@article {pmid41238102,
year = {2025},
author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q},
title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156436},
doi = {10.1016/j.metabol.2025.156436},
pmid = {41238102},
issn = {1532-8600},
abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.},
}

@article {pmid41237982,
year = {2025},
author = {Streltsov, VA and Ganio, KE and Nuttall, SD and Hernandez, JA and Dennys, CN and Crouch, PJ and Estevez, AG and Franco, MC and Beckman, JS and Roberts, BR},
title = {The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107189},
doi = {10.1016/j.nbd.2025.107189},
pmid = {41237982},
issn = {1095-953X},
abstract = {A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). Over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, the motor neuron disease accelerates in rodent models that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1. Previously, we have shown that the loss of zinc from SOD1 triggers motor neuron death in culture due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer showed that the zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.},
}

@article {pmid41236695,
year = {2025},
author = {Ciocarlan, A and Shvetsova, M and Aricu, A and Lungu, L and Peshkova, A and Zinicovscaia, I and Deleanu, M and Duca, G},
title = {Comparative Study of Nicotine Content in Moldavian Tobacco by UV-Vis Spectrophotometry and UHPLC and their Mineral Composition by ICP-OES.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41236695},
issn = {1559-0720},
abstract = {Tobacco is one of the oldest cultures known to mankind for more than 5000 years. Despite the proven harm by smoking, the number of smokers in Moldova is growing, making the quality control of tobacco products an important task. This study focused on the quantification of nicotine and the determination of the mineral composition in autochthonous Moldavian tobacco selections. Ultraviolet-visible (UV-Vis) spectroscopy and ultrahigh performance liquid chromatography (UHPLC) were applied for quantification of nicotine in ten tobacco varieties (Molovata, Trapezond 209, Doina 210, Moldavschi 237, Virginia 263, Moldavschi 272, Burley 320, Virginia 401, Moldavschi 456, Jubileu M) and Nicotiana rustica L. species of Moldavian origin. The nicotine content determined by UV-Vis analysis ranged from 1.24% to 2.74%, while UHPLC analysis yielded a range of 0.97% to 2.16% and the difference is due to the higher selectivity and accuracy of the UHPLC method. A total of 14 chemical elements, Al, S, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sr, Cd, Ba and Hg, were identified in tobacco varieties by inductively coupled plasma-optical emission spectrometry. The mean elements content in tobacco leaves samples was the following: Al (1390 ± 795 mg/kg), S (3043 ± 749 mg/kg), V (1.9 ± 1.1 mg/kg), Cr (2.5 ± 1.3 mg/kg), Mn (126 ± 21 mg/kg), Fe (1077 ± 579 mg/kg), Co (0.39 ± 0.19 mg/kg), Ni (2.4 ± 0.9 mg/kg), Cu (3.9 ± 1.5 mg/kg), Zn (13.8 ± 3.3 mg/kg), Sr (164 ± 17 mg/kg), Cd (1.4 ± 0.3 mg/kg), Ba (62 ± 12 mg/kg) and Hg (0.04 ± 0.005 mg/kg). Principal components analysis, applied for element grouping, revealed two groups of elements, which can be associated with elements uptake by plants from soil, agricultural practices, fuel combustion, and vehicles and road dust.},
}

@article {pmid41234489,
year = {2025},
author = {Chan, JM and Romano, C and Lee, AY and Wang, S and Lombardo, D and Kamdar, F and Dora, M and Khan, S and Mammen, P and Kimonis, V},
title = {Cardiomyopathy in valosin-containing protein multisystem proteinopathy: Evaluation, diagnosis, and management.},
journal = {American heart journal plus : cardiology research and practice},
volume = {60},
number = {},
pages = {100644},
pmid = {41234489},
issn = {2666-6022},
abstract = {Valosin-containing protein (VCP)-associated multisystem proteinopathy is a rare, autosomal dominant disease that affects skeletal muscle, bone, central nervous system, and the heart. While VCP mutations are well established as causing inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, their role in cardiomyopathy remains underrecognized. This review aims to evaluate the pathophysiology, diagnostic approach, and management of VCP-associated cardiomyopathy to provide a framework for clinical care and future research. Emerging evidence from animal models and human case studies suggests that VCP dysfunction disrupts cardiomyocyte homeostasis, impairs protein degradation, and alters mitochondrial function, leading to maladaptive cardiac remodeling and susceptibility to dilated or hypertrophic cardiomyopathy. Echocardiographic studies in patients with VCP variants reveal a significant prevalence of diastolic dysfunction, conduction abnormalities, and variable degrees of systolic impairment. Despite these findings, there are no standardized guidelines for the diagnosis and management of VCP-associated cardiomyopathy. Current treatment strategies are extrapolated from heart failure guidelines, incorporating neurohormonal blockades with angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Our review highlights the need for systematic screening protocols, genotype-phenotype correlation studies, and the development of targeted therapies. Future research should focus on identifying biomarkers for early detection, elucidating the molecular mechanisms underlying cardiac dysfunction, and assessing the efficacy of novel treatment strategies. Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.},
}

@article {pmid41234281,
year = {2025},
author = {Polito, V and Howarth, S and Roberts, A and Arbige, S},
title = {Does transliminality predict subperceptual information processing?.},
journal = {Neuroscience of consciousness},
volume = {2025},
number = {1},
pages = {niaf044},
pmid = {41234281},
issn = {2057-2107},
abstract = {Anomalous experiences, such as hallucinations and mystical experiences, are positively related to delusional ideation, religiosity, and paranormal beliefs. Some researchers argue that these relationships are explained by 'transliminality'-a trait describing sensitivity to stimuli crossing the threshold into consciousness. This claim suggests such beliefs may be attempts to interpret barely perceptible stimuli. The strongest evidence for this comes from Crawley et al. (2002), who found transliminality was associated with responses to subperceptual primes. In the current study, we attempted a high-powered replication of Crawley et al.'s findings that: (i) transliminality predicts identification of subperceptual visual primes, and (ii) this relationship is explained by stimulus sensitivity rather than response bias. Participants completed a transliminality measure and an online card guessing task in two parts. In part one, participants were shown 100 images of playing cards and asked to guess which of five shapes was on the other side of the card. A total of 50 trials contained a subperceptual prime in the form of a target shape, and 50 trials were unprimed. In part two, participants were shown 20 primed and 20 unprimed trials. They were told a prime was sometimes present and asked to report whether they noticed this on each trial. We found strong evidence against an association between transliminality and prime perception in both tasks. These results do not support conceptualizing transliminality as a measure of subperceptual processing capabilities. This study did demonstrate the feasibility of conducting research involving rapidly presented visual stimuli in an online setting.},
}

@article {pmid41234248,
year = {2025},
author = {Evans, M},
title = {Race, Crime, and Lending Risk in Chicago: The Relevance of Crime and Disorder for HOLC's Neighborhood Assessments.},
journal = {Race and social problems},
volume = {17},
number = {4},
pages = {307-321},
pmid = {41234248},
issn = {1867-1748},
abstract = {UNLABELLED: While scholars have documented the importance of race for decisions on lending risk and value in the U.S. housing market, less is known about how crime shaped lending risk assessments or how a neighborhood's racial composition influenced appraisers' perceptions of crime and disorder. Drawing on the Home Owners' Loan Corporation (HOLC) residential security maps, this study examines appraisers' narratives around neighborhood crime and disorder, how observed neighborhood conditions shaped these narratives, and how both observed crime and perceptions of disorder influenced decisions on lending risk. Using the case of Chicago, this study integrates multiple historical datasets, including the HOLC residential security maps and their corresponding neighborhood area descriptions, the 1940 Census, and data on criminal activity reflected through Clifford Shaw et al.'s residence of male offenders map and Frederic Thrasher's gangland activity map. Findings suggest that perceptions of crime and disorder are largely driven by a neighborhood's Black racial composition, independent of observed measures of crime. While both observed crime and a neighborhood's Black racial composition predicted lending risk assessments, appraisers' perceptions of disorder did not. The results indicate that although HOLC appraisers' perceptions of crime and disorder were racially motivated, their biased perceptions did not exert a unique, independent influence on their decisions to redline Black neighborhoods. Rather, racial discrimination was already explicitly embedded into their neighborhood valuation practices. This study provides new insights into the historical roots of neighborhood stigmatization and institutional disinvestment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12552-025-09442-4.},
}

@article {pmid41233462,
year = {2025},
author = {Cattaneo, M and Bonanomi, M and Chirizzi, C and Malacarne, C and Giagnorio, E and Farinazzo, G and Bonanno, S and Porro, D and Lauria, G and Metrangolo, P and Bombelli, FB and Gaglio, D and Marcuzzo, S},
title = {Metabolic reprogramming in amyotrophic lateral sclerosis ependymal stem cells by FM19G11 nanotherapy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39847},
pmid = {41233462},
issn = {2045-2322},
support = {1157625//Fondazione Regionale per la Ricerca Biomedica POR FESR/ ; IR0000010//Italian Ministry of University and Research (MIUR)-ELIXIR-IT through the empowering project ELIXIRNextGenIT/ ; T4-AN-09//CALabria HUB per Ricerca Innovativa ed Avanzata/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; Animals ; Mice ; Male ; *Nanoparticles/chemistry ; *Ependyma/metabolism/cytology/pathology/drug effects ; *Stem Cells/metabolism/drug effects ; Metabolomics ; Metabolome/drug effects ; Mice, Transgenic ; Disease Models, Animal ; *Cellular Reprogramming/drug effects ; Motor Neurons/metabolism ; Humans ; Metabolic Reprogramming ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the motor cortex, brainstem, and the spinal cord. In response to neurodegeneration, spinal cord exhibits ineffective regenerative attempt, thus suggesting that therapeutic strategies aimed at enhancing regenerative capacity of ependymal stem/progenitor cells (epSPCs), residing in the spinal cord, could promote neurogenesis. Dysregulated levels of metabolites might disturb epSPC differentiation, and their restoration might favour neurogenesis. This study aimed to investigate the metabolomic profile of epSPCs from ALS mice to identify altered metabolites as novel therapeutic targets for precision treatment. We performed a metabolome analysis to investigate changes in epSPCs from ALS compared to control male mice (B6SJL-Tg (SOD1*G93A)1Gur/J) and treated the epSPCs with FM19G11-loaded nanoparticles (NPs) to reestablish metabolic balance. Metabolomics analysis revealed significant changes in ALS epSPCs compared to controls. In vitro treatment with FM19G11-loaded nanoparticles (NPs) restored key metabolic networks, particularly in pathways related to glucose, glutamate and glutathione metabolism. These findings highlight the potential of FM19G11-loaded NPs to revert metabolic dysregulation in ALS epSPCs, providing a basis for innovative metabolic therapies and precision medicine approaches to counteract motor neuron degeneration in ALS and other motor neuron diseases.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy
Animals
Mice
Male
*Nanoparticles/chemistry
*Ependyma/metabolism/cytology/pathology/drug effects
*Stem Cells/metabolism/drug effects
Metabolomics
Metabolome/drug effects
Mice, Transgenic
Disease Models, Animal
*Cellular Reprogramming/drug effects
Motor Neurons/metabolism
Humans
Metabolic Reprogramming

@article {pmid41233180,
year = {2025},
author = {Fukutake, T},
title = {[Charcot and Sherlock Holmes: The Contemporary Rise of Neurodiagnostics and Detective Science and Its Significance].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1221-1229},
doi = {10.11477/mf.188160960770111221},
pmid = {41233180},
issn = {1881-6096},
mesh = {History, 19th Century ; Humans ; *Neurology/history ; History, 20th Century ; *Nervous System Diseases/diagnosis/history ; },
abstract = {Jean-Martin Charcot (1825-1893) gradually shifted his medical interest from internal medicine to neurology. Furthermore, he established neurodiagnostic methods that emphasized observation, such as in tabes dorsalis, and summarized core neurological diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis in a clinical-anatomical/pathological manner. For his contributions, he is known as the father of neurology. He then worked to elucidate hysteria. Sir Arthur Conan Doyle (1859-1930), born more than 30 years later, opened an ophthalmology clinic after earning his doctorate in research on tabes dorsalis. However, he then changed direction to writing books, such as Sherlock Holmes stories, and created full-fledged detective studies. Later, he shifted his focus to spiritualism, with an interest in Charcot's hypnotism. Although their careers are similar, there is no direct connection between Charcot's neurological studies and Conan Doyle's detective stories. However, neurodiagnostic and detective studies emerged in the second half of the 19th century at the same time, although they shared a commonality in content, in that they both emphasized observation and deduction without preconceptions. This contemporaneity was inevitable, as the background to this was the emergence of a middle class and urbanization in the era of war and revolution under capitalism after the Industrial Revolution.},
}

History, 19th Century
Humans
*Neurology/history
History, 20th Century
*Nervous System Diseases/diagnosis/history

@article {pmid41233177,
year = {2025},
author = {Ando, T and Fukutake, T},
title = {[Charcot and Spinal Cord Disease].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1194-1200},
doi = {10.11477/mf.188160960770111194},
pmid = {41233177},
issn = {1881-6096},
mesh = {Humans ; *Spinal Cord Diseases/history/pathology/diagnosis ; History, 19th Century ; *Arthropathy, Neurogenic/history ; },
abstract = {This paper outlines the contributions of Jean-Martin Charcot (1825-1893) to the study of spinal cord diseases. Charcot pioneered the anatomoclinical method, which correlated clinical symptoms with pathological findings through detailed observations and autopsies. He elucidated the dual structure of the motor system-gray and white matter-and established the clinical and pathological framework of amyotrophic lateral sclerosis, distinguishing it from other disorders. He also contributed to the understanding of tabes dorsalis by linking sensory ataxia to lesions of the dorsal columns and roots, and identified neurogenic joint disease (Charcot joint). Furthermore, Charcot described compressive myelopathy based solely on clinical signs and postmortem findings, highlighting the importance of symptom distribution, such as hand muscle atrophy, in the differential diagnosis. His legacy continues to influence modern neurology, reinforcing the value of precise clinical observation in the diagnostic process.},
}

Humans
*Spinal Cord Diseases/history/pathology/diagnosis
History, 19th Century
*Arthropathy, Neurogenic/history

@article {pmid41172876,
year = {2025},
author = {Li, C and Fan, W and Wu, G},
title = {Comment on "LMO2 confers value as a potential immunotherapy marker in pan-cancer analysis and inhibits progression of clear cell renal cell carcinoma".},
journal = {Translational oncology},
volume = {63},
number = {},
pages = {102588},
pmid = {41172876},
issn = {1936-5233},
abstract = {• Commendation of LMO2′s role: Wang et al.'s study demonstrates LMO2 as a promising immunotherapy marker and tumor suppressor in clear cell renal cell carcinoma (ccRCC), supported by multi-omics integration and mechanistic insights into the ZC3H13-m6A-LMO2-GATA2-BEX1-NF-κB axis. • Methodological enhancements suggested: Implement rigorous statistical corrections (e.g., Bonferroni or FDR for TCGA data) and adopt immunocompetent models (e.g., syngeneic ccRCC grafts in C57BL/6 mice) to improve robustness and translational relevance. • Direct validation required: Verify protein interactions (e.g., LMO2-GATA2 binding via co-immunoprecipitation) and m6A modification sites in LMO2 mRNA to strengthen mechanistic claims. • Functional testing for immunotherapy: Conduct in vitro co-culture or in vivo immunotherapy response models to causally link LMO2 to immune regulation and validate its biomarker potential. • Future innovation pathways: Explore epigenetic layers (e.g., m1A or m5C modifications via nanopore sequencing), apply single-cell multi-omics, and advance preclinical studies combining LMO2-targeted therapies with immune checkpoint inhibitors.},
}

@article {pmid41233174,
year = {2025},
author = {Uchihara, T},
title = {[Success and Failure during Three Centuries of Charcot's Clinical Neuropathology: From Amyotrophic Lateral Sclerosis to Functional Neurological Disorders].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1165-1175},
doi = {10.11477/mf.188160960770111165},
pmid = {41233174},
issn = {1881-6096},
mesh = {*Amyotrophic Lateral Sclerosis/history/pathology ; Humans ; History, 19th Century ; History, 20th Century ; *Nervous System Diseases/history/pathology ; Hysteria/history ; *Neuropathology/history ; },
abstract = {Clinical neuropathology was advanced by Charcot at la Salpêtrière Hospital in the 19th century. The lower and upper motor signs of amyotrophic lateral sclerosis were corroborated at autopsy by degeneration of the anterior horns and lateral columns, respectively. The redefinition of paralysis agitans as Parkinson's disease was substantiated in the 20th century through a series of pathological, biochemical, and genetic studies that provided definitive, museum-like evidence of neurological diseases. In contrast to these scientific achievements, the phenomenology of hysteria was publicly evaluated and recognized in front of the audiences that included non-medical professionals. This theater-like format, which encouraged interaction between patients and spectators, might have influenced the clinical presentation of hysteria and complicated its interpretation. Contrary to Charcot's expectations, attempts to identify the causative lesions of hysteria were unsuccessful. Paradoxically, however, this failure paved the way for the development of dynamic psychiatry by Freud and Janet, and later, the conceptualization of functional neurological disorders in the 21st century.},
}

*Amyotrophic Lateral Sclerosis/history/pathology
Humans
History, 19th Century
History, 20th Century
*Nervous System Diseases/history/pathology
Hysteria/history
*Neuropathology/history

@article {pmid41233143,
year = {2025},
author = {Cook, BE and McLaren, DG and Sullivan, JM and El Fakhri, G and Yokell, DL and Freeman, MW and Currier, N and Oestergaard, ME and Dobson, H and Hesterman, J and Salem, N and Nestorov, I and Monine, M and Martarello, L and Evans, KC and Fradette, S and Ferguson, TA and Graham, D and Passamonti, L},
title = {Central Nervous System Biodistribution and Pharmacokinetics of Radiolabeled Tofersen in Rodents, Nonhuman Primates, and Humans.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.270731},
pmid = {41233143},
issn = {1535-5667},
abstract = {Antisense oligonucleotides (ASOs) are an important therapeutic modality across several therapeutic areas, offering currently available and potential future treatment options for patients. ASO pharmacokinetics, biodistribution, and regional brain uptake are not fully characterized, particularly in humans. Here, we report preclinical studies and the first-in-human imaging trial measuring the biodistribution of [[99m]Tc]Tc-MAG3-tofersen. The tracer was designed to be a proxy for tofersen (Qalsody; Biogen), an ASO approved for the treatment of amyotrophic lateral sclerosis in adults who have a variant in the SOD1 gene (SOD1-ALS). Methods: Tofersen was conjugated to a MAG3 moiety, which chelates [99m]Tc to yield [[99m]Tc]Tc-MAG3-tofersen. [[99m]Tc]Tc-MAG3-tofersen and unlabeled tofersen were intrathecally injected in rats, nonhuman primates (NHPs), and healthy human volunteers (n = 3) via lumbar puncture, followed by SPECT/CT imaging. Tofersen was coadministered at a therapeutic dose. The tracer [[99m]Tc]Tc-MAG3-tofersen was prepared with greater than 99% purity. Results: Findings in rats demonstrated that [[99m]Tc]Tc-MAG3-tofersen was a proxy measure of unlabeled tofersen, and dosimetry was calculated from NHP imaging data. In a clinical study, unlabeled tofersen coadministered with a microdose of [[99m]Tc]Tc-MAG3-tofersen (≤129.5 MBq [3.5 mCi]) was well-tolerated. Human dosimetry estimates were within safe radiation dose levels. Imaging showed consistent distribution of radiolabeled ASO throughout the spinal cord and brain across species, with clearance patterns diverging in humans. Although rats and NHPs demonstrated declining brain concentrations over the study duration, human brain uptake increased during the first 4 h after injection. Additionally, tracer clearance from the spine in rodents and NHPs plateaued after 6 h but continued to decrease in humans. Radiolabeled ASO clearance from the lumbar spine was observed across all species, with peripheral clearance mediated primarily through the liver and kidneys. Broad uptake of the ASO in the brain and spinal cord is consistent with the clinical effects of tofersen observed in individuals with the SOD1-ALS variation. Conclusion: In preclinical and human SPECT/CT studies, [[99m]Tc]Tc-MAG3-tofersen mirrored unlabeled drug distribution, showing broad spinal cord and brain uptake, with some differences in kinetics among species.},
}

@article {pmid41232736,
year = {2025},
author = {Papathomas, A},
title = {Abandoning The Big Mick: A commentary on Smith et al.'s 25 years of qualitative research in sport and exercise psychology.},
journal = {Psychology of sport and exercise},
volume = {},
number = {},
pages = {103025},
doi = {10.1016/j.psychsport.2025.103025},
pmid = {41232736},
issn = {1878-5476},
abstract = {This essay provides a reflective commentary on Smith et al.'s "25 years of qualitative research in sport and exercise psychology" piece. Alongside summarising the primary insights of their review, I seek to situate current qualitative sport and exercise work within psychology's long-standing quest for scientific legitimacy. Including a whistle-stop tour of the history of psychology, I argue that a form of disciplinary imposter syndrome has shaped psychological science and continues to influence contemporary qualitative research. The consequences of this scientism are a trend towards formulaic, risk-averse, qualitative inquiry-by-numbers. Extending Brinkmann's (2015) McDonaldization metaphor, I propose McDowellisation; which positions qualitative methodolatry as motivated by a quest to appear more objective, more scientific, and ultimately more like our "real science" quantitative cousins. The danger is that the field of qualitative research foregoes the very qualities that inspired its rise. My optimistic conclusion is to follow the lead of those scholars that have rejected rigid fast-food processes in favour or rigorous, reflexive, interpretive work across a broad range of methodologies.},
}

@article {pmid41231952,
year = {2025},
author = {Lu, YN and Li, X and Hayes, L and Zhao, XF and Wang, J},
title = {MARK2 regulates C9orf72 repeat-associated non-AUG translation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {46},
pages = {e2514182122},
doi = {10.1073/pnas.2514182122},
pmid = {41231952},
issn = {1091-6490},
mesh = {*C9orf72 Protein/genetics/metabolism ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Protein Biosynthesis ; Frontotemporal Dementia/genetics/metabolism/pathology ; *Protein Serine-Threonine Kinases/metabolism/genetics ; DNA Repeat Expansion ; Eukaryotic Initiation Factor-2/metabolism/genetics ; Neurons/metabolism ; Signal Transduction ; Disease Models, Animal ; },
abstract = {Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2α kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2α signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.},
}

*C9orf72 Protein/genetics/metabolism
Animals
Humans
Mice
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*Protein Biosynthesis
Frontotemporal Dementia/genetics/metabolism/pathology
*Protein Serine-Threonine Kinases/metabolism/genetics
DNA Repeat Expansion
Eukaryotic Initiation Factor-2/metabolism/genetics
Neurons/metabolism
Signal Transduction
Disease Models, Animal

@article {pmid41231679,
year = {2025},
author = {Wang, T and Yu, G and Wu, Y and Wang, S and Zhu, Y and Li, H and Li, H and Yu, G},
title = {A Chiral Electrocatalyst for High-Performance Aluminum-Sulfur Battery.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c14506},
pmid = {41231679},
issn = {1520-5126},
abstract = {Aluminum-sulfur (Al-S) batteries are regarded as promising electrochemical energy storage systems due to their high energy density, cost-effectiveness, and environmental compatibility. However, their practical application is hindered by sluggish sulfur conversion kinetics. Although certain achievements have been made, conventional strategies for modulating the spin state of electrocatalysts, such as heteroatom doping or lattice strain engineering, exhibit inherent limitations in optimizing electron orbital interactions. Herein, we report a novel MoS2 electrocatalyst with spin orientation manipulation achieved through the chiral-induced spin selectivity (CISS) effect. This approach couples chiral molecules with layered MoS2 to regulate the spin polarization of molybdenum atoms, thereby enhancing the sulfur redox kinetics without relying on chemical modification. Electrochemical analyses demonstrated that the cathode with chiral MoS2 delivers a reversible specific capacity of ∼700 mAh g[-1] at 2 A g[-1] over 3000 cycles, accompanied by improved sulfur utilization efficiency. This work not only provides a paradigm for designing high-performance electrocatalysts in sulfur-based batteries but also highlights the critical role of spin effects in electrocatalytic systems, offering new perspectives for the innovation of electrocatalyst materials in batteries.},
}

@article {pmid41229731,
year = {2025},
author = {Nasir, AR and Delpirou Nouh, C},
title = {TDP-43-proteinopathy at the crossroads of tauopathy: on copathology and current and prospective biomarkers.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1671419},
pmid = {41229731},
issn = {1662-5102},
abstract = {Though usually described as isolated models, neurodegenerative diseases exist in a significant proportion of cases as mixed pathologies, particularly in older adults. The presence of co-pathologies may influence phenotypes and progression, and the correct classification in vivo has proven to be challenging, particularly without proper biomarker panels. Recent breakthroughs in biomarkers, enabling earlier detection in Alzheimer's disease and, more recently, in synuclein-related diseases, are promising as a first step toward the wider detection of all other abnormal proteins involved in neurodegenerative diseases. Over the past decade, the growing body of research on TDP-43 pathology has led to considering TDP-43 as a potential major contributor to the neurodegenerative process. TDP-43's normal function is essential for neuronal survival and the regulation of RNA processing and cellular stress response; abnormal TDP-43 protein leads to altered cell function and survival. TDP-43 is notably the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) as well as some form of frontotemporolobar degeneration (FTLD). Tauopathies, divided in primary or secondary tauopathies cover other forms of FTLD including Pick disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) but also non-FTLD diseases like Alzheimer's disease (AD) which can be classified as secondary tauopathy. As the importance of copathology is more and more recognized, TDP-43 is also frequently observed in conjunction with other proteinopathies, possibly with a synergistic or additive effect, although the exact mechanism is still unclear. In Alzheimer's disease, the limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-occurrence with Alzheimer's disease neuropathologic changes (ADNC) lead to a more rapid course. Although there are currently no approved and validated biomarkers for its early detection, several promising tools, including neuroimaging and biofluid biomarkers, are under development, offering hope for the earlier detection of TDP-43 pathology in vivo. Accurate identification of the underlying proteinopathies and pathological processes could lead to better diagnosis and classification, more precise selection of clinical trial candidates, and ultimately, disease-specific tailored treatments.},
}

@article {pmid41229403,
year = {2025},
author = {Ackrivo, J and Bracy, D and Elman, LB and Hansen-Flaschen, J and Simmons, Z and Pasinelli, P and Heiman-Patterson, T and Kawut, SM and Lane-Fall, MB},
title = {How Patients With Amyotrophic Lateral Sclerosis Perceive Respiratory Interventions: A Mixed-Methods Study to Inform Implementation Efforts.},
journal = {Neurology. Clinical practice},
volume = {15},
number = {6},
pages = {e200560},
pmid = {41229403},
issn = {2163-0402},
abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that commonly leads to respiratory failure. Early respiratory interventions that may improve symptoms and outcomes are underused when prescribed. We sought to characterize patient perspectives and preferences for respiratory care to enable identification of implementation strategies to improve the uptake of ALS respiratory interventions.

METHODS: A prospective multicenter mixed-methods observational study was conducted using semistructured interviews of participants recently diagnosed with ALS at 4 academic centers in the United States. Eligible patients were those with an ALS diagnosis in the previous 12 months, forced vital capacity <80% predicted normal, or presence of dyspnea or orthopnea.

RESULTS: Twenty-four patients with ALS were interviewed. Ten participants were using some form of respiratory therapy, including 8 using noninvasive ventilation (NIV). The most endorsed factors related to openness to initiate respiratory therapy were a doctor's recommendation and abnormal pulmonary function test results. The most commonly endorsed preferences for learning about a respiratory device included kinesthetic and reading. Descriptions of lung volume recruitment were received with more openness than of NIV. For those not prescribed NIV, reasons for hesitancy to start NIV included fear of mask discomfort, claustrophobia, and lack of perceived benefit. Perceptions about NIV differed in participants identifying as "proactive" rather than "reactive" with their health.

DISCUSSION: Patients in the first year after ALS diagnosis have variable receptiveness to respiratory care. These patients place different weights on the factors supporting NIV and may have different educational needs about respiratory interventions. Implementation strategies for respiratory care interventions in ALS should consider patients' motivations for adopting interventions such as NIV, provide multiple educational formats, and identify barriers to incorporating home respiratory care.},
}

@article {pmid41229135,
year = {2025},
author = {Vacchiano, V and Ragucci, C and Rizzo, G and Di Stasi, V and Pastorelli, F and Rinaldi, R and Provini, F and Postiglione, E and Fiorentino, A and Carelli, V and Liguori, R},
title = {Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With SOD1-Linked Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70434},
pmid = {41229135},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/pathology/physiopathology/diagnosis ; Male ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Aged ; *Spinal Nerve Roots/pathology/diagnostic imaging ; Adult ; *Cerebrospinal Fluid Proteins/cerebrospinal fluid ; },
abstract = {INTRODUCTION: The superoxide dismutase type 1 (SOD1) gene has been implicated in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). We report four ALS cases carrying pathogenic or likely pathogenic SOD1 variants, characterized by albuminocytologic dissociation and nerve root enhancement.

METHODS: We present the results of the diagnostic work-up, including lumbosacral magnetic resonance imaging (MRI) with gadolinium, electromyography (EMG), and cerebrospinal fluid (CSF) analysis. We also assessed the relationship between the albumin quotient (Q-Alb)-an index of blood-brain barrier (BBB) dysfunction-and the disease progression rate (DPR) in 12 SOD1-linked ALS patients (including the four described above) and in a cohort of 137 non-genetic ALS (NgALS) cases.

RESULTS: The four patients presented with spinal onset (progressive lower limb weakness). The EMG ultimately showed diffuse subacute neurogenic changes, while CSF analysis revealed albuminocytologic dissociation. Lumbosacral MRI demonstrated contrast enhancement of the cauda equina roots. Immunomodulatory treatment was administered due to suspected immune-mediated neuropathy, but all patients continued to deteriorate. Genetic testing revealed pathogenic or likely pathogenic variants in the SOD1 gene, confirming the diagnosis of ALS. CSF Q-Alb and protein levels were similarly distributed between SOD1-linked and NgALS patients. Q-Alb and CSF protein levels showed a positive correlation with DPR in SOD1-linked patients (Rho = 0.625, p = 0.03; Rho = 0.755, p = 0.005), but not in NgALS patients.

CONCLUSION: Albuminocytologic dissociation and nerve root enhancement may occur in SOD1-related ALS, expanding the spectrum of atypical ALS phenotypes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/pathology/physiopathology/diagnosis
Male
*Superoxide Dismutase-1/genetics
Middle Aged
Female
Magnetic Resonance Imaging
Aged
*Spinal Nerve Roots/pathology/diagnostic imaging
Adult
*Cerebrospinal Fluid Proteins/cerebrospinal fluid

@article {pmid41228417,
year = {2025},
author = {de la Rubia Ortí, JE and Bargues-Navarro, G and Privado, J and Menarques-Ramírez, R and Sanchis-Sanchis, CE and Sancho-Castillo, S and Rubio, CP and Pardo-Marin, L and Benlloch, M and Martín-Ruiz, J},
title = {Dietary Vitamin Intake and Blood Biomarkers in Relation to Muscle Activation in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
pmid = {41228417},
issn = {2072-6643},
support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Biomarkers/blood ; *Amyotrophic Lateral Sclerosis/blood/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Muscle, Skeletal/physiopathology ; *Diet ; Aryldialkylphosphatase/blood ; Muscle Strength ; *Vitamins/administration & dosage ; Butyrylcholinesterase/blood ; },
abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor function, which affects mobility and leads to secondary complications, including altered dietary intake due to dysphagia, fatigue, and hypermetabolism, particularly affecting vitamin consumption, which are essential micronutrients for neuromuscular performance. The specific relationship between vitamin intake and muscle activation is not well understood in patients with ALS; thus, it is relevant to identify blood biomarkers that reflect muscle status. Methods: A cross-sectional study was conducted with 61 patients with bulbar- or spinal-onset ALS. The dietary intake of B vitamins (B1, B2, B6, B12, folate, and niacin); vitamins C, A, D, and E; and the B6/protein ratio were assessed using a seven-day dietary record and a Food Frequency Questionnaire. Blood concentrations of butyrylcholinesterase (BuChE), albumin, haptoglobin, C-reactive protein (CRP), and paraoxonase 1 (PON1) were determined. Basal muscle activation was measured using surface electromyography of the biceps brachii, triceps brachii, rectus femoris, and tibialis anterior muscles. Two confirmatory predictive models were developed to evaluate the effects of muscle damage and vitamin intake on muscle strength. Results: Arm muscle activation was negatively predicted by the B6/protein ratio (β = -0.33). Leg activation was positively predicted by vitamin B9 (β = 0.39) and B6/protein (β = 0.17) and negatively predicted by vitamin A (β = -0.24). For biomarkers, albumin (β = 0.18) and PON1 (β = 0.28) positively predicted activation. For legs, albumin predicted activation (β = 0.31), whereas BuChE and haptoglobin predicted negative activation (β = -0.32 and β = -0.15, respectively). Conclusions: Weak associations were observed in patients with ALS: vitamin B9 intake showed a modest association with leg activation, the B6/protein ratio exhibited inconsistent associations across muscle groups, and vitamin A showed a negative association with leg activation. Albumin demonstrated the most consistent association as a potential biomarker of muscle function. These findings are exploratory and require validation in larger, longitudinal studies.},
}

Humans
Cross-Sectional Studies
Biomarkers/blood
*Amyotrophic Lateral Sclerosis/blood/physiopathology
Male
Female
Middle Aged
Aged
*Muscle, Skeletal/physiopathology
*Diet
Aryldialkylphosphatase/blood
Muscle Strength
*Vitamins/administration & dosage
Butyrylcholinesterase/blood

@article {pmid41228121,
year = {2025},
author = {Wityshyn, S and Sanghai, N and Tranmer, GK},
title = {My Amyotrophic Lateral Sclerosis (ALS) Journey from Weakness to Diagnosis: A Journey of Hope.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {21},
pages = {},
pmid = {41228121},
issn = {2227-9032},
support = {202210PJT-495295/CAPMC/CIHR/Canada ; },
abstract = {Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a progressive neurodegenerative disease that attacks and kills motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy, eventually causing respiratory failure and death within 2-5 years after diagnosis. By 2040, the global population of individuals living with ALS is projected to approach 400,000. Since ALS was discovered by Charcot 150 years ago, only two drugs (Edaravone and Riluzole) have been available, offering modest clinical benefits in slowing disease progression. The increasing number of cases, along with the high costs of treatment and care, creates a growing burden on communities and the healthcare system. However, despite this rising burden and the failure of most clinical trials, the ALS community remains hopeful because of the patients themselves. ALS patients are the beating heart of the ALS community. They engage in efforts to improve lives for others, raising awareness through their real-life experiences, participating in research activities, fundraising, providing samples for research, and advocating strongly in front of communities and governments to raise funds. Their engagement is highly valuable, and collaboration with the research community is essential to understanding the disease process and developing effective disease-modifying therapies. Here, we share the story of Mrs. Sherry Wityshyn, an ALS patient and a true ALS warrior from Winnipeg, Manitoba, Canada. We believe her story will inspire and motivate the entire community to learn more about ALS. Furthermore, her story gives hope to everyone impacted. In this manuscript, we also emphasize the different stages of Sherry's journey from weakness to diagnosis and our efforts to share her enduring words with policymakers in the government.},
}

@article {pmid41227857,
year = {2025},
author = {Ma, H and Zong, M and Cedrick, N and Sun, Y and Wang, W and Yan, X and Liu, H and Zhu, P and Hua, M},
title = {Influence Mechanism of Chemically Modified Alumina on the Hydration of Gypsum-Based Self-Leveling Mortar.},
journal = {Materials (Basel, Switzerland)},
volume = {18},
number = {21},
pages = {},
pmid = {41227857},
issn = {1996-1944},
support = {42202034//National Natural Science Foundation of China/ ; 52508248//National Natural Science Foundation of China/ ; BK20220626//Natural Science Foundation of Jiangsu Province/ ; },
abstract = {This study investigates the effect of γ-aminopropyltriethoxysilane (KH550)-functionalized nano-active Al2O3 (KH-Al) on the properties of gypsum-based self-leveling mortar (GSL) prepared from industrial by-product gypsum. First, the effects of incorporating KH-Al at dosages of 0.05%, 0.1%, 0.25%, 0.5%, and 1% on the fluidity, setting time, and mechanical properties of GSL were analyzed. Subsequently, using X-ray diffraction (XRD), hydration heat analysis, thermogravimetric analysis (TG), and scanning electron microscopy (SEM), the influences of the nanomaterial on the mortar's morphology, hydration characteristics, and crystal forms of hydration products were thoroughly examined. Finally, by comparing the modified GSL with ordinary GSL, the mechanism of KH-Al's action on GSL was elucidated. The results demonstrate that nano-active Al2O3 modified with KH550 exhibits excellent dispersibility in the GSL paste. As the dosage of KH-Al increases, both the fluidity and setting time of GSL decrease. Upon incorporating KH-Al, the mechanical properties of GSL initially improve and then decline, with optimal mechanical performance observed at a 0.5% KH-Al addition. However, when the KH-Al dosage exceeds 0.5%, excess nano-active Al2O3 causes nanoparticle agglomeration, which impedes the hydration process. The nucleation effect of KH-Al promotes the formation of CŜH2 and AFt, refines the crystals of hydration products, and enhances the phase transformation efficiency of the mortar. These findings indicate that KH-Al has significant potential to improve the mechanical strength and hydration kinetics of gypsum mortar and provide theoretical support for the application of nanomaterials in gypsum building materials.},
}

@article {pmid41227379,
year = {2025},
author = {Spedding, M},
title = {Does Amyotrophic Lateral Sclerosis (ALS) Have Metabolic Causes from Human Evolution?.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
pmid = {41227379},
issn = {2073-4409},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; *Biological Evolution ; Mixed Function Oxygenases/metabolism/genetics ; },
abstract = {As so many drugs have failed in ALS a new approach is needed. The author proposes that recent human genetic variants may play major roles in the disease, changing metabolism. Evolution of hominins was accelerated 3-2.5 Mya, by cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) becoming a unitary pseudogene after a pathogenic infection, changing the sialome, and hence metabolism, brain development and neuromuscular junctions (NMJs). This was when hominins evolved to run in Africa and develop bigger brains. Deletion of CMAH in mice allows them to run for longer (~50%). The enzyme CMAH is critical for the sialome, particularly the neurotrophin GM1, a critical hub for viral infection and for NMJ stability, but which is lost from NMJs at the beginning of denervation, probably due a 10-fold increase in spinal cord glucosylceramidases (non-lysosomal GBA2). A GBA2 inhibitor, ambroxol, is currently in phase II for ALS. Human-specific GM1 may be critical for human evolution, lactate metabolism and ALS. Lipid/lactate metabolism changed to support these evolutionary changes and lactate is a major body/brain fuel, but compromised in ALS patients and a marker of disease progression. Recent progress in sports science involving lactate metabolism and human performance may also be relevant to ALS therapies, and incidence.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/genetics
Animals
*Biological Evolution
Mixed Function Oxygenases/metabolism/genetics

@article {pmid41226491,
year = {2025},
author = {Cappelli, S and Peradinovic, J and Mohovic, N and Mandal, P and Stuani, C and Longo, A and Cannon, JR and Baloni, P and Leoni, B and Krsmanovic, T and Stojanov, K and Apic, G and Russell, RB and Romano, M and Buratti, E and Munitic, I},
title = {Optineurin Shapes Basal and LPS-Induced Transcriptomes in BV2 Microglia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
pmid = {41226491},
issn = {1422-0067},
support = {IP-2024-05-5814//Croatian Science Foundation/ ; IP-2018-01-8563//Croatian Science Foundation/ ; DOK-2018-09-7739//Croatian Science Foundation/ ; DOK-2020-01-8703//Croatian Science Foundation/ ; 861 329//SCiLS/ ; },
mesh = {*Lipopolysaccharides/pharmacology ; Animals ; *Microglia/metabolism/drug effects ; Mice ; *Transcriptome/drug effects ; Membrane Transport Proteins/genetics ; *Cell Cycle Proteins/genetics/metabolism ; *Transcription Factor TFIIIA/genetics/metabolism ; Cell Line ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; },
abstract = {The OPTN gene, which encodes the adaptor protein optineurin, is genetically linked to amyotrophic lateral sclerosis and frontotemporal dementia, diseases characterized by chronic microglial activation. Optineurin regulates inflammatory signaling, autophagy, and trafficking, but its role in microglia remains incompletely understood. Here, we used bulk RNA sequencing to profile CRISPR-Cas9-mediated optineurin knockout (KO) and wild-type BV2 microglia under basal conditions and upon LPS stimulation. At baseline, optineurin KO altered ~7% of the transcriptome, with a predominant downregulation of type I interferon and antiviral pathways, suggesting its role in maintaining basal immune readiness. LPS stimulation reprogrammed ~35% of genes in wild-type microglia, inducing immune effectors and suppressing cell cycle regulators, whereas in optineurin-deficient cells, the response was blunted with only ~16% of genes changing relative to the KO baseline. Furthermore, LPS-treated optineurin KO microglia notably diverged from LPS-treated wild-type cells, with ~26% differentially expressed genes (DEGs). This included impaired induction of inflammatory programs and persistence of cell cycle-associated transcripts. Most DEGs in LPS-treated KO cells were unique to this condition, highlighting optineurin-dependent pathways specific to inflammatory challenge. Overall, our study provides a systems-level framework for investigating optineurin in microglia and neurodegeneration, establishing it as a key regulator of the microglial transcriptome, with its loss reshaping innate immune and cell cycle programs.},
}

*Lipopolysaccharides/pharmacology
Animals
*Microglia/metabolism/drug effects
Mice
*Transcriptome/drug effects
Membrane Transport Proteins/genetics
*Cell Cycle Proteins/genetics/metabolism
*Transcription Factor TFIIIA/genetics/metabolism
Cell Line
Gene Expression Profiling
Gene Expression Regulation/drug effects

@article {pmid41226363,
year = {2025},
author = {Thakur, B and Tarazi, S and Doležalová, L and Behbahani, H and Darreh-Shori, T},
title = {Comparative Analysis of Cholinergic Machinery in Carcinomas: Discovery of Membrane-Tethered ChAT as Evidence for Surface-Based ACh Synthesis in Neuroblastoma Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
pmid = {41226363},
issn = {1422-0067},
support = {//Åhlén-Foundation/ ; //Frimurarna Foundation/ ; //Ulla-Carin Linquist Foundation for ALS research/ ; AARG-24-1310046//Alzheimer´s Association/ ; //Dementia Foundation (Demensfonden)/ ; //Foundation for Old Servants (Gamla Tjänarinnor)/ ; //Karolinska Institutet´s Research Foundations/ ; //Olle Engkvist Byggmästare Foundation/ ; //Magnus Bergvalls Foundation/ ; //Gun and Bertil Stohnes Foundation/ ; ALF Med N 20200330//grant from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; #CAN2021/1469, and # 24 3793//the Swedish Cancer Society/ ; #221212, #241282 and #221383//the Stockholm Cancer Society/ ; },
mesh = {Humans ; *Neuroblastoma/metabolism/pathology ; *Acetylcholine/biosynthesis/metabolism ; Cell Line, Tumor ; *Choline O-Acetyltransferase/metabolism ; Choline/metabolism ; Cell Membrane/metabolism ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Signal Transduction ; },
abstract = {The cholinergic system is one of the most ancient and widespread signaling systems in the body, implicated in a range of pathological conditions-from neurodegenerative disorders to cancer. Given its broad relevance, there is growing interest in characterizing this system across diverse cellular models to enable drug screening, mechanistic studies, and exploration of new therapeutic avenues. In this study, we investigated four cancer cell lines: one of neuroblastoma origin previously used in cholinergic signaling studies (SH-SY5Y), one non-small cell lung adenocarcinoma line (A549), and two small cell lung carcinoma lines (H69 and H82). We assessed the expression and localization of key components of the cholinergic system, along with the cellular capacity for acetylcholine (ACh) synthesis and release. Whole-cell flow cytometry following membrane permeabilization revealed that all cell lines expressed the ACh-synthesizing enzyme choline acetyltransferase (ChAT). HPLC-MS analysis confirmed that ChAT was functionally active, as all cell lines synthesized and released ACh into the conditioned media, suggesting the presence of autocrine and/or paracrine ACh signaling circuits, consistent with previous reports. The cell lines also demonstrated choline uptake, indicative of functional choline and/or organic cation transporters. Additionally, all lines expressed the ACh-degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as the alfa seven (α7) nicotinic and M1 muscarinic ACh receptor subtypes. Notably, flow cytometry of intact SH-SY5Y cells revealed two novel findings: (1) ChAT was localized to the extracellular membrane, a feature not observed in the lung cancer cell lines, and (2) BChE, rather than AChE, was the predominant membrane-bound ACh-degrading enzyme. These results were corroborated by both whole-cell and surface-confocal microscopy. In conclusion, our findings suggest that a functional cholinergic phenotype is a shared feature of several carcinoma cell lines, potentially serving as a survival checkpoint that could be therapeutically explored. The discovery of extracellular membrane-bound ChAT uniquely in neuroblastoma SH-SY5Y cells points to a novel form of in situ ACh signaling that warrants further investigation.},
}

Humans
*Neuroblastoma/metabolism/pathology
*Acetylcholine/biosynthesis/metabolism
Cell Line, Tumor
*Choline O-Acetyltransferase/metabolism
Choline/metabolism
Cell Membrane/metabolism
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Signal Transduction

@article {pmid41226260,
year = {2025},
author = {Cutter, LR and Ren, AR and Banerjee, IA},
title = {Advances in Naturally and Synthetically Derived Bioactive Sesquiterpenes and Their Derivatives: Applications in Targeting Cancer and Neurodegenerative Diseases.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226260},
issn = {1420-3049},
support = {N/A//Henry Luce Foundation/ ; N/A//Fordham University/ ; },
mesh = {Humans ; *Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neoplasms/drug therapy/metabolism ; Animals ; *Biological Products/chemistry/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/chemistry ; Antioxidants/chemistry/pharmacology ; },
abstract = {Sesquiterpenes are a diverse class of natural products that have garnered considerable interest for their potent bioactivity and structural variability. This review highlights advances in the derivatization of various sesquiterpene lactones, quinones, and alcohols, particularly in targeting cancer and neurodegenerative diseases. The structural modifications discussed include the incorporation of triazole, arylidene, or thiol moieties with eudesmane, guaiane, and germacranolide-type sesquiterpenes, among others. In addition, the conjugation with chemotherapeutics, as well as the development of nanoscale therapeutics, is also discussed. Such modifications have expanded the pharmacological potential, enabling improved specificity, cytotoxicity profiles, and sensitization toward tumor cells. Additionally, sesquiterpenes such as parthenolide (20), pterosinsade A (176), and cedrol (186) have demonstrated potential in mitigating neurodegeneration via anti-inflammatory and antioxidant signaling pathway-modulation mechanisms, with potential applications in Alzheimer's, Parkinson's, and ALS diseases. Mechanistic insights into redox signaling modulation, NF-κB inhibition, ROS regulation, and disruption of aggregation underscore their multifaceted modes of action. This review highlights the translational promise of sesquiterpene derivatives as dual-action agents for potential drug development in a plethora of diseases that are caused by inflammation and free-radical damage. It provides a framework for future rational design of multifunctional drug candidates and therapeutics.},
}

Humans
*Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis
*Neurodegenerative Diseases/drug therapy/metabolism
*Neoplasms/drug therapy/metabolism
Animals
*Biological Products/chemistry/pharmacology/therapeutic use
*Antineoplastic Agents/pharmacology/chemistry
Antioxidants/chemistry/pharmacology

@article {pmid41225259,
year = {2025},
author = {Ghayal, NB and Crook, RJ and Jain, A and Sachdeva, G and Jiang, P and Roemer, SF and Sekiya, H and DeTure, MA and Baker, MC and De Coster, W and Oskarsson, B and Josephs, KA and Rademakers, R and van Blitterswijk, MM and Dickson, DW},
title = {Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {52},
pmid = {41225259},
issn = {1432-0533},
support = {P30 AG062677/AG/NIA NIH HHS/United States ; R01-AG037491//Foundation for the National Institutes of Health/ ; UG3 NS103870/NS/NINDS NIH HHS/United States ; G064223N//Fund for Scientific Research Flanders (FWO)/ ; },
mesh = {Humans ; *Frontotemporal Lobar Degeneration/pathology/genetics/metabolism ; *Motor Neuron Disease/pathology/metabolism/genetics ; Male ; Female ; Aged ; Middle Aged ; *Annexins/metabolism/genetics ; DNA-Binding Proteins/metabolism ; Aged, 80 and over ; TDP-43 Proteinopathies/pathology ; Brain/pathology/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; },
abstract = {Aggregation of TAR-DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases diagnosed with a primary TDP-43 proteinopathy, including FTLD-TDP, FTLD-MND, and MND-TDP. Cases with FTLD-MND and MND-TDP were classified further into PLS, ALS, and PMA based on the relative loss of upper and lower motor neurons. ANXA11 proteinopathy was present in over 40% of FTLD-MND cases. Further, ANXA11 colocalized with TDP-43 in the pathologic inclusions of all FTLD-TDP type C cases, as well as 38 out of 40 FTLD-PLS cases (95%), of which 84% had TDP type B or an unclassifiable TDP-43 proteinopathy and 16% had TDP type C. Genetic analysis excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated two novel ANXA11 proteinopathies strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship between TDP-43 and ANXA11 in neurodegenerative disease, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises a distinct group of molecular pathologies and define three TAP types based on key clinical and neuropathologic characteristics.},
}

Humans
*Frontotemporal Lobar Degeneration/pathology/genetics/metabolism
*Motor Neuron Disease/pathology/metabolism/genetics
Male
Female
Aged
Middle Aged
*Annexins/metabolism/genetics
DNA-Binding Proteins/metabolism
Aged, 80 and over
TDP-43 Proteinopathies/pathology
Brain/pathology/metabolism
Amyotrophic Lateral Sclerosis/pathology

@article {pmid41224659,
year = {2025},
author = {Moss, KR and Darvishi, FB and Badawi, Y and Fish, LA and Funke, JR and Pedersen, TH and Robitaille, R and Arnold, WD and Burgess, RW and Meriney, SD and Nishimune, H and Saxena, S},
title = {The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {45},
number = {46},
pages = {},
doi = {10.1523/JNEUROSCI.1353-25.2025},
pmid = {41224659},
issn = {1529-2401},
mesh = {Humans ; *Neuromuscular Junction/pathology/physiopathology/physiology ; *Aging/pathology/physiology ; Animals ; *Neuromuscular Diseases/physiopathology/pathology ; Schwann Cells ; },
abstract = {The neuromuscular junction (NMJ) is a specialized synapse essential for effective motor neuron-muscle communication and is increasingly recognized as a vulnerable site in aging and neuromuscular disease. While traditionally considered a final common pathway for motor deficits, accumulating evidence demonstrates that NMJ dysfunction is an early and critical driver of disease onset and progression in conditions such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. This review highlights shared and disease-specific mechanisms contributing to NMJ impairment, including presynaptic, postsynaptic, and perisynaptic Schwann cell defects in these diseases. We also discuss age-related changes at the NMJ, emphasizing its role in sarcopenia and muscle weakness in older adults. Furthermore, we explore emerging molecular drivers of NMJ dysfunction uncovered through studies in congenital myasthenic syndromes, autoimmune disorders, and advanced omics approaches. By integrating insights across diseases and aging, we underscore the potential for shared therapeutic strategies aimed at stabilizing NMJ function. Promising interventions targeting presynaptic neurotransmitter release, postsynaptic excitability, and perisynaptic Schwann cells are discussed as avenues to improve neuromuscular transmission and maintain muscle strength. Finally, we discuss the challenges and opportunities in translating these mechanistic insights into clinical therapies and highlight how novel human neuromuscular organoid models and advanced molecular profiling can bridge this gap. Together, these insights establish the NMJ as a critical, modifiable target for preserving motor function across neuromuscular diseases and aging.},
}

Humans
*Neuromuscular Junction/pathology/physiopathology/physiology
*Aging/pathology/physiology
Animals
*Neuromuscular Diseases/physiopathology/pathology
Schwann Cells

@article {pmid41224274,
year = {2025},
author = {Takubo, M and Matsumoto, Y and Sasaki, C and Ikeda, K and Sugeno, N and Warita, H and Aoki, M},
title = {Spinocerebellar Ataxia Type 3 Accompanied by Amyotrophic Lateral Sclerosis: A Case Report and Comprehensive Literature Review.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.6369-25},
pmid = {41224274},
issn = {1349-7235},
abstract = {Spinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder characterized by cerebellar ataxia, whereas amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. We herein report a 62-year-old man with genetically confirmed SCA3 who subsequently developed rapidly progressive asymmetric muscle weakness, atrophy, and fasciculations. Clinical features, including preserved tendon reflexes and widespread denervation observed on electromyography, support the diagnosis of concomitant sporadic ALS. Our literature review revealed only a few similar cases, suggesting the under-recognition of this rare combination. This case underscores the importance of considering coexisting ALS in patients with SCA3 to enable a timely diagnosis and management.},
}

@article {pmid41224202,
year = {2025},
author = {Metelmann, M and Heyne, S and Peuker, M and Claßen, J and Mehnert-Theuerkauf, A and Esser, P},
title = {[Experiences with the Application of Short-Term Psychotherapy in Patients with Amyotrophic Lateral Sclerosis: What Can We Learn from It?].},
journal = {Psychotherapie, Psychosomatik, medizinische Psychologie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2711-2085},
pmid = {41224202},
issn = {1439-1058},
abstract = {Amyotrophic lateral sclerosis (ALS) is associated with elevated distress, but evidence on psychosocial interventions is limited. We tested the feasibility of a psychotherapy for palliative cancer patients in ALS patients.We applied CALM (Managing Cancer and Living Meaningfully), an effective psychodynamic short-term therapy for advanced cancer patients, within a pre-post study among patients with ALS. We provided patient flow and formal treatment information. Based on the treatment protocols, the therapist reflected on the applicability of the treatment structure, specifics in the psychosocial work with ALS patients and suggestions for treatment modification.Among 15 eligible patients, five participated. Three patients completed the treatment, two patients provided complete study data. The trial was prematurely stopped due to issues in feasibility. Six (22%) sessions were conducted via telephone, 10 (37%) were attended by family caregivers. The structure showed limited applicability largely because fear-laden topics including suffering and death were extensively avoided. Compared to palliative cancer patients, ALS patients fluctuated more strongly in their psychological and physical symptom burden and were more strongly distressed by disease-related practical issues. Recommendations included a multi-professional team, booster sessions and a direct support for caregivers.A psychotherapy effective for cancer patients showed features that limit its applicability among ALS patients. Some of these limitations are treatment-inherent and thus hard to adapt. Rather than modifying the program, we suggest to develop a specific supportive psychotherapeutic intervention within a participatory approach.},
}

@article {pmid41223995,
year = {2025},
author = {Michelerio, A and Tomasini, C and Brazzelli, V},
title = {Response to Gronbeck et al.'s "Dermatologic toxicities of antibody-drug conjugates": why ado-trastuzumab emtansine-associated telangiectasias deserve clinical attention.},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.11.008},
pmid = {41223995},
issn = {1097-6787},
}

@article {pmid41223829,
year = {2025},
author = {Patil, N and Mirveis, Z and Byrne, HJ},
title = {Exploration of multivariate curve resolution- alternating least squares (MCR-ALS) for datamining kinetically evolving complex cellular spectroscopic data (Spectralomics).},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {348},
number = {Pt 2},
pages = {127156},
doi = {10.1016/j.saa.2025.127156},
pmid = {41223829},
issn = {1873-3557},
abstract = {Multivariate curve resolution- alternating least squares (MCR-ALS) approach for datamining the complex spectral fingerprints from kinetically evolving cellular Raman spectroscopy data was explored in this study. Principal components analysis and partial least squares- discriminant analysis indicated the metabolic changes were captured in individual metabolic conditions (Control, Stimulation and Inhibition) as a function of time; however, MCR-ALS could not resolve the spectral components accurately. Hence simulated datasets were generated to test the limit of resolution which revealed the significance of initial estimation of spectral components in the MCR, and the effect of equality constraints in the ALS was studied. The resolved rate constants for the time evolution of the components were not quantitatively accurate at higher cellular background overlayed on the evolving components, although they did exhibit a consistent qualitative trend across the modulated conditions. Hence, the cellular data was analysed qualitatively, and the initial estimates constraint in MCR along with a kinetic hard model constraint in ALS was deduced to be the best strategy for datamining complex cellular spectra. The spectral fingerprints of both glycolytic and non-glycolytic cellular processes were resolved in all the modulated conditions, highlighting the high-content insights from the label-free approach. The study demonstrates the potential of Raman spectroscopy coupled with a spectralomics approach for datamining of the complex spectral fingerprints as a function of time and highlights its limitations. This approach could potentially find applications in high-content drug screening, drug discovery, disease diagnostics and process analytical techniques for monitoring bioprocesses.},
}

@article {pmid41223590,
year = {2025},
author = {Elmansy, MF and Soares, P and Dos Remedios, JRD and Nowar, R and Fox, SG and Yu, A and Klein, WL and Morimoto, RI and Silverman, RB},
title = {Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109190},
doi = {10.1016/j.bioorg.2025.109190},
pmid = {41223590},
issn = {1090-2120},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fast-progressing disease characterized by the loss of voluntary movements and death due to respiratory failure. The presence of protein aggregates is a major hallmark of the disease. Hence, targeting the pathological protein aggregation may provide more efficient therapeutics for ALS. Recently, we reported a cyclohexane-1,3-dione (NU-9) with in vitro anti-aggregation capacity and promising in vivo efficacy in ALS animal models, which validated our approach toward the development of novel and potentially more effective ALS therapeutics. Herein, we report the design and synthesis of a new series of small-molecule derivatives of NU-9 and the evaluation of their in vitro anti-aggregation activity in a PC12 cellular model containing an SOD1[G85R] familial ALS mutation. The most promising compound (20) presented an in vitro anti-aggregation potency comparable to that of NU-9. Moreover, the better in vitro BBB permeability, microsomal stability, and toxicity profile of 20 also suggests a potentially higher efficacy in vivo.},
}

@article {pmid41222918,
year = {2025},
author = {Feng, J and Jiang, H and Bi, X},
title = {Letter to the editor: re-evaluating perioperative antibiotic strategies in mild-to-moderate acute cholecystitis: addressing unresolved questions from Park et al.'s randomized trial.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000003976},
pmid = {41222918},
issn = {1743-9159},
}

@article {pmid41222589,
year = {2025},
author = {Heyming, T and Knudsen-Robbins, C and Kain, A and Morphew, T and Ta-Perez, Z and Darabpour, A and Lee, H and Brukman, S and Shelton, SK},
title = {Prehospital PAT - Real World Data; EMS Use of the Pediatric Assessment Triangle in the Prehospital Environment.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/10903127.2025.2581753},
pmid = {41222589},
issn = {1545-0066},
abstract = {OBJECTIVES: Emergency medical services (EMS) clinicians report lack of training and experience with children, leading to discomfort and uncertainty regarding assessment and treatment. The Pediatric Assessment Triangle (PAT) was designed to provide a rapid and standardized approach. Despite widespread adoption, literature examining EMS implementation of PAT remains limited. We examined EMS use of PAT and assessment of clinical stability, and the association between EMS use of PAT and prehospital interventions, EMS transport decisions (ALS versus BLS), emergency department (ED) interventions, and ED disposition.

METHODS: This was a retrospective cohort study of pediatric patients 0 to <15 years transported to a quaternary care pediatric ED via EMS between October 2022 and November 2023. Data were abstracted from EMS and ED electronic health records (EHRs) including PAT evaluation, demographics, EMS and ED interventions, and ED disposition. Data were analyzed using counts and percentages, logistic regression, chi-square and McNemar's test.

RESULTS: A total of 2,929 patients were included. Most patients, 65.9%, had a PAT score of 0; for those with non-zero PATs, abnormalities in the appearance domain were most prevalent, 50.7%. A PAT score of 1 or higher was associated with transport via Advanced Life Support (OR 67.9; 95% CI 32.0, 144.1) compared to a PAT of 0. Most patients, 62.2%, received an EMS intervention; the most common was diagnostics (blood glucose or EKG). The EMS administered medications to 22% of patients. Pediatric Assessment Triangle scores of ≥2 were associated with double the odds of admission to the floor (OR 2.09; 95% CI 1.4, 3.0) and quadruple the odds of admission to ICU level of care/direct to surgery/expired (OR 4.9; 95% CI 2.9, 8.3); PATs abnormal for work of breathing only were associated with increased odds of admission to the floor (OR 2.5; 95% CI 1.8, 3.6).

CONCLUSIONS: This study suggests that EMS PAT assessment in the field appropriately reflects patient stability and may be associated with EMS intervention en-route. The EMS PAT scores demonstrate promise as an adjunct to ED assessment, alerting clinicians to increased likelihood of admission. The PAT has potential to serve as a practical mechanism for EMS feedback and quality improvement studies.},
}

@article {pmid41222474,
year = {2025},
author = {Bagheri, S and Saboury, AA and Ahmad, O and Khan, RH and Ryszkiel, I and Stanek, A},
title = {Association of mercury exposure with neurodegenerative diseases - a reality or a misconception?.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.108158},
pmid = {41222474},
issn = {0028-3843},
abstract = {INTRODUCTION: Exposure to heavy metals has long been considered a potential risk factor for neurodegenerative diseases.

STATE OF THE ART: Most existing studies include in vitro and animal models, and research involving human subjects has yielded conflicting results, obscuring the overall understanding of this topic.

AIMS OF THE STUDY: In this article, the aim is to clarify the situation by carefully reviewing and categorizing the available body of knowledge in this field. Specifically, the focus is on research that explores the relationship between mercury exposure and common neurodegenerative diseases.

CONCLUSIONS: Despite its neurotoxic properties, results show that mercury is not associated with frequent neurodegenerative disorders.},
}

@article {pmid41221610,
year = {2025},
author = {},
title = {Platform Communications: Abstract Book 36th International Symposium on ALS/MND (Complete printable file).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {sup2},
pages = {1-78},
doi = {10.1080/21678421.2025.2564539},
pmid = {41221610},
issn = {2167-9223},
}

@article {pmid41221045,
year = {2025},
author = {Zhang, D and Han, L and Zhang, W and Wang, D and Huo, D and Tan, X and Su, X and Wang, M and Xu, J and Cheng, J and Wang, J and Feng, H},
title = {Neuroprotective mechanisms of valproic acid and alpha-lipoic acid in ALS: a network pharmacology-based investigation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1681929},
pmid = {41221045},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, and its multi-mechanism pathology makes single-target therapy insufficient. Valproic acid (VPA) and alpha-lipoic acid (ALA) are known neuroprotective agents, but their combined therapeutic potential and mechanisms in ALS remain unclear.

METHODS: In this study, network pharmacology method was used to integrate the target data of VPA, ALA and ALS, and key targets and pathways were screened by function enrichment, protein-protein interaction (PPI), network analysis and molecular docking. Furthermore, Mendel randomization (MR) was used to analyze the causal relationship between targets and ALS risk. The synergistic neuroprotective effects of VPA and ALA were then validated in the hSOD1[G93A] ALS cell and mouse models.

RESULTS: In this study, four core targets-TNF, EGFR, MAPK1 and MAPK8-were identified for the first time. Genetic analysis indicated that higher TNF levels and reduced MAPK8 expression are linked to a greater risk of ALS. Molecular docking demonstrated strong binding affinities of both compounds to these targets. In vitro and in vivo experiments showed that the combined therapy significantly improved neuronal survival and motor function, inhibited inflammation and apoptosis by activating the PI3K/AKT/FoxO3a pathway, and yielded significantly better therapeutic effects compared to the single drug treatments.

DISCUSSION: VPA and ALA synergistically alleviate ALS by modulating multiple targets and activating the PI3K/AKT/FoxO3a pathway. These findings support their potential as a combinatorial therapeutic strategy for ALS.},
}

@article {pmid41220979,
year = {2025},
author = {Konopka, A},
title = {Colocalizing Telomeres With PML or γH2AX Foci by IF-FISH in Mouse Brain Neurons.},
journal = {Bio-protocol},
volume = {15},
number = {21},
pages = {e5485},
pmid = {41220979},
issn = {2331-8325},
abstract = {Telomere length maintenance is strongly linked to cellular aging, as telomeres progressively shorten with each cell division. This phenomenon is well-documented in mitotic, or dividing, cells. However, neurons are post-mitotic and do not undergo mitosis, meaning they lack the classical mechanisms through which telomere shortening occurs. Despite this, neurons retain telomeres that protect chromosomal ends. The role of telomeres in neurons has gained interest, particularly in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where aging is a major risk factor. This has sparked interest in investigating telomere maintenance mechanisms in post-mitotic neurons. Nevertheless, most existing telomere analysis techniques were developed for and optimized using mitotic cells, posing challenges for studying telomeres in non-dividing neuronal cells. Thus, this protocol adapts an already established technique, the combined immunofluorescence and telomere fluorescent in situ hybridization (IF-FISH) on mitotic cells to study the processes occurring at telomeres in cortical neurons of the mouse ALS transgenic model, TDP-43 rNLS. Specifically, it determines the occurrence of DNA damage and the alternative lengthening of telomeres (ALT) mechanism through simultaneous labeling of the DNA damage marker, γH2AX, or the ALT marker, promyelocytic leukemia (PML) protein, together with telomeres. Therefore, the protocol enables the visualization of DNA damage (γH2AX) or the ALT marker (PML) concurrently with telomeres. This technique can be successfully applied to brain tissue and enables the investigation of telomeres specifically in cortical neurons, rather than in bulk tissue, offering a significant advantage over Southern blot or qPCR-based techniques. Key features • This protocol enables the labeling of telomeres in mouse brain tissue prepared from paraffin-embedded brain sections. • This method facilitates concurrent labeling of proteins that are colocalized at telomere sites.},
}

@article {pmid41220958,
year = {2025},
author = {Highlander, M and Elbasiouny, S},
title = {Methodological and analytical limitations undermine reported outcomes of spinal DC stimulation in ALS.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1706131},
pmid = {41220958},
issn = {1664-2295},
}

@article {pmid41220229,
year = {2025},
author = {Sehgal, D and Martín-Sanz, A and Sayago, A and Perraki, A and Kaundun, SS},
title = {Prevalence of two acetolactate synthase target site resistance mutations in sunflower broomrape from Europe as determined by robust kompetitive allele-specific assays (KASP).},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.70355},
pmid = {41220229},
issn = {1526-4998},
abstract = {BACKGROUND: Orobanche cumana is an important pest of sunflower crops in Europe and Asia. Recently, two highly virulent populations of sunflower broomrape from Greece were found to have evolved resistance to imazamox owing to the A205D and S653N acetolactate synthase (ALS) target-site mutations. We have developed two robust fluorophore-based kompetitive allele-specific (KASP) assays to cost-effectively genotype a large European collection of O. cumana for these two mutations.

RESULTS: The KASP assays were established using 94 tubercules from the two imazamox-resistant populations of sunflower broomrape from Orestiada (GR-ORE) and Drama (GR-DRA) regions in Greece, and two sensitive populations from Romania (RO-TUL) and Spain (SP-VIL). The genotype calls generated by the two KASP assays completely matched with those from sanger sequencing, demonstrating the reliability of the two assays developed here. Genotyping of 2114 individuals from 94 European O. cumana populations collected between 2014 and 2022 did not reveal the A205D mutation in any sample, whereas the S653N mutation, in the homozygous state, was present in a single population (OR-183) from the Drama region in Greece. Cluster analysis of ALS gene sequences suggests that resistance has evolved independently in the two geographically close populations GR-DRA and OR-183 from Drama.

CONCLUSION: The KASP assays developed here allowed high-throughput reliable genotyping of the A205D and S653N mutations in a large number of O. cumana samples from Europe. The study indicates that, so far, resistance to imazamox owing to the A205D and S653N mutations in sunflower broomrape is limited to only three populations from Greece. © 2025 Society of Chemical Industry.},
}

@article {pmid41220184,
year = {2025},
author = {Lei, J and Gong, L and Wei, S and Deng, J},
title = {Causal Relationship Between Inflammatory Bowel Disease and Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71046},
pmid = {41220184},
issn = {2162-3279},
mesh = {Humans ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Inflammatory Bowel Diseases/genetics/epidemiology ; *Mental Disorders/genetics/epidemiology ; Crohn Disease/genetics ; Schizophrenia/genetics ; Depressive Disorder, Major/genetics ; Colitis, Ulcerative/genetics ; Genetic Predisposition to Disease ; Bipolar Disorder/genetics ; },
abstract = {BACKGROUND: Observational studies have indicated a correlation between inflammatory bowel disease (IBD) and neuropsychiatric disorders, yet the causal relationship remains unclear.

OBJECTIVE: We aim to employ two-sample Mendelian randomization (MR) to ascertain the potential causal relationship between IBD and seven major neuropsychiatric disorders.

METHODS: We conducted a bidirectional two-sample MR analysis utilizing genome-wide association study (GWAS) summary statistics of European ancestry for IBD (31,665 cases and 33,977 controls) and its subtypes, ulcerative colitis (UC, 13,768 cases and 33,977 controls) and Crohn's disease (CD, 17,897 cases and 51,874 controls), along with seven major neuropsychiatric disorders: major depressive disorder (MDD, 135,458 cases and 344,901 controls), bipolar disorder (BD, 41,917 cases and 371,549 controls), schizophrenia (SCZ, 33,640 cases and 43,456 controls), Alzheimer's disease (AD, 39,106 cases and 46,828 controls), Parkinson's disease (PD, 33,674 cases and 449,056 controls), multiple sclerosis (MS, 14,498 cases and 24,091 controls), and amyotrophic lateral sclerosis (ALS, 27,205 cases and 110,881 controls).

RESULTS: Our analysis revealed potential positive causal effects of IBD and CD on MDD and SCZ. Similarly, SCZ was positively correlated with an increased risk of IBD and UC. There was a bidirectional positive association between IBD, UC, and MS, whereas CD showed a positive causal effect on MS. Similar to the investigation of the seven specified neuropsychiatric disorders on CD, we did not find evidence supporting causal effects of MDD, BD, AD, PD, or ALS on IBD or UC. Sensitivity analyses further reinforced the robustness of the MR estimates.

CONCLUSION: Our results support potential causal relationships between IBD (including its subtypes CD and UC) and several neuropsychiatric disorders, reinforcing the gut-brain axis concept and enhancing our understanding of extra-intestinal manifestations of IBD and neuropsychiatric manifestations in the context of IBD.},
}

Humans
Mendelian Randomization Analysis
Genome-Wide Association Study
*Inflammatory Bowel Diseases/genetics/epidemiology
*Mental Disorders/genetics/epidemiology
Crohn Disease/genetics
Schizophrenia/genetics
Depressive Disorder, Major/genetics
Colitis, Ulcerative/genetics
Genetic Predisposition to Disease
Bipolar Disorder/genetics

@article {pmid41219975,
year = {2025},
author = {Camero-Ortiz, EA and Delgado-García, SK and Bendezu-Quispe, G and Grandez-Castillo, GA},
title = {Diagnostic criteria for HPV infection classification: a comment on Wen et al.},
journal = {Virology journal},
volume = {22},
number = {1},
pages = {369},
pmid = {41219975},
issn = {1743-422X},
mesh = {Humans ; *Papillomavirus Infections/diagnosis/virology/epidemiology/classification ; *Papillomaviridae/classification/genetics/isolation & purification ; Genotype ; Male ; Prevalence ; China/epidemiology ; Coinfection/virology/epidemiology ; },
abstract = {BACKGROUND: We read with great interest Wen et al.'s article on HPV infection in Huizhou men, commending this pioneering research as the first systematic analysis of HPV epidemiology in the region. The findings, including a 30.53% positivity rate and prevalent genotypes like HPV6, HPV52, HPV11, and HPV16, offer valuable insights for developing effective prevention strategies.

MAIN BODY: We are concerned, however, about the study's HPV classification methodology. Categorizing infections into "low-risk," "high-risk," and "mixed" (which includes any combination of high and low-risk genotypes) might obscure the true incidence of high-risk HPV infections. High-risk HPV types are strongly linked to malignant transformations. Hence, a single high-risk genotype poses a significant health risk, irrespective of low-risk co-infection. Grouping high-risk infections with low-risk types in the "mixed" category could therefore underestimate the proportion of patients with high-risk HPV.

CONCLUSION: For future research, we suggest presenting high-risk HPV prevalence by distinguishing between solely low-risk, solely high-risk, and high-risk mixed infections (multiple infections that include at least one high-risk genotype). This offers a more accurate understanding of the burden, aiding public health efforts, screening, and vaccination programs.},
}

Humans
*Papillomavirus Infