro-survival signaling in the angiogenic endothelial cells within the tumor microenvironment. Together, these effects sensitize osteosarcoma tumors to SDRT, improving therapeutic outcomes (Illustration created using BioRender (BioRender.com, 2025)).},
}

@article {pmid41279899,
year = {2025},
author = {Le, P and Lal, NK and Xu, S and Mumford, S and Huang, M and Yang, D and Mizrahi, O and Hoover, B and Yee, B and Mei, Y and Rothamel, K and Her, HL and Blue, SM and Shneider, NA and Yeo, GW},
title = {KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.31.685813},
pmid = {41279899},
issn = {2692-8205},
abstract = {UNLABELLED: Neuronal health depends on the precise transport and local translation of mRNAs to maintain synaptic function across highly polarized cellular architecture. While kinesin motor proteins are known to mediate mRNA transport, the specificity and direct involvement of individual kinesins as RNA-binding proteins (RBPs) remain unclear. Here, we demonstrate that KIF5A, a neuron-specific kinesin implicated in amyotrophic lateral sclerosis (ALS), functions as an RBP. We show that KIF5A directly binds mRNAs encoding synaptic ribosomal proteins and is required for their synaptic localization and for maintaining normal synaptic composition and function. Additionally, we show ALS-linked KIF5A mutations confer gain-of-function properties, enhancing mRNA binding, increasing synaptic ribosomal protein accumulation, inducing neuronal hyperexcitability, and impairing stress responses. These findings reveal a previously unrecognized mechanism by which mutant KIF5A disrupts synaptic homeostasis. Our work positions a kinesin motor protein as an RBP with critical roles in mRNA transport, local translation, and stress response.

HIGHLIGHTS: KIF5A interacts with mRNA encoding synaptic ribosomal proteinsKIF5A is required for normal synaptic composition and functionKIF5A binds to G3BP1 and G3BP1 stress granule associated proteinsKIF5A mutant ALS patient-derived motor neurons have abnormal synaptic function and stress response.},
}

@article {pmid40721287,
year = {2025},
author = {Vyas, J and Johns, JR and Trivedi, A and Ali, FM and Ingram, JR and Salek, S and Finlay, AY},
title = {Systematic review of the use of the Dermatology Life Quality Index in routine clinical practice: evidence from 287 articles across 56 countries.},
journal = {Clinical and experimental dermatology},
volume = {50},
number = {12},
pages = {2456-2465},
doi = {10.1093/ced/llaf343},
pmid = {40721287},
issn = {1365-2230},
mesh = {Humans ; *Quality of Life ; *Skin Diseases/psychology ; *Dermatology ; },
abstract = {BACKGROUND: Although quality of life instruments are widely used in research, it is challenging to find evidence of their use in routine clinical use. The most widely used measure for skin disease burden is the Dermatology Life Quality Index (DLQI), and its scores have validated clinical meaning.

OBJECTIVES: To identify evidence of the use of the DLQI in routine clinical practice and explore the nature of its use.

METHODS: The study followed PRISMA guidelines, and the protocol was registered with PROSPERO. MEDLINE (Ovid), Embase, Scopus and CINAHL (EBSCO) databases were systematically searched for articles describing studies using the DLQI in routine clinical practice. Studies were excluded if participants were aged < 16 years and if there were predetermined treatment interventions, as in a clinical trial. Information was extracted on publications' authors' opinions on the use of the DLQI in their routine practice.

RESULTS: In total, 2178 publications were screened and 287 articles met the inclusion criteria, reporting on 112 diseases and describing 66 434 patients from 56 countries, using the DLQI in at least 29 languages. Of the studies, 121 (42.2%) were reported as retrospective and 63 (22.0%) as observational. Fifty-two (18.1%) stated DLQI data were retrieved from patient records, 29 (10.1%) as 'real life', 39 (13.6%) reported 'real-world data' and 47 (16.4%) used consecutive patient recruitment. In total, 264 (92.0%) studies were conducted in a single country; 96 (33.4%) were multicentred studies, whereas 171 (59.6%) were conducted at a single site. There were 93 (32.4%) that were conducted in hospitals, 66 (23.0%) specified outpatient clinics, 38 (13.2%) tertiary care, 33 (11.5%) clinics, 4 (1.4%) in the community, 18 (6.3%) in other settings and 35 (12.2%) were unspecified. The most common diseases in the study settings were psoriasis (106 studies, 36.9%), atopic dermatitis (32, 11.1%), urticaria (24, 8.4%), hidradenitis suppurativa (22, 7.7%) and vitiligo (17, 5.9%). Thirty studies (10.5%) used Hongbo et al.'s (J Invest Dermatol 2005; 125:659-64) DLQI score banding.

CONCLUSIONS: The DLQI was widely used in routine care locations internationally, informing clinical decisions and monitoring of treatment. The DLQI was embedded into some clinics' continuing routine practice.},
}

Humans
*Quality of Life
*Skin Diseases/psychology
*Dermatology

@article {pmid41279779,
year = {2025},
author = {Chen, H and Wang, H and Lu, Y and Chen, P and Zheng, Z and Zhang, T and Wang, J},
title = {Noncanonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41279779},
issn = {2692-8205},
abstract = {We report a minimally disruptive labeling strategy for stress granule protein G3BP1 and ALS-linked protein TDP-43 using the fluorescent noncanonical amino acid Anap. By integrating genetic code expansion 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 {pmid41279722,
year = {2025},
author = {Prova, NS and Elsayyid, M and Tanis, JE},
title = {Superoxide dismutase impacts extracellular vesicle biogenesis and uptake.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.04.686557},
pmid = {41279722},
issn = {2692-8205},
abstract = {Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play an important role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and the potential for EVs as diagnostic biomarkers, while the effect of pathogenic factors on EV release is less understood. Here, we defined how the key antioxidant enzyme superoxide dismutase 1 (SOD-1) affects EV shedding from sensory neuron primary cilia, enrichment of ciliary proteins packaged into EVs, and uptake of EVs by surrounding glia in vivo by imaging C. elegans expressing fluorescent protein-tagged EV cargos. We discovered that loss of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different cargo present in EVs shed from the ciliary base. Together, this suggests that redox balance has a subtype-specific effect on EV biogenesis, influencing neuron communication in vivo .},
}

@article {pmid41279504,
year = {2025},
author = {Yang, X and Taghavi, A and Akahori, Y and Pedrini, M and Ishii, T and Disney, MD},
title = {RNA-Focused DNA-Encoded Library Construction, Screening, and Integration of Docking Identify Bioactive Ligands of Pathogenic r(G 4 C 2) [exp] RNA.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.06.686979},
pmid = {41279504},
issn = {2692-8205},
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(G 4 C 2) [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. Strong correlations were observed between docking predictions and experimental enrichment trends, supporting lead identification. The lead compound was subsequently optimized based on its docked pose to an NMR structure, resulting in analogs 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 {pmid41278912,
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-dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.15.682441},
pmid = {41278912},
issn = {2692-8205},
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. To explore how ALS-associated mutations impact UBQLN2 function, we performed quantitative mass spectrometry (MS)-based interactome analysis using affinity-purified UBQLN2 from inducible pluripotent stem cells (iPSCs) and induced motor neurons (iMNs) expressing wild-type UBQLN2 (UBQLN2WT), a UBQLN2P497H clinical mutant, or a UBQLN24XALS allele harboring four disease mutations. Proteins showing enhanced association with ALS-mutant UBQLN2 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 wild-type and ALS-mutant UBQLN2 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. The aggregation prone UBQLN24XALS mutant showed increased PEG10 binding and modestly delayed PEG10 turnover while PEG10 degradation was not significantly different between UBQLN2WT and UBQLN2P497H iPSCs. The combined findings implicate BAG6 a UBQLN2 holdase and identify a suite of proteins whose altered binding may contribute to pathologic changes in UBQLN2-associated ALS/FTD.},
}

@article {pmid41278665,
year = {2025},
author = {Hubbard, I and Dubnau, J},
title = {Glial cell-intrinsic and non-cell autonomous toxicity in a Drosophila C9orf72 neurodegeneration model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.07.680869},
pmid = {41278665},
issn = {2692-8205},
abstract = {The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G 4 C 2 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 G 4 C 2 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 G 4 C 2 repeat that is capable of producing both DPRs and RNA repeats to systematically investigate both the glial cell-intrinsic and non-cell autonomous toxicity of each of these components. Our results show that as with neurons, the GR and G 4 C 2 transgenes, produce the highest degree of cell-intrinsic toxicity when expressed in glia. Both of these transgenes are capable of producing the GR DPR, which is also typically found to be the most toxic factor in neurons. We demonstrate that both the GR and G 4 C 2 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 and contributes to both cell intrinsic and non-cell autonomous toxicity. We find that only the G 4 C 2 transgene produces measurable non-cell autonomous effects that result in loss of nearby neurons. But manipulations of apoptosis reveal non-cell autonomous or systemic effects from either GR or G 4 C 2 expressing glia. Blocking apoptotic cell death of either GR or G 4 C 2 expressing glia via the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects.},
}

@article {pmid41278139,
year = {2025},
author = {Prodromos, CC and Del Villar, R and Jin, MY and Abd-Elsayed, A and Candido, K},
title = {Exosome-rich mesenchymal stem cell secretome improves strength in patients with amyotrophic lateral sclerosis, Kennedy disease, congenital myasthenic syndrome and Lewy body dementia.},
journal = {American journal of stem cells},
volume = {14},
number = {4},
pages = {217-229},
pmid = {41278139},
issn = {2160-4150},
abstract = {AIM: Amyotrophic lateral sclerosis (ALS), Lewy Body dementia (LBD), Kennedy disease (KD), and Congenital Myasthenic Syndrome (CMS) are progressive motor disorders for which no disease modifying treatment exists. ALS and LBD are uniformly, and often rapidly, fatal. No treatment of any kind has ever resulted in actual improvement for ALS patients; the best that has been achieved is minor slowing of their progression. Forty-one preclinical studies of intra-nasal instillation of mesenchymal stem cell exosomes have, however, demonstrated complete safety and efficacy for models of a variety of neurocognitive and motor disorders. We hypothesized that intranasal exosomes treatment in humans would be completely safe and also effective for the treatment of motor disorders such as ALS, LBD, KD and CMS.

METHODS: 18 patients with ALS, Kennedy Disease, Congenital Myasthenic Syndrome, or Lewy Body Dementia had 32 AlloEx Exosome[®] treatments to assess safety, attenuation of disease, and increase in strength and motor function. The study was conducted under the clinical trial NCT07105371 found at clinicaltrials.gov/study/NCT07105371.

RESULTS: There were no adverse events of any kind reported among these treatments. All patients, except for one, achieved some degree of clinical and strength improvement; the longest improvement was recorded at the 6-month follow-up.

CONCLUSION: Intranasally-instilled AlloEx Exosomes[®] are completely safe, attenuate progression, and improve strength in ALS, Kennedy Disease, CMS, and LBD.},
}

@article {pmid41277874,
year = {2025},
author = {Ferreira-Junior, JR and de Lima Camandona, V and Barros, MH},
title = {From Yeast to Therapeutics: Modeling Neurodegenerative Diseases in Saccharomyces cerevisiae.},
journal = {Yeast (Chichester, England)},
volume = {},
number = {},
pages = {},
doi = {10.1002/yea.70008},
pmid = {41277874},
issn = {1097-0061},
support = {//This study was supported by grants and fellowships from Fundacao de Amparo a Pesquisa de Sao Paulo (FAPESP 2024/01152-3; 2023/14056-0), Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq 305054/2022-8), and Coordenacao de Aperfeicoamento de Pessoal de Nıvel Superior-Brasil (CAPES-Finance Code 001)./ ; },
abstract = {Here, we review the use of Saccharomyces cerevisiae as a powerful model organism for studying cellular processes implicated in neurodegenerative disorders, including stress responses, proteostasis impairment, and vesicle trafficking defects. Over the last two decades, baker's yeast models have been developed for complex diseases such as Parkinson's, Alzheimer's, Huntington's, and Amyotrophic lateral sclerosis (ALS). Yeast cells expressing human proteins, such as amyloid-β, α-synuclein, huntingtin, and TDP-43, have become crucial tools for high-throughput drug screening aimed at counteracting disease progression. These yeast models have unveiled key components involved in the metabolism and toxicity of these proteins, enabling the identification of interacting partners and novel factors within each pathway. Importantly, these pathways were subsequently shown to be conserved in mammalian models. Furthermore, drug candidates identified using yeast models have provided significant leads for drug discovery, highlighting their potential for developing treatments for these neurodegenerative diseases.},
}

@article {pmid41277873,
year = {2025},
author = {},
title = {Correction to "Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions".},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78107},
pmid = {41277873},
issn = {1531-8249},
}

@article {pmid41277170,
year = {2025},
author = {Jiang, Y and Zhang, Y and Ma, L and Li, C},
title = {Comprehensive Genome-Wide Analysis of Shared Genetic Factors in Gastrointestinal and Neurodegenerative Diseases.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71029},
doi = {10.1002/brb3.71029},
pmid = {41277170},
issn = {2162-3279},
support = {TSYC202401B119//Third Batch of "Tianshan Talent" High-Level Medical and Health Personnel Project/ ; },
mesh = {Humans ; Genome-Wide Association Study/methods ; *Neurodegenerative Diseases/genetics ; *Gastrointestinal Diseases/genetics ; Polymorphism, Single Nucleotide/genetics ; Mendelian Randomization Analysis ; Genetic Predisposition to Disease/genetics ; Genetic Pleiotropy ; },
abstract = {BACKGROUND: This study investigates the shared genetic basis between gastrointestinal (GI) diseases and neurodegenerative diseases (ND) using genome-wide association study (GWAS) data and statistical genetic methods.

METHODS: GWAS data, primarily from European populations, covered four types of GI diseases and three types of ND. Genetic correlations were assessed using Linkage Disequilibrium Score Regression (LDSC), High-Definition Likelihood (HDL), and Local Analysis of Covariant Annotation (LAVA). Pleiotropic and functional genetic overlaps were explored using the Genomic Partitioning Approach (GPA), pleiotropic analysis under the composite null hypothesis (PLACO), and Functional Mapping and Annotation of Genetic Associations (FUMA). Multi-marker analysis of genomic annotation (MAGMA) was used for biological annotation and enrichment analysis, while summary data-based Mendelian randomization (SMR) analysis linked pleiotropic genes with gene expression. Two-sample Mendelian randomization (TSMR) investigated potential causal relationships.

RESULTS: Significant genetic correlations and shared genetic features were identified. The research identified 1,457 pleiotropic single nucleotide variants(SNVs) distributed across 47 chromosomal regions and 74pleiotropic genes, predominantly involved in pathways related tosignal transduction, amyloid regulation, and lipid metabolism. Nine colocalization loci (PPH4 > 0.8) were identified, while SMR analysis linked 26 pleiotropic genes to disease expression levels. Key genes, including EP300, CHRNB1, KNOP1, P2RY14, and POLR2A, were significantly associated with both disease types. Drug-gene interaction analysis highlighted 8 genes with drug targets, among which EP300, PRKCB, VKORC1, and CHRNB1 were found to anchor enriched pathways including purinergic signaling, amyloid/protein aggregation, and cholesterol/lipoprotein transport. Mendelian randomization corroborated possible causal association.

CONCLUSION: This study confirms a shared genetic basis between GI and ND, emphasizing the gut-brain axis in their etiology. These findings offer clues about shared pathways, potential therapeutic targets, and future research directions.},
}

Humans
Genome-Wide Association Study/methods
*Neurodegenerative Diseases/genetics
*Gastrointestinal Diseases/genetics
Polymorphism, Single Nucleotide/genetics
Mendelian Randomization Analysis
Genetic Predisposition to Disease/genetics
Genetic Pleiotropy

@article {pmid41277110,
year = {2025},
author = {Lu, J and Di Florio, DN and Boya, P and Maday, S and Springer, W and Chu, CT},
title = {Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-43},
doi = {10.1080/15548627.2025.2581217},
pmid = {41277110},
issn = {1554-8635},
abstract = {The human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy at the synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining high-quality mitochondria, and alterations in selective mitochondrial autophagy (mitophagy) are heavily implicated in both genetic and environmental etiologies of neurodegenerative diseases. The unique spatial and functional demands of neurons result in differences in the regulation of metabolic, autophagic, mitophagic and biosynthetic processes compared to other cell types. Here, we review recent advances in autophagy and mitophagy research with an emphasis on studies involving primary neurons in vitro and in vivo, glial cells, and iPSC-differentiated neurons. The synaptic functions of genes whose mutations implicate autophagic or mitophagic dysfunction in hereditary neurodegenerative and neurodevelopmental diseases are summarized. Finally, we discuss the diagnostic and therapeutic potentials of autophagy-related pathways.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; APP: amyloid beta precursor protein; ASD: autism-spectrum disorder; BDNF: brain-derived neurotrophic factor; BPAN: β-propeller protein associated neurodegeneration; CR: caloric restriction; ΔN111: deleted N-terminal region 111 residues; DLG4/PSD95: discs large MAGUK scaffold protein 4; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HD: Huntington disease; LIR: LC3-interacting region; LRRK2: leucine rich repeat kinase 2; LTD: long-term depression; LTP: long-term potentiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMM: outer mitochondrial membrane; PD: Parkinson spectrum diseases; PGRN: progranulin; PINK1: PTEN induced kinase 1; PRKA/PKA: protein kinase cAMP-activated; PtdIns3P: phosphatidylinositol-3-phosphate; p-S65-Ub: ubiquitin phosphorylated at serine 65; PTM: post-translational modification; TREM2: triggering receptor expressed on myeloid cells 2.},
}

@article {pmid41276980,
year = {2025},
author = {Patel, K and Sarathamani, T and Kothandasamy, K and Sethy, PK and Behera, SK and Nanthaamornphong, A},
title = {Computational Approaches to Neurological Disorder Diagnosis: An In-Depth Review of Current Methods and Future Prospects.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056404224251026110800},
pmid = {41276980},
issn = {1573-4056},
abstract = {The rapid advancement of computational technologies has significantly transformed medical diagnostics, particularly in the realm of neurological disorders. This review provides a comprehensive analysis of the current computational approaches employed for the diagnosis of five major neurological disorders: Alzheimer's disease, Parkinson's disease, Epilepsy, Huntington's disease, and Amyotrophic Lateral Sclerosis. By evaluating 140 peer-reviewed studies, we explored a diverse array of diagnostic methods, including machine learning algorithms, neuroimaging techniques, and electrophysiological signal analysis. Our review highlights the efficacy, accuracy, and limitations of these diagnostic methods, emphasizing their role in early detection and differential diagnosis. Furthermore, we discuss the integration of multimodal data and the potential of emerging technologies such as deep learning and artificial intelligence to enhance diagnostic practices. We also address the current challenges in clinical implementation and propose future research directions to improve diagnostic precision and patient outcomes. This review aims to serve as a valuable resource for researchers, clinicians, and stakeholders in the field of neurodiagnostics, fostering a deeper understanding of computational methodologies that shape the future of neurological disorder diagnosis.},
}

@article {pmid41276866,
year = {2025},
author = {Raoufinia, R and Alyari, G and Nia, AT and Abbaszadegan, MR and Mahmoudi, A and Shafaeibajestan, S and Saburi, E and Tavakol-Afshari, J and Hassani, M and Jamali, F and Salari, S and Boroumand, AR and Rahimi, HR},
title = {Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies.},
journal = {Stem cell research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13287-025-04781-w},
pmid = {41276866},
issn = {1757-6512},
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective loss of motor neurons (MNs), leading to progressive muscle weakness, atrophy, and ultimately paralysis. This review provides a comprehensive overview of the molecular mechanisms underlying ALS pathogenesis, the genetic mutations associated with both familial and sporadic forms of the disease, and the latest therapeutic strategies aimed at mitigating disease progression. mutations in genes such as C9orf72, SOD1, TARDBP, and FUS have been implicated in ALS, with an intricate interplay of protein misfolding, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation contributing to motor neuron degeneration. While current FDA-approved treatments such as Riluzole and Edaravone offer only modest benefits and do not significantly halt disease progression. Emerging therapies, including gene therapies (e.g., antisense oligonucleotides (ASOs) and CRISPR/Cas9, stem cell-based approaches, and neurotrophic factor supplementation, are demonstrating promising results in preclinical and early-phase clinical trials. novel approaches aim to target, modulate, and promote regeneration, renewed hope for future ALS treatments. However, several challenges remain, including effective delivery methods, safety concerns, and the inherent complexity of ALS pathology, ongoing research continues to explore these innovative interventions with the goal of improving clinical outcomes for patients. This review highlights the importance of personalized therapeutic approaches and underscores the necessity of continued innovation in ALS research, with the ultimate goal of developing disease-modifying therapies and, potentially, a cure for this fatal condition.},
}

@article {pmid41276413,
year = {2025},
author = {Isik, FI and Pickford, R and Dzamko, N and Rye, KA and Kim, WS},
title = {Upregulation of sphingomyelin and ABCA8 in response to TDP-43 pathology in amyotrophic lateral sclerosis brain.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70053},
doi = {10.1111/bpa.70053},
pmid = {41276413},
issn = {1750-3639},
support = {IM-202303-00957//FightMND/ ; R28AA012725//National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and the presence of TAR DNA-binding protein 43 (TDP-43) aggregation in the brain. Dyslipidemia is a common feature of ALS, and increasing evidence indicates that lipid dysregulation in the central nervous system underlies ALS pathology. Sphingomyelin is a sphingolipid that is highly enriched in the human brain. However, very little is known about changes in sphingomyelin in the context of ALS brain. We therefore undertook a comprehensive analysis of sphingomyelin in the disease-affected motor cortex and disease-unaffected cerebellum in sporadic ALS with TDP-43 pathology using liquid chromatography-mass spectrometry. We found that sphingomyelin was significantly increased in the ALS motor cortex compared to controls and was strongly associated with disease duration. In contrast, sphingomyelin was unaltered in the cerebellum. The increase in sphingomyelin was associated with an upregulation of ATP-binding cassette subfamily A member 8 (ABCA8), a sphingomyelin transporter, only in the motor cortex of ALS. Importantly, both sphingomyelin and ABCA8 were associated with TDP-43 only in the motor cortex. These results suggest that increases in sphingomyelin and ABCA8 could be a protective response against TDP-43 pathology.},
}

@article {pmid41276122,
year = {2025},
author = {Han, GM and Zhang, XY and Li, ZX and Zheng, XW},
title = {Comment on Lorizzo et al.'s "Acrodermatitis Continua of Hallopeau - clinical review and proposed management algorithm.".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.07.079},
pmid = {41276122},
issn = {1097-6787},
}

@article {pmid41275793,
year = {2025},
author = {Rezaei, K and Seyedalipour, B and Behjou, NK and Faradonbeh, SMH and Hosseinkhani, S},
title = {Modulation of amyloid formation in the hSOD1 R115G mutant by an ionic liquid ([BMIM][SCN]).},
journal = {Biochemical and biophysical research communications},
volume = {793},
number = {},
pages = {153017},
doi = {10.1016/j.bbrc.2025.153017},
pmid = {41275793},
issn = {1090-2104},
abstract = {Protein aggregation is crucial to the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), particularly in cases involving superoxide dismutase 1 (hSOD1) mutants. There is increasing focus on the development of small-molecule modulators that can disrupt aggregation pathways. Recently, ionic liquids (ILs) have been recognized as effective modulators of protein aggregation due to their tunable physicochemical properties. This study employed a combined computational and experimental approach to assess the inhibitory efficacy of 1-butyl-3-methylimidazolium thiocyanate ([BMIM][SCN]) on amyloid formation induced by the ALS-associated R115G mutation in hSOD1. Molecular dynamics (MD) simulations were conducted to obtain atomic-level insight into the inhibitory mechanism, demonstrating that [BMIM][SCN] primarily interacts with aggregation-prone loop regions in the R115G mutant, diminishing local flexibility and stabilizing partially folded intermediates. These interactions likely disrupt early nucleation processes essential for fibril propagation. The anti-amyloidogenic effects of [BMIM][SCN] were further confirmed under aggregating conditions using Thioflavin T (ThT) fluorescence kinetics, which exhibited a significant, concentration-dependent decrease in fibril formation. This trend was confirmed by transmission electron microscopy (TEM), which demonstrated a distinct suppression of fibrillar structures. Furthermore, ANS binding assays indicated reduced exposure of hydrophobic regions, implying a shift toward more compact, less aggregation-prone conformations. Fourier-transform infrared (FTIR) spectroscopy supported these findings by demonstrating a decrease in β-sheet-rich secondary structures commonly linked to mature amyloids. These findings indicate that [BMIM][SCN] modulates aggregation of the R115G mutant, providing mechanistic insights into how [BMIM][SCN] influences amyloid formation. These results may guide the rational design of biocompatible ionic-liquid-based analogs with potential therapeutic applications for ALS.},
}

@article {pmid41274655,
year = {2025},
author = {Kaplan, J and Smith, R and Craig, T and Carder, P and Taylor, J and Gadkari, G and Pollack, CE and Thomas, KS},
title = {Using the Low-Income Housing Tax Credit to Fund Assisted Living: Mapping the Current Environment.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106008},
doi = {10.1016/j.jamda.2025.106008},
pmid = {41274655},
issn = {1538-9375},
abstract = {OBJECTIVES: The Low-Income Housing Tax Credit (LIHTC) has been responsible for creating more units of affordable housing than any other federal program. However, the extent to which it has been used to finance the development of assisted living (AL) is unknown. The objective of this study is to understand the prevalence of LIHTC-funded AL and how ALs funded with LIHTC differ from other ALs.

DESIGN: We linked the Department of Housing and Urban Development's LIHTC database (1987-2022) and a national list of licensed ALs (2023) to identify LIHTC-funded ALs (LIHTC-ALs) operating in 2023.

SETTING: Nationwide study of the location of ALs funded by LIHTC.

METHODS: We used geospatial coordinates, street addresses, and property names to link the data. Characteristics of ALs were compared using descriptive statistics.

RESULTS: We identified 197 LIHTC-ALs out of 37,510 total ALs (0.53%) and 50,471 LIHTC properties (0.39%). LIHTC-ALs were highly concentrated in a handful of states including Massachusetts (n = 31), Indiana (n = 26), Iowa (n = 13), Colorado (n = 12), and Maine (n = 12). Thirteen states did not have any LIHTC-ALs. Compared with other ALs, LIHTC-ALs were significantly more likely to be in a medically underserved area (11.7% vs 5.8%, P < .001), less likely to be in a higher-income area (median income of $71,758 vs $87,164, P < .001), and more likely to be in an area with a higher proportion of White individuals (71.1% vs 66.9%, P = .005). In addition, when compared with non-AL LIHTC properties, LIHTC-ALs were more likely to be in a higher-income area (median income of $71,758 vs $59,659.49, P < .001).

CONCLUSIONS AND IMPLICATIONS: LIHTC has been used to fund a small proportion of total ALs, with a high degree of between-state variability. Compared with other ALs, LIHTC-ALs tend to be in areas of lower socioeconomic status and higher medical need, signaling they may serve a different population than other ALs.},
}

@article {pmid41274569,
year = {2025},
author = {Liu, X and Guo, S and Wang, J and Zhang, L and Lin, Y and Liu, Y and Ouyang, J and Shi, D and Xu, B and Fang, W and Ran, Y},
title = {Reply to: "Comments on Liu et al.'s 'Caged-hypocrellin mediated antimicrobial photodynamic therapy as a dual-action strategy for fungal clearance and immune response regulation in drug-resistant Candida auris wound infections'".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.11.050},
pmid = {41274569},
issn = {1097-6787},
}

@article {pmid41274565,
year = {2025},
author = {Chen, SC and Lee, YT},
title = {Comments on Liu et al.'s "Caged-hypocrellin mediated antimicrobial photodynamic therapy as a dual-action strategy for fungal clearance and immune response regulation in drug-resistant Candida auris wound infections".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.10.152},
pmid = {41274565},
issn = {1097-6787},
}

@article {pmid41274292,
year = {2025},
author = {Cohen, Y and Sinai, I and Magen, I and Danino, YM and Wuu, J and Malaspina, A and Benatar, M and Hornstein, E},
title = {IsomiR utility in amyotrophic lateral sclerosis prognostication.},
journal = {Med (New York, N.Y.)},
volume = {},
number = {},
pages = {100928},
doi = {10.1016/j.medj.2025.100928},
pmid = {41274292},
issn = {2666-6340},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA (miRNA) isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored.

METHODS: Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing and two orthogonal statistical approaches.

FINDINGS: We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181.

CONCLUSIONS: These results establish isomiRs as a novel class of blood-based biomarkers in ALS with the potential to refine prognostication in clinical trials for neurodegenerative diseases.

FUNDING: This study was funded by Target ALS the Israel Science Foundation (3497/21, 424/22) and the CReATe Consortium. All additional funding can be found under the Acknowledgments.},
}

@article {pmid41273627,
year = {2025},
author = {Wang, W and Tan, S and Zuo, X and Gao, X and Ma, L and Sun, R and Liang, G and Yin, L and Pu, Y and Zhang, J},
title = {Brain Organoids in Neurodegenerative Disease Modeling: Advances, Applications and Future Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {142},
pmid = {41273627},
issn = {1559-1182},
mesh = {*Organoids/pathology ; Humans ; *Neurodegenerative Diseases/pathology ; *Brain/pathology ; Animals ; Disease Models, Animal ; *Models, Biological ; },
abstract = {Neurodegenerative diseases (NDDs) represent incurable and debilitating conditions characterized by progressive deterioration of neurological function. Investigating neurodegeneration remains a critical global challenge in aging societies. Brain organoids-self-organizing three-dimensional structures derived from human pluripotent stem cells-recapitulate cell types and cytoarchitectures of the developing human brain. This in vitro model system has advanced our bridge between conventional two-dimensional cultures and in vivo models. Brain organoids emulate early neural tube formation, neuroepithelial differentiation, and whole-brain regionalization. Furthermore, region-specific organoid models now facilitate mechanistic investigation into acquired and inherited NDDs' pathogenesis, alongside drug discovery and toxicity screening. In this review, we (i) delineate the epidemiology and pathobiology of major NDDs, (ii) analyze limitations of current animal models, (iii) critically evaluate brain organoid generation methodologies, and (iv) focus on organoid applications in modeling Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).},
}

*Organoids/pathology
Humans
*Neurodegenerative Diseases/pathology
*Brain/pathology
Animals
Disease Models, Animal
*Models, Biological

@article {pmid41273593,
year = {2026},
author = {Paplomatas, P and Nikolidaki, M and Vrahatis, A},
title = {Uncovering Key Genes in Neurodegenerative Diseases Through Unsupervised Learning: A Variance-Based LSTM and Enrichment Analysis Approach.},
journal = {Advances in experimental medicine and biology},
volume = {1487},
number = {},
pages = {559-568},
pmid = {41273593},
issn = {0065-2598},
mesh = {Humans ; *Unsupervised Machine Learning ; *Neurodegenerative Diseases/genetics ; Cluster Analysis ; Gene Expression Profiling/methods ; Neural Networks, Computer ; Parkinson Disease/genetics ; Gene Regulatory Networks ; Alzheimer Disease/genetics ; Computational Biology/methods ; },
abstract = {This study presents an integrated approach for discovering and clustering significant genes associated with neurodegenerative diseases using a combination of variance-based filtering, Long Short-Term Memory (LSTM) neural networks, and enrichment analysis. By first filtering genes based on their variance across samples, we retain genes with high biological relevance. These selected genes are then used to train an LSTM model, capturing complex interactions between gene expression patterns. Using Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and K-Means for clustering, we group genes with similar expression profiles. The optimal number of clusters is determined using the Silhouette Score. To refine the model, we introduce a feedback loop where cluster labels are fed back into the LSTM as additional features, enhancing the model's ability to detect significant gene associations. We compare various network architectures to assess their impact on clustering performance. Finally, enrichment analysis reveals key biological pathways, such as immune regulation and protein signaling, related to Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Our approach demonstrates the potential of machine learning and clustering to uncover meaningful gene associations, offering insights into the molecular mechanisms underlying neurodegenerative diseases.},
}

Humans
*Unsupervised Machine Learning
*Neurodegenerative Diseases/genetics
Cluster Analysis
Gene Expression Profiling/methods
Neural Networks, Computer
Parkinson Disease/genetics
Gene Regulatory Networks
Alzheimer Disease/genetics
Computational Biology/methods

@article {pmid41272780,
year = {2025},
author = {Kumar, A and Shukla, S and Rai, A and Pathak, P and Narayan, KP},
title = {Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen).},
journal = {Orphanet journal of rare diseases},
volume = {20},
number = {1},
pages = {598},
pmid = {41272780},
issn = {1750-1172},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Genetic Therapy/methods ; Orphan Drug Production ; *Oligonucleotides/therapeutic use ; United States Food and Drug Administration ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord. With a global incidence of 1.9 to 6 per 100,000 people, ALS is slightly more common in men and prevalent in individuals over 60. However, this review provides a concise update on the regulatory landscape and therapeutic advancements in managing ALS, focusing on the recent approval of Tofersen, the first gene therapy specifically targeting SOD1 mutation-related ALS.

RESULTS: It highlights Tofersen unique role as an orphan drug approved by the US FDA, emphasizing its mechanism of action, gene silencing and its impact on reducing neurodegeneration. Additionally, the review synthesizes data from ongoing clinical trials, pharmacovigilance reports, and case studies to comprehensively understand Tofersen's safety, efficacy and market exclusivity. Beyond this, it explores the emerging potential of nanotherapeutic approaches to ALS treatment, identifying critical research gaps and future directions.

CONCLUSION: Integrating regulatory updates, clinical evidence, and innovative therapeutic strategies, the review uniquely contributes to the ALS literature by bridging current treatment realities with potential future therapies, aiming to inform researchers, clinicians, and policymakers on optimizing ALS management.},
}

*Amyotrophic Lateral Sclerosis/drug therapy
Humans
Genetic Therapy/methods
Orphan Drug Production
*Oligonucleotides/therapeutic use
United States Food and Drug Administration

@article {pmid41271785,
year = {2025},
author = {Faggioli, G and Menotti, L and Marchesin, S and Trescato, I and Ahmad, L and Aidos, H and Alungulese, AL and Bellazzi, R and Bergamaschi, R and Birolo, G and Bosoni, P and Cabrera-Umpiérrez, MF and Cavalla, P and Chió, A and Dagliati, A and de Carvalho, M and Fariselli, P and García Dominguez, JM and González Martínez, S and Gromicho, M and Guazzo, A and Jovanović, A and Kostić, B and Longato, E and Madeira, SC and Manera, U and Muñoz Blanco, JL and Tavazzi, E and Tavazzi, E and Trasobares Iglesias, E and Urošević, V and Vettoretti, M and Di Nunzio, GM and Silvello, G and Di Camillo, B and Ferro, N},
title = {The BRAINTEASER Datasets: Clinical, Wearable and Environmental Data for ALS & MS Progression Modeling.},
journal = {Scientific data},
volume = {12},
number = {1},
pages = {1854},
pmid = {41271785},
issn = {2052-4463},
support = {GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; GA101017598//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Disease Progression ; *Multiple Sclerosis/physiopathology ; *Wearable Electronic Devices ; Artificial Intelligence ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are debilitating diseases with unpredictable progression. Artificial Intelligence-based tools for modelling disease progression could significantly improve the quality of life for patients and caregivers while supporting clinicians in delivering more personalized and timely care. However, the limited availability of data hinders the development, testing, and reproducibility of such predictive tools. To address this challenge, we curated, in the context of the H2020 BRAINTEASER project, four datasets containing clinical data from a total of 2,290 ALS patients and 723 MS patients. These datasets also include environmental data and information collected through wearable devices. Unlike most existing resources, the BRAINTEASER datasets are gathered from clinical practice, offering a more accurate representation of the data that an AI progression prediction tool would encounter in real-world scenarios. In addition to manual and automated data quality checks, the research community has validated the datasets through three editions of the intelligent Disease Progression Prediction challenges held within the Conference and Labs of the Evaluation Forum (CLEF).},
}

*Amyotrophic Lateral Sclerosis/physiopathology
Humans
Disease Progression
*Multiple Sclerosis/physiopathology
*Wearable Electronic Devices
Artificial Intelligence

@article {pmid41271780,
year = {2025},
author = {Hou, X and Tang, X and Zhao, Y and Liu, Z and Zhang, J and Gong, Z and Kang, Z and Li, Z and Chen, H and Wang, J and Tang, B and Zhou, X and Lei, L},
title = {Characterization of the genetic and clinical landscapes of DCTN1 gene in neurodegenerative diseases: a series of large case-control study.},
journal = {NPJ genomic medicine},
volume = {10},
number = {1},
pages = {75},
pmid = {41271780},
issn = {2056-7944},
support = {2022JJ30879//the Natural Science Foundation of Hunan Province/ ; 2024JJ5509//the Natural Science Foundation of Hunan Province/ ; 2023SK2037//the Hunan Innovative Province Construction Project/ ; 81971086//the Program of the National Natural Science Foundation of China/ ; },
abstract = {Impairment of axonal transport has been emphasized as a common feature in a series of neurodegenerative diseases (NDs). Variations in DCTN1 have been reported in NDs such as Parkinson's disease (PD), Perry syndrome (PS) and Amyotrophic lateral sclerosis (ALS). The overall objective of this study was to investigate the contribution of DCTN1 variants in different NDs and to explore the correlation between DCTN1 variants and disease phenotypes. We identified a previously published mutation p.G71E in three unrelated PS families. In the PD cohort, 30 putative deleterious variants (PDVs) were identified in DCTN1. Gene-based burden analysis showed a nominal association between DCTN1 rare PDVs and PD (uncorrected p = 0.042); however, this association did not remain statistically significant after multiple testing correction (FDR-corrected p = 0.084). In the ALS cohort, 10 PDVs were all rare damaging missense variants, and the PDVs were not enriched in ALS patients. Our findings first provide the independent evidence that PDVs in DCTN1 may be a risk factor for PD, but do not support the genetic involvement of DCTN1 in ALS of Asian ancestry.},
}

@article {pmid41271702,
year = {2025},
author = {Resnick, SJ and Qamar, S and Krishna, P and Korobeynikov, V and Ausserwoger, H and Miller, A and Esposito, P and Varela, JA and Sheng, J and Huang, LH and Nixon-Abell, J and Melore, S and Chung, CW and Läubli, NF and Kapsiani, S and Li, X and Wang, J and Zhang, N and Alam, MM and Burguete, AS and Swayne, TC and Chen, Y and Liao, YC and Shneider, NA and Vendruscolo, M and Knowles, TPJ and Kaminski, CF and Ruggeri, FS and Kaminski Schierle, GS and St George-Hyslop, P and Chavez, A},
title = {Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {10285},
pmid = {41271702},
issn = {2041-1723},
support = {406915, Canadian Consortium on Neurodegeneration in Aging Grant//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; F31NS111851//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; /WT_/Wellcome Trust/United Kingdom ; 337969//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AL190073//U.S. Department of Defense (United States Department of Defense)/ ; Career Awards for Medical Scientists//Burroughs Wellcome Fund (BWF)/ ; 5R01NS106236//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; MR/K02292X/1//RCUK | Medical Research Council (MRC)/ ; 203249/Z/16/Z//Wellcome Trust (Wellcome)/ ; R01 NS106236/NS/NINDS NIH HHS/United States ; R01 HG006137/HG/NHGRI NIH HHS/United States ; 2R01HG006137-10//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 804581//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; F31 NS111851/NS/NINDS NIH HHS/United States ; 21-IIA-571//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; P30 CA013696/CA/NCI NIH HHS/United States ; AS-PhD-19a-016/ALZS_/Alzheimer's Society/United Kingdom ; 10100161//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 2113646//National Science Foundation (NSF)/ ; ZEN-18-529769/ALZ/Alzheimer's Association/United States ; },
mesh = {*HSP40 Heat-Shock Proteins/metabolism/genetics ; Humans ; Animals ; *Molecular Chaperones/metabolism/genetics ; Mice ; *RNA-Binding Protein FUS/metabolism/genetics/chemistry ; *Nerve Tissue Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Frontotemporal Dementia/metabolism/genetics/pathology ; Saccharomyces cerevisiae/metabolism/genetics ; Disease Models, Animal ; *Neurodegenerative Diseases/metabolism/genetics ; },
abstract = {Neurodegenerative disorders (NDDs) are a family of diseases that remain poorly treated despite their growing global health burden. To gain insight into the mechanisms and modulators of neurodegeneration, we developed a yeast-based multiplex genetic screening platform. Using this platform, 32 NDD-associated proteins are probed against a library of 132 molecular chaperones from both yeast and humans, and an unbiased set of ~900 human proteins. We identify both broadly active and specific modifiers of our various cellular models. To illustrate the translatability of this platform, we extensively characterize a potent hit from our screens, the human chaperone DNAJB6. We show that DNAJB6 modifies the toxicity and solubility of multiple amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)-linked RNA-binding proteins (RBPs). Biophysical examination of DNAJB6 demonstrated that it co-phase separates with, and alters the behavior of FUS containing condensates by locking them into a loose gel-like state which prevents their fibrilization. Domain mapping and a deep mutational scan of DNAJB6 revealed key residues required for its activity and identified variants with enhanced activity. Finally, we show that overexpression of DNAJB6 prevents motor neuron loss and the associated microglia activation in a mouse model of FUS-ALS.},
}

*HSP40 Heat-Shock Proteins/metabolism/genetics
Humans
Animals
*Molecular Chaperones/metabolism/genetics
Mice
*RNA-Binding Protein FUS/metabolism/genetics/chemistry
*Nerve Tissue Proteins/metabolism/genetics
Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
Frontotemporal Dementia/metabolism/genetics/pathology
Saccharomyces cerevisiae/metabolism/genetics
Disease Models, Animal
*Neurodegenerative Diseases/metabolism/genetics

@article {pmid41271630,
year = {2025},
author = {Woo, E and Tasnim, F and Kawamata, H and Manfredi, G and Konrad, C},
title = {Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-025-08126-6},
pmid = {41271630},
issn = {2041-4889},
support = {MDA602762//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; MDA961871//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01NS139141//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS122209//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1[A4V], TDP-43[N352S], FUS[R521G], CHCHD10[R15L], and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1[A4V], C9orf72, and TDP-43[N352S] iMN had increased mitochondrial membrane potential, while in CHCHD10[R15L] cells membrane potential was decreased. TDP-43[N352S] iMN displayed changes in mitochondrial morphology and increased motility. SOD1[A4V], TDP-43[N352S], and CHCHD10[R15L] iMN had increased oxygen consumption rates and altered extracellular acidification rates. FUS[R521G] mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. SOD1[A4V], C9orf72, and TDP-43[N352S] had increased, while FUS[R521G] had decreased mitochondrial reactive oxygen species production. We tested the viability of iMN and found decreases in survival in SOD1[A4V], C9orf72, and FUS[R521G], which were corrected by small molecules that target mitochondrial stress and worsened by bioenergetic stressors. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.},
}

@article {pmid41269901,
year = {2025},
author = {Peters, T and Yang, H and Zou, Z and Ye, W},
title = {Thyroid Disease and Amyotrophic Lateral Sclerosis.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-15},
doi = {10.1159/000549662},
pmid = {41269901},
issn = {1423-0208},
abstract = {INTRODUCTION: Thyroid disease has been implicated in the pathology of neurodegenerative diseases. However, its role in amyotrophic lateral sclerosis (ALS) is unclear. This study aimed to investigate the association between thyroid disease, including hypothyroidism and hyperthyroidism, and the risk of ALS.

METHODS: We used a matched cohort design to evaluate UK Biobank data on participants enrolled between 2006 and 2010 who were followed up until 2022. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: The study cohort comprised 42,684 patients with thyroid disease (females: 80%). Thyroid disease was moderately associated with an increased risk of ALS development (HR: 1.44, 95% CI: 1.02-2.02), and this association remained similar following adjustment for comparative height at the age of 10 years (HR: 1.44, 95% CI: 1.03-2.03). Hyperthyroidism showed a potential association with an increased risk of ALS development among individuals aged ≤60 years (HR: 21.22, 95% CI: 1.64-274.46) and in females (HR: 3.02, 95% CI: 1.13-8.08).

CONCLUSION: Our findings demonstrate that thyroid disease is associated with a moderately increased risk of ALS development. Given the multifunctional role of the thyroid gland, further in-depth studies examining the relationship between thyroid conditions and ALS are warranted.},
}

@article {pmid41269662,
year = {2025},
author = {Milella, G and Fiorella, ML and Velucci, V and Sciancalepore, D and Luisi, F and Fraddosio, A and D'Errico, E and Muroni, A and Defazio, G},
title = {Unrevealing the sequence of dysphagia progression in ALS: an event-based, FEES-driven staging approach.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41269662},
issn = {1435-1463},
abstract = {Dysphagia drives morbidity and mortality in amyotrophic lateral sclerosis (ALS), yet staging systems treat it as a binary milestone and do not capture its trajectory. Reports diverge on the earliest abnormality, with some citing cohesive-bolus inefficiency and others thin-liquid impairment. Furthermore, how these findings relate to patient-perceived dysphagia remains unclear. In a prospective cohort, 78 incident ALS patients underwent one or more fiberoptic endoscopic evaluations of swallowing (FEES), yielding 108 assessments. Pharyngeal residue for four consistencies was rated with a validated scale. An event-based model (EBM) inferred the temporal order of abnormalities and defined a five-stage, FEES-based dysphagia staging system (DSS). Construct, convergent, discriminant, and prognostic validity were tested against established measures; responsiveness was assessed in patients with longitudinal FEES. The EBM identified a consistent sequence of swallowing impairment: solids, semisolids, liquids, saliva. Patient-perceived dysphagia occurred in 38% of DSS 1-2 evaluations versus 100% of DSS 3-4. The DSS showed construct validity by distinguishing bulbar- from spinal-onset ALS and convergent validity with the ALSFRS-R bulbar subscore and LMN bulbar score. Discriminant validity was supported by weak, non-significant associations with spinal/respiratory measures. Agreement with King's staging was moderate, and all King's stage IV patients mapped to DSS stages 3-4. The DSS was responsive to change (Stuart-Maxwell χ[2] = 11.034; p = 0.026). The EBM reconciles prior discrepancies: pathophysiology begins with solids, whereas symptom recognition typically coincides with liquid-phase residue. The FEES-based DSS is reproducible and clinically meaningful for tracking bulbar involvement and identifying higher-risk patients.},
}

@article {pmid41269513,
year = {2025},
author = {Jude, EB and Saluja, S and Mannan, F and Heagerty, A and Frier, B},
title = {UK Resuscitation Advanced Life Support Guidelines: Should the Paradigm be Extended?.},
journal = {Diabetes therapy : research, treatment and education of diabetes and related disorders},
volume = {},
number = {},
pages = {},
pmid = {41269513},
issn = {1869-6953},
abstract = {Cardiac arrest continues to be a predominant cause of mortality worldwide, necessitating its rapid identification, and intervention by reversible aetiologies to optimise successful outcomes. The established 4H 4T framework has served as a foundational guide for advanced life support (ALS) protocols since its formal introduction in the 2000 International Guidelines on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC), effectively targeting critical conditions such as hypoxia, hypothermia, hypo-/hyperkalaemia, hypovolaemia, tension pneumothorax, cardiac tamponade, thrombosis, and exposure to toxins. However, this framework inadequately addresses other significant factors: specifically hypoglycaemia and tachy- and bradyarrhythmias. Hypoglycaemia, a reversible and treatable metabolic state, poses substantial threats to cardiovascular stability, particularly in people with diabetes and in association with sepsis. It disrupts myocardial repolarisation, prolongs the QT interval, and may instigate the R-on-T phenomenon, which can precipitate life-threatening arrhythmias. Likewise, tachyarrhythmias and bradyarrhythmias often precipitate cardiac arrest, thereby warrant dedicated attention within ALS protocols. This paper advocates expanding the current 4H 4T framework to include hypoglycaemia and tachy- and bradyarrhythmias as critical and reversible causes of cardiac arrest (5H 5T). The rationale for such a paradigm shift is supported by evidence from clinical studies, case reports, and experimental models that demonstrate the adverse effect of these conditions on cardiovascular integrity and alert clinicians to look for these reversible factors. The inclusion of these factors into ALS protocols will necessitate revising resuscitation guidelines, modifying training for healthcare practitioners, and including systematic monitoring of blood glucose alongside routine assessment of cardiac rhythm during resuscitation procedures. Future research should focus on elucidating the pathophysiological mechanisms underlying these conditions, to establish operational thresholds for intervention, and validate their integration into resuscitation frameworks. By expanding the conceptualisation of reversible causes, the proposed 5H/5T framework would offer a more rational and practical approach to the management of cardiac arrest, to improve the survival and recovery of these critically ill patients.},
}

@article {pmid41269421,
year = {2025},
author = {Asadinejad, H and Taherkhani, S and Golboos, SM and Azizi, Y and Mohammadkhanizadeh, A},
title = {Targeting Neurodegeneration with SGLT2is: From Molecular Mechanisms to Clinical Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {119},
pmid = {41269421},
issn = {1559-1182},
mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a class of antidiabetic drugs that have demonstrated significant cardiovascular and renal benefits. Accumulating evidence suggests that SGLT2is also exert neuroprotective effects and may influence the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). SGLT2is modulate glucose metabolism, reduce oxidative stress, suppress inflammation, and enhance mitochondrial function. Beyond glycemic control, they show potential therapeutic effects in ameliorating the metabolic dysregulation associated with neurodegenerative pathologies. Current preclinical and clinical evidence including metabolic regulation, anti-inflammatory actions, and neuroprotective effects mediated through SGLT2is associated molecular pathways have been critically evaluated to delineate their therapeutic potential in neurodegenerative disorders. Although preclinical studies have shown promising results, more clinical trials are needed. This review highlights key research gaps and proposes future translational applications.},
}

Humans
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology

@article {pmid41269403,
year = {2025},
author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA},
title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {121},
pmid = {41269403},
issn = {1559-1182},
mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; },
abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.},
}

*Receptors, sigma/antagonists & inhibitors/agonists/metabolism
*Huntington Disease/drug therapy/pathology/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
Sigma-1 Receptor
*Piperidines/pharmacology/therapeutic use
Mice
Humans
Neurons/drug effects/metabolism/pathology
Huntingtin Protein/metabolism

@article {pmid41269363,
year = {2025},
author = {Schito, P and Domi, T and Russo, T and Pozzi, L and Falzone, YM and Pipitone, GB and Agosta, F and Carrera, P and Quattrini, A and Riva, N and Filippi, M},
title = {The genetic architecture of primary lateral sclerosis in a cohort of Italian patients.},
journal = {Journal of neurology},
volume = {272},
number = {12},
pages = {780},
pmid = {41269363},
issn = {1432-1459},
mesh = {Humans ; Italy ; Male ; Female ; Middle Aged ; Aged ; Cohort Studies ; Adult ; C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics ; High-Throughput Nucleotide Sequencing ; Amyotrophic Lateral Sclerosis/genetics ; },
abstract = {BACKGROUND AND PURPOSE: Recent studies suggest that primary lateral sclerosis (PLS) may have a genetic component. In this work, we performed a next-generation sequencing (NGS) analysis in order to explore the genetic architecture of PLS in a cohort of Italian patients.

METHODS: NGS was conducted to analyze 228 genes associated with amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), and parkinsonian syndromes (PS) in a cohort of PLS patients diagnosed between 2003 and 2021 at our center. All patients were also screened for C9orf72 hexanucleotide repeat expansion (C9orf72-HRE) by repeat-primed PCR. Genetic variants were classified according to the ACMG criteria.

RESULTS: In our study, including 47 PLS patients, we detected 22 rare variants in 17 patients, including 8 likely pathogenic or pathogenic variants and 14 variants of uncertain significance. Four patients carried more than one variant. Among the variants identified, 18 (81.8%) were found in ALS-associated genes. Variants in TBK1 were associated with extra-motor involvement.

CONCLUSIONS: Although the majority of the PLS patients in our cohort tested negative for an expanded panel of genes associated with ALS, HSP and PS, in 36.2% of the cases, a genetic variant was identified and it mostly belongs to genes associated with ALS, including a C9orf72 expansion and a rare SOD1 variant. Based on these results, we emphasize the need for genetic screening in PLS patients. Further studies on the genetic background are necessary to better understand the complex pathomechanism of each phenotype within the MND-FTD spectrum disorder.},
}

Humans
Italy
Male
Female
Middle Aged
Aged
Cohort Studies
Adult
C9orf72 Protein/genetics
*Motor Neuron Disease/genetics
High-Throughput Nucleotide Sequencing
Amyotrophic Lateral Sclerosis/genetics

@article {pmid41269218,
year = {2025},
author = {Elias, LLK and Elias, PCL and Antunes-Rodrigues, J and Moreira, AC},
title = {Plasma osmolality affects ACTH and cortisol regulation besides magnocellular vasopressin.},
journal = {European journal of endocrinology},
volume = {193},
number = {5},
pages = {L29-L30},
doi = {10.1093/ejendo/lvaf224},
pmid = {41269218},
issn = {1479-683X},
mesh = {Humans ; Osmolar Concentration ; *Hydrocortisone/blood ; *Adrenocorticotropic Hormone/blood ; *Arginine Vasopressin/deficiency ; Hypothalamo-Hypophyseal System/metabolism ; Pituitary-Adrenal System/metabolism ; *Vasopressins ; },
abstract = {The recently published article entitled "Disrupted ACTH and cortisol response to osmotic and non-osmotic stress in patients with arginine vasopressin deficiency," authored by Nikaj et al. evaluated the HPA axis response to osmotic and non-osmotic stimuli in patients with AVP deficiency (AVP-D) and with primary polydipsia (PP). Patients with AVP-D showed increased plasma ACTH and cortisol concentrations, in response to arginine stimulation, compared to patients with PP. The authors attributed altered ACTH and cortisol responses in AVP-D patients mainly to non-osmotic stress. However, PP patients may also show impaired osmolality and psychological comorbidities, which would be better assessed if there was a healthy control group in the study. We raised this aspect because data from our previous published study (Elias et al.), evaluating the interaction of plasma osmolality and plasma AVP, as well as plasma ACTH and cortisol responses to human CRH alone and combined with osmotic stimulus or isotonic volume loading in patients with AVP-D and healthy controls, showed a significant correlation between plasma osmolality and the ACTH response to hCRH across both healthy and AVP-D subjects during tests. Moreover, the enhanced ACTH and cortisol responses to hCRH with increasing pOsm were also observed in both healthy controls and patients with AVP-D. These findings suggest that the acute rise in plasma osmolality amplifies the ACTH and cortisol responses to hCRH, involving factors beyond magnocellular AVP. Importantly, Itagaki. et al. also demonstrated a positive correlation between plasma ACTH and plasma osmolality in AVP-D patients subjected to hypertonic saline infusion. In conclusion, while Nikaj. et al.'s study provides confirmation of the HPA axis activity in AVP-D patients, it seems unlikely that disruption of HPA axis regulation in these patients is due to impaired feedback regulation between AVP and CRH.},
}

Humans
Osmolar Concentration
*Hydrocortisone/blood
*Adrenocorticotropic Hormone/blood
*Arginine Vasopressin/deficiency
Hypothalamo-Hypophyseal System/metabolism
Pituitary-Adrenal System/metabolism
*Vasopressins

@article {pmid41268542,
year = {2025},
author = {Baird, LA and Teener, SJ and Webber-Davis, IF and Carter, AD and Huang, F and Jang, DG and Famie, JP and Piecuch, CE and Guo, K and Feldman, EL and Murdock, BJ},
title = {Tofacitinib extends survival in a mouse model of ALS through NK cell-independent mechanisms.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1662197},
pmid = {41268542},
issn = {1664-3224},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality/pathology ; *Pyrimidines/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; *Killer Cells, Natural/immunology/drug effects ; Mice, Transgenic ; *Protein Kinase Inhibitors/pharmacology ; Superoxide Dismutase-1/genetics ; Spinal Cord/drug effects/immunology ; Motor Neurons/drug effects/immunology ; Male ; Female ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with few treatment options, rendering the development of new, effective therapeutics of critical importance. The immune system plays a substantial role in ALS pathology, with multiple cell populations implicated in disease progression. Natural killer (NK) cells are innate immune cells that accumulate in the brain and spinal cord during ALS, increasing neuroinflammation and killing motor neurons. Depleting NK cells extends survival in mouse models of ALS. Tofacitinib, an FDA-approved janus kinase (Jak) and signal transducer and activator (STAT) pathway inhibitor, reduces NK cytotoxicity and decreases overall levels in peripheral blood and may represent a potential ALS therapy. Therefore, we aimed to evaluate the effects of tofacitinib treatment on survival and phenotype in an ALS mouse model. Additionally, we sought to determine the impact of dose and regimen on efficacy.

METHODS: SOD1 [G93A] mice, the most used rodent model of ALS, were treated with low- (5 mg/kg) and high-dose (30 mg/kg) tofacitinib following a prevention regimen, an intervention regimen, or a drug-cycling regimen, with survival being the primary outcome. Symptom onset was assessed via body weight, agility, and grip strength measurements. At end-stage disease (i) motor neurons and neuromuscular junctions were counted, (ii) immune populations were quantified via flow cytometry in peripheral blood and spinal cord, (iii) microglial surface marker expression was quantified to assess neuroinflammation, and (iv) bulk RNA-seq was performed on spinal cord.

RESULTS: Low-dose, but not high-dose, tofacitinib significantly increased survival and delayed weight loss. Notably, beginning treatment before symptom onset (prevention) did not offer any survival advantage over the intervention nor cycling regimen; further analyses were pooled by dose. There were no differences in motor neuron or neuromuscular junction counts. Peripheral NK and CD8+ T cells were decreased dose-dependently. Interestingly, spinal cord infiltrating NK cells increased with low-dose tofacitinib, though no other changes in neuroinflammation were observed. RNA-seq revealed that low-dose tofacitinib treatment reversed the dysregulation of multiple immune and metabolic pathways.

CONCLUSIONS: These data support the repurposing of tofacitinib as a potential ALS treatment.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality/pathology
*Pyrimidines/pharmacology/therapeutic use
*Piperidines/pharmacology/therapeutic use
Disease Models, Animal
Mice
*Killer Cells, Natural/immunology/drug effects
Mice, Transgenic
*Protein Kinase Inhibitors/pharmacology
Superoxide Dismutase-1/genetics
Spinal Cord/drug effects/immunology
Motor Neurons/drug effects/immunology
Male
Female

@article {pmid41268324,
year = {2025},
author = {Thakur, DK and Padole, S and Sarkar, T and Arumugam, S and Chattopadhyay, S},
title = {Liquid-Liquid Phase Separation: Mechanisms, Roles, and Implications in Cellular Function and Disease.},
journal = {FASEB bioAdvances},
volume = {7},
number = {11},
pages = {e70054},
pmid = {41268324},
issn = {2573-9832},
abstract = {Liquid-liquid phase separation is a basic biophysical process that creates essential membraneless organelles that support different cellular activities, including chromatin organization and gene expression. The malfunction of liquid-liquid phase separation (LLPS) plays a critical role in numerous diseases, such as neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), which involve TDP-43 and Tau, various cancers that utilize SPOP and YAP/TAZ proteins, and viral infections where pathogens use LLPS to replicate and avoid immune detection. This review brings together the fast-growing knowledge about LLPS across multiple scientific fields. The paper examines the physiological functions of LLPS along with its disease pathogenesis mechanisms and presents various experimental techniques (e.g., advanced microscopy, FRAP, FCS) for its investigation. It introduces new therapeutic approaches such as PTM modulation, small molecules like 1,6-hexanediol and Lipoamide, and advanced genetic tools including CRISPR and PROTACs like PSETAC, which also explores diagnostic applications. The thorough integration of knowledge presented here is essential to connect separate scientific findings while propelling research forward and turning LLPS discoveries into new biomedical developments.},
}

@article {pmid41267644,
year = {2025},
author = {Tahedl, M and Siah, WF and Karavasilis, E and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Tan, EL and Christidi, F and Kleinerova, J and Bede, P},
title = {Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78099},
pmid = {41267644},
issn = {1531-8249},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a very specific neuroimaging signature, but the molecular underpinnings of the strikingly selective anatomic involvement have not elucidated to date. Accordingly, a large neuroimaging study was conducted with 258 participants to evaluate associations between patterns of neurodegeneration and focal metabolic metrics.

METHODS: Structural and diffusivity alterations were systematically evaluated in a genetically stratified cohort. Voxelwise associations between neurodegeneration and physiological mitochondrial indices were systematically evaluated over the entire brain and also examined in specific regions.

RESULTS: Significant topological associations were identified between physiological mitochondria tissue density, nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome c oxidase (COX), mitochondrial respiratory capacity (MRC), tissue respiratory capacity (TRC), and propensity to focal atrophy in ALS. Anatomic correlations between mitochondrial metrics and morphometric change were particularly strong in GGGGCC hexanucleotide repeat carriers in C9orf72. Diffusivity analyses also confirmed associations between brain metabolism and microstructural degeneration. Higher focal mitochondria tissue density was associated with higher likelihood of frontal, temporal, cerebellar, opercular, thalamic, cingulum, putamen, corpus callosum, and corona radiata degeneration. Uncinate fasciculus degeneration was associated with higher Complex I, II, COX, and TRC activity. Topological associations were readily replicated in an external validation cohort.

INTERPRETATION: Our data indicate that brain regions with high metabolic activity are particularly vulnerable to neurodegeneration in ALS. Anatomic associations between physiological cerebral metabolism and patterns of neurodegeneration implicate mitochondrial dysfunction in the pathophysiology of ALS. Although mitochondrial dysfunction may not be the primary etiological factor, it may represent a shared bottleneck of multiple converging molecular and genetic pathways, offering a potential opportunity for meaningful pharmacological intervention. ANN NEUROL 2025.},
}

@article {pmid41267271,
year = {2025},
author = {Xue, S and Wang, T and Zhou, J and Liu, S and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y},
title = {Safety evaluation of aristolactams from the edible herb Houttuynia cordata: implications for dietary exposure and food safety.},
journal = {Food research international (Ottawa, Ont.)},
volume = {222},
number = {Pt 1},
pages = {117663},
doi = {10.1016/j.foodres.2025.117663},
pmid = {41267271},
issn = {1873-7145},
mesh = {Animals ; *Houttuynia/chemistry ; Mice, Inbred BALB C ; Mice ; *Aristolochic Acids/toxicity/pharmacokinetics ; *Food Safety ; Humans ; Male ; *Dietary Exposure/adverse effects ; Biological Availability ; Oxidative Stress/drug effects ; Kidney/drug effects ; Cell Line ; *Drugs, Chinese Herbal/toxicity ; Complement Activation/drug effects ; },
abstract = {Houttuynia cordata Thunb., a traditional edible and medicinal herb widely consumed in Asia, has raised concerns about food safety due to the presence of aristolactams (ALs), which are structural analogues of the nephrotoxic aristolochic acid I (AA I). This study investigated the subacute toxicity, metabolism and oral bioavailability of predominant ALs-aristolactam I (AL I), aristolactam BII (AL BII), and ALs fractions from H. cordata (HCA)-in BALB/c mice, with AA I as a positive control. The AL I, AL BII and HCA groups exhibited only modest elevations in body weight, serum renal indicators and urinary injury biomarkers. In contrast, AA I induced significant increases through oxidative stress and complement activation (C3a/C3aR and C5a/C5aR pathways). Although AL I demonstrated greater cytotoxicity to HK-2 cells (IC50 = 2.76 μM) than its metabolite AL Ia (IC50 = 35.41 μM) and even AA I (IC50 = 79.85 μM) in vitro, its in vivo toxicity was lower. This was attributed to the lower oral bioavailability of AL I (52.71 %) and AL BII (39.60 %) compared to AA I (99.83 %), combined with metabolism into less toxic derivatives. Furthermore, no parent ALs were detected in urine. These toxicokinetic properties limited renal exposure and reduced in vivo toxicity despite their notable cytotoxicity in vitro. These findings provided scientific support for the safe consumption of H. cordata at typical dietary levels, while emphasizing the importance of monitoring ALs content in edible herbs to ensure food safety and inform regulatory guidelines.},
}

Animals
*Houttuynia/chemistry
Mice, Inbred BALB C
Mice
*Aristolochic Acids/toxicity/pharmacokinetics
*Food Safety
Humans
Male
*Dietary Exposure/adverse effects
Biological Availability
Oxidative Stress/drug effects
Kidney/drug effects
Cell Line
*Drugs, Chinese Herbal/toxicity
Complement Activation/drug effects

@article {pmid41266705,
year = {2025},
author = {Di Rienzo, L and Genovese, I and Galluzzi, G and Ruocco, G and Fornetti, E},
title = {Uncovering the molecular details of the 14-3-3 recruitment by mutant Sod1 species.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41091},
pmid = {41266705},
issn = {2045-2322},
mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *14-3-3 Proteins/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; *Mutation ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Molecular Docking Simulation ; Protein Binding ; },
abstract = {Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial Amyotrophic Lateral Sclerosis (ALS), promoting disease progression through metal depletion, aggregation, and abnormal protein interactions. Among proteins interacting with pathological SOD1 aggregates, 14-3-3 proteins are involved in key cellular pathways often disrupted in ALS, such as cell survival, axonal growth, and DNA repair. Their sequestration by mutant SOD1 may impair their neuroprotective functions, exacerbating disease pathology. Despite this, 14-3-3 proteins remain understudied in ALS research, presenting an opportunity for novel insights. This study employs molecular dynamics simulations to investigate structural changes in two ALS-linked SOD1 mutations, A4V and L144F, compared to wild-type SOD1. A4V is associated with a severe disease form, while L144F leads to a slower progression, allowing an analysis of different ALS severities. Using Zernike polynomials and hydropathy assessments, we identified key structural alterations that promote aggregation and aberrant interactions. Large-scale docking simulations further suggest a stable complex between mutant SOD1 and 14-3-3 proteins, confirmed through molecular dynamics analyses. By elucidating structural features driving SOD1 aggregation and pathological interactions, our findings support targeting protein-protein interactions as a potential therapeutic strategy in ALS, offering an alternative to direct aggregate inhibition.},
}

*Superoxide Dismutase-1/genetics/metabolism/chemistry
*14-3-3 Proteins/metabolism/chemistry
Humans
Molecular Dynamics Simulation
*Mutation
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
Molecular Docking Simulation
Protein Binding

@article {pmid41265061,
year = {2025},
author = {Aphale, P and Dokania, S and Shekhar, H},
title = {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 = {155},
number = {},
pages = {102708},
doi = {10.1016/j.tube.2025.102708},
pmid = {41265061},
issn = {1873-281X},
}

@article {pmid41264881,
year = {2025},
author = {Genuis, SK and Luth, W and Adams, B and Johnston, WS},
title = {Patient-based evidence for amyotrophic lateral sclerosis prognostic health communication: "the clock is ticking…how long do I have?".},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2589782},
pmid = {41264881},
issn = {2167-9223},
abstract = {Objectives: Prognostic health communication is a critical challenge for amyotrophic lateral sclerosis (ALS) health-care professions, however patient-based evidence for best practice remains limited. We investigated how the experiences of ALS patients and caregivers can inform prognostic communication and whether patient-based evidence supports clinical use of predictive tools. Methods: Data were drawn from ALS Talk, an asynchronous, online focus group study. Patients and family caregivers were recruited from across Canada. Seven groups interacted in a threaded web-forum structure. Sixty-four participants shared experiences and perspectives on prognostic communication. Data were qualitatively analyzed using conventional content analysis and the constant-comparative approach. Results: Primary themes were prognostic communication as an ongoing, evolving conversation; prognostic heterogeneity; progression as an embodiment of prognosis; and functional prognosis. The theme, information needs/wants, contributed to the primary themes. Participants highlighted the importance of stepwise discussions of general and personalized prognosis; prognostic heterogeneity as a source of hope and a potential communication barrier; and how progression facilitates material understanding of prognosis, adaptation, and future planning. Further, participants wanted more information about functional prognosis and the impact of interventions/therapies on function and survival. Conclusions: We discuss participants' central questions: "how long" and "how well," and provide recommendations for patient-centred ALS prognostic communication. Participants' embodied understanding of prognosis and desire for information that anticipates functional change, informs disease management, and facilitates timely planning suggests that clinical application of ALS staging systems may meet patient and caregiver need. Testing in real-world clinical settings is needed to ensure the development of patient-centred predictive tools.},
}

@article {pmid41263806,
year = {2025},
author = {Kalkowski, K},
title = {[Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge].},
journal = {Postepy biochemii},
volume = {71},
number = {3},
pages = {252-259},
doi = {10.18388/pb.2021_599},
pmid = {41263806},
issn = {0032-5422},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; Genetic Therapy ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to progressive degeneration of motor neurons, muscle weakness and respiratory failure. Despite intensive research, the pathomechanisms of ALS have not been fully elucidated. This article presents the current state of knowledge on the genetic and molecular mechanisms of this disease, with a focus on mutations in the SOD1, C9ORF72, TARDBP, FUS, TBK1 genes, as well as recent discoveries in this area. Key pathogenetic processes are discussed, including disruption of RNA homeostasis, oxidative stress, mitochondrial dysfunction and protein aggregation. In addition, current therapeutic strategies are reviewed, including both registered drugs, such as riluzole and edaravone, and modern approaches, such as gene therapy, antisense oligonucleotides, immunotherapy and gene editing technologies, including CRISPR/Cas9. Special attention was given to clinical trials and their potential impact on future treatment options for ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy
Humans
Genetic Therapy
Superoxide Dismutase-1/genetics
C9orf72 Protein/genetics
Mutation
RNA-Binding Protein FUS/genetics
DNA-Binding Proteins/genetics
Protein Serine-Threonine Kinases/genetics

@article {pmid41262412,
year = {2025},
author = {Rajagopalan, V and Pioro, EP},
title = {Detour ahead: possible causes of corticospinal tract truncation in upper motor neuron-predominant amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf419},
pmid = {41262412},
issn = {2632-1297},
abstract = {Clinical diagnosis of amyotrophic lateral sclerosis (ALS) depends on finding evidence of combined of upper motor neuron (UMN) and lower motor neuron degeneration. T2- and proton density (PD)-weighted images reveal intracranial corticospinal tract (CST) hyperintensity in some UMN-predominant ALS patients who also exhibit faster disease progression compared to those without CST hyperintensity. Our previous study identified CST fibre tract truncation in a subset of UMN-predominant ALS patients, both with and without CST hyperintensity. In this study, we investigated the underlying cause(s) of CST fibre tract truncation in such ALS patients. Routine clinical diffusion tensor imaging (DTI) scans were acquired in 14 neurologic controls and 45 ALS patients using a 1.5 T magnetic resonance imaging (MRI) scanner. UMN-predominant ALS patients were categorized into two subgroups based on their clinically-acquired conventional MRI findings. DTI reconstruction was performed using both single-exponential and bi-exponential fitting approaches (the latter for free water [FW] estimation). DTI along the perivascular space (ALPS) index was also measured. CST fibres were reconstructed using tractography in both control and ALS subgroups. In CST-truncated ALS patients, the fibres deviated from their normal trajectory and entered the superior longitudinal fasciculus (SLF) at the level of the centrum semiovale, resulting in apparent truncation and overlap with the SLF. Axial diffusivity, radial diffusivity, FW content, and mean diffusivity values were normal along the expected CST pathway in cases of truncation, suggesting that axonal or myelin degeneration, inflammation, or oedema were unlikely to be responsible for CST truncation. ALPS index was significantly increased in CST-truncated patients compared to those without CST truncation. Based on these results, we hypothesize that impaired axonal guidance mechanisms or dysfunction of the glymphatic system may contribute to CST fibre tract truncation in ALS.},
}

@article {pmid41262008,
year = {2025},
author = {Scott, MR and Sverdlov, O and Davis-Plourde, K and Tripodis, Y},
title = {Assessment of Wiener Process Degradation Models With Application to Amyotrophic Lateral Sclerosis Decline.},
journal = {Statistics in medicine},
volume = {44},
number = {25-27},
pages = {e70323},
doi = {10.1002/sim.70323},
pmid = {41262008},
issn = {1097-0258},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Monte Carlo Method ; *Models, Statistical ; Computer Simulation ; Likelihood Functions ; Disease Progression ; Longitudinal Studies ; Stochastic Processes ; },
abstract = {Degradation models are commonly used in engineering to analyze the deterioration of systems over time. These models offer an alternative to standard longitudinal methods as they explicitly account for within-subject temporal variability through a latent stochastic process, allowing random fluctuations within a patient to be captured. This work investigates Wiener process-based degradation models with linear drift (i.e., slope) while considering a diffusion term to represent within-subject temporal variability, a random-effects term to capture between-subject variability of the slope, and a time-invariant term to account for measurement error. First-difference estimators that stabilize covariance matrix inversion and remove the influence of time-invariant confounders are presented and validated in clinically relevant settings. Monte Carlo simulations assessing relative error and coverage probability demonstrate that these models yield consistent and stable estimates. Profile likelihood methods, which reduce the dimensionality of the parameter space, also performed reliably, but should be used with caution when follow-up times are highly clustered. As a proof of concept, we applied these models to amyotrophic lateral sclerosis (ALS) data from the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT). We observed steeper slopes of the revised ALS Functional Rating Scale (ALSFRS-R) in individuals who died compared to those who survived, indicating that degradation model estimates are consistent with expected patterns of ALS decline. Our results demonstrate that these stochastic models provide accurate and efficient estimates of longitudinal deterioration. Future work aims to incorporate Wiener process degradation models into a joint modeling framework.},
}

*Amyotrophic Lateral Sclerosis/physiopathology
Humans
Monte Carlo Method
*Models, Statistical
Computer Simulation
Likelihood Functions
Disease Progression
Longitudinal Studies
Stochastic Processes

@article {pmid41261682,
year = {2025},
author = {Huang, X and Wang, X and Yang, Y and Chen, H},
title = {Assessing the potential causal influence of myasthenia gravis on neurodegenerative diseases via multivariable Mendelian randomization.},
journal = {Medicine},
volume = {104},
number = {44},
pages = {e45340},
pmid = {41261682},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Myasthenia Gravis/genetics/complications/epidemiology ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/etiology/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Alzheimer Disease/genetics/epidemiology/etiology ; Parkinson Disease/genetics ; Genetic Predisposition to Disease ; Risk Factors ; },
abstract = {Myasthenia gravis (MG), an autoimmune condition known for impairing neuromuscular signaling, has increasingly been implicated in broader neurological dysfunctions. Recent studies point toward a possible connection between autoimmune and neurodegenerative processes. However, whether MG contributes causally to the onset of major neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) remains unclear. This study utilizes Mendelian randomization (MR) to explore the potential causal influence of MG on these disorders from a genetic standpoint. A univariable Mendelian randomization (UVMR) framework was employed using summary-level data from genome-wide association studies (GWAS) to evaluate the effect of MG on the risk of AD, PD, and ALS. To confirm the robustness of the association between MG and AD, 2 independent AD GWAS datasets were incorporated for external replication, followed by a meta-analysis to combine the evidence. Additionally, multivariable Mendelian randomization (MVMR) was conducted to adjust for smoking behavior as a potential confounding factor. The UVMR analysis revealed a statistically significant causal relationship between MG and increased susceptibility to AD (odds ratio (OR): 1.037; 95% confidence interval (CI): 1.007-1.068; P = .016). No significant causal effects were observed for PD (OR: 1.019; 95% CI: 0.964-1.077; P = .509) or ALS (OR: 1.055; 95% CI: 0.977-1.140; P = .171). The association between MG and AD was consistently validated in 2 independent datasets (ieu-a-297: OR = 1.084; 95% CI: 1.017-1.156; P = .013; ieu-b-2: OR = 1.054; 95% CI: 1.006-1.104; P = .027). Meta-analysis reinforced the evidence supporting MG as a risk factor for AD (OR: 1.047; 95% CI: 1.023-1.072; P < .001). Furthermore, MVMR adjusting for smoking confirmed that MG independently contributes to AD risk (OR: 1.037; 95% CI: 1.006-1.069; P = .020). This study provides robust genetic evidence suggesting that MG is a causal and independent risk factor for AD. These findings highlight a novel link between autoimmunity and neurodegeneration, offering new directions for mechanistic and therapeutic research.},
}

Humans
Mendelian Randomization Analysis
*Myasthenia Gravis/genetics/complications/epidemiology
Genome-Wide Association Study
*Neurodegenerative Diseases/genetics/etiology/epidemiology
Amyotrophic Lateral Sclerosis/genetics
Alzheimer Disease/genetics/epidemiology/etiology
Parkinson Disease/genetics
Genetic Predisposition to Disease
Risk Factors

@article {pmid41261122,
year = {2025},
author = {Gobert, F and Merida, I and Maby, E and Seguin, P and Jung, J and Morlet, D and André-Obadia, N and Dailler, F and Berthomier, C and Otman, A and Le Bars, D and Scheiber, C and Hammers, A and Bernard, E and Costes, N and Bouet, R and Mattout, J},
title = {Disorder of consciousness rather than complete Locked-In Syndrome for end stage Amyotrophic Lateral Sclerosis: a case series.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {482},
pmid = {41261122},
issn = {2730-664X},
abstract = {BACKGROUND: The end-stage of amyotrophic lateral sclerosis (ALS) is commonly regarded as a complete Locked-In Syndrome (cLIS). Shifting the perspective from cLIS (assumed consciousness) to Cognitive Motor Dissociation (potentially demonstrable consciousness), we aimed to assess the preservation of covert awareness (internally preserved but externally inaccessible) using a multimodal battery.

METHODS: We evaluate two end-stage ALS patients using neurophysiological testing, passive and active auditory oddball paradigms, an auditory Brain-Computer Interface (BCI), functional activation-task imaging, long-term EEG, brain morphology, and resting-state metabolism to characterize underlying brain function.

RESULTS: Patient 1 initially follows simple commands but fails twice at BCI control. At follow-up, command following is no longer observed and his oddball cognitive responses disappear. Patient 2, at a single evaluation, is unable to follow commands or control the BCI. Both patients exhibit altered wakefulness, brain atrophy, and a global cortico-subcortical hypometabolism pattern consistent with a disorder of consciousness, regarded as an extreme manifestation of ALS-associated fronto-temporal dementia.

CONCLUSIONS: Although it is not possible to firmly prove the absence of awareness, each independent measure concurred with suggesting that a "degenerative disorder of consciousness" rather than a cLIS may constitute the final stage of ALS. This condition appears pathophysiologically distinct from typical tetraplegia and anarthria, in which behavioural communication and BCI use persist to enhance quality of life. Identifying the neuroimaging signatures of this condition represents a substantial milestone in understanding end-stage ALS. Large-scale longitudinal investigations are warranted to determine the prevalence of this profile among patients whose communication appears impossible.},
}

@article {pmid41260310,
year = {2025},
author = {Alberti, C and Parente, V and Corti, S and Sansone, VA},
title = {From molecular convergence to clinical divergence: Comparative pathogenic mechanisms and therapeutic trajectories in C9orf72-ALS/FTD and myotonic dystrophy.},
journal = {Neurobiology of disease},
volume = {217},
number = {},
pages = {107192},
doi = {10.1016/j.nbd.2025.107192},
pmid = {41260310},
issn = {1095-953X},
abstract = {Short tandem repeat expansions in C9orf72, DMPK, and CNBP genes cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and myotonic dystrophy types 1 and 2 (DM1/DM2), respectively. Despite distinct clinical phenotypes, these disorders share convergent molecular mechanisms with tissue-specific vulnerability, offering a framework to inform precision therapeutic strategies. Shared pathogenic features include nuclear RNA foci sequestering RNA-binding proteins that disrupt splicing, and repeat-associated non-AUG translation generating toxic dipeptide repeat proteins. In C9orf72, GGGGCC repeats form RNA-driven condensates, including protein-free condensates, via G-quadruplex formation. Evidence also implicates autophagy-lysosome and mitochondrial dysfunction, suggesting a potential "two-hit" loss/gain-of-function model. Clinically, C9orf72 expansions primarily affect motor neurons and frontotemporal circuits, with ALS progression typically occurring over 2-5 years. Conversely, myotonic dystrophy manifests as a muscle-predominant multisystem disorder progressing over decades. Genomic instability contributes to disease variability, with anticipation and parent-of-origin effects strongest in DM1, not confirmed in DM2 and controversial in C9orf72. Sequence interruptions modulate repeat stability and phenotype, influencing diagnostic interpretation. Therapeutic development has yielded contrasting outcomes. Antisense oligonucleotides targeting C9orf72 achieved target engagement and reduced dipeptide repeat proteins but failed clinically, potentially due to sense-strand selectivity and persistence of TDP-43 pathology. In contrast, RNA-targeting conjugates for DM1 (delpacibart etedesiran and DYNE-101) received FDA Breakthrough Therapy designation. Therapeutic success depends on tissue accessibility and addressing both shared and circuit-specific pathogenic cascades. While nuclear RNA targets appear druggable in myotonic dystrophy, the bidirectional transcription and compartmentalized pathology of C9orf72 ALS/FTD may require multi-targeted approaches for precision medicine.},
}

@article {pmid41259707,
year = {2025},
author = {He, T and Lu, Y and Chen, Y and Wang, J and Zhang, H},
title = {Intelligent Microsphere Soil Conditioner Based on Aminated Lignosulfonate and Thermoresponsive Polymer.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.5c04647},
pmid = {41259707},
issn = {1520-5827},
abstract = {In this research, a composite hydrogel microsphere material, SA/P(NVCL-ALS)-N-ZnO/A-Dol-urea (hereafter referred to as SA-PANZ), with dual responsiveness to temperature and pH, was developed by integrating aminated lignosulfonate sodium (ALS), poly(N-vinylcaprolactam) (PNVCL), nano zinc oxide (N-ZnO), and alkali-treated dolomite (A-Dol). The material exhibited excellent controlled-release performance, with a cumulative urea release rate of 67.22% at 40 °C and pH = 4. The Ritger-Peppas model fitted well with the release data, providing strong theoretical support for optimizing the microspheres. Compared to control groups, both the loading efficiency and encapsulation efficiency were significantly improved, achieving 38.50 and 12.83%, respectively. Water retention tests demonstrated that the microspheres maintained 39.92% of their moisture after 5 h, indicating an excellent water-holding capacity. Degradation experiments indicated a degradation rate of 60.14% under acidic conditions, demonstrating excellent biodegradability. Antibacterial assays revealed a clear inhibitory effect against Aspergillus niger, and plant cultivation experiments confirmed that the microspheres promoted pea growth under acidic and high-temperature stress. This research introduced a novel biodegradable microsphere-based soil conditioner with strong potential to improve nutrient use efficiency and soil quality in agricultural environments.},
}

@article {pmid41259564,
year = {2025},
author = {Araújo, RCP and Godoy, CMA and Ferreira, LMBM and Godoy, JF and Magalhães, H},
title = {Fiberoptic endoscopic evaluation of swallowing in amyotrophic lateral sclerosis: comparison with older people with dysphagia and relationship with time since diagnosis.},
journal = {CoDAS},
volume = {37},
number = {6},
pages = {e20240296},
doi = {10.1590/2317-1782/e20240296pt},
pmid = {41259564},
issn = {2317-1782},
mesh = {Humans ; *Deglutition Disorders/physiopathology/etiology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Cross-Sectional Studies ; Male ; Retrospective Studies ; Aged ; Female ; Middle Aged ; *Deglutition/physiology ; Time Factors ; Fiber Optic Technology ; Aged, 80 and over ; Severity of Illness Index ; },
abstract = {PURPOSE: (1) to compare the findings of the instrumental swallowing assessment between individuals with amyotrophic lateral sclerosis (ALS) and older dysphagic adults without neurological diagnosis; (2) to compare the onset of pharyngeal response, pharyngeal residues, and the level of oral intake in relation to the time since diagnosis in the ALS group.

METHODS: This cross-sectional, retrospective study collected data from medical records. Altogether, 101 individuals with dysphagia were included and stratified into two groups: the first had 56 patients diagnosed with ALS, and the second had 45 older adults. Dysphagia signs were analyzed through fiberoptic endoscopic evaluation of swallowing, using four food consistencies, classified by the International Dysphagia Diet Standardisation Initiative (IDDSI). Pharyngeal residues were classified by the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS), and oral intake by the Functional Oral Intake Scale (FOIS).

RESULTS: The ALS group had differences in multiple swallows with one IDDSI consistency; posterior oral leakage, pharyngeal residues, and laryngeal penetration with three consistencies; and aspiration with one consistency. Individuals with more than 3 years since diagnosis had differences in the onset of the pharyngeal response in the pyriform sinuses, moderate pharyngeal residues, and oral intake.

CONCLUSION: The ALS group had significant differences in the occurrence of multiple swallows, posterior oral leakage, pharyngeal residues, penetration, and aspiration with three IDDSI consistencies. Furthermore, the time since diagnosis was a determining factor for all three parameters.},
}

Humans
*Deglutition Disorders/physiopathology/etiology/diagnosis
*Amyotrophic Lateral Sclerosis/physiopathology/complications
Cross-Sectional Studies
Male
Retrospective Studies
Aged
Female
Middle Aged
*Deglutition/physiology
Time Factors
Fiber Optic Technology
Aged, 80 and over
Severity of Illness Index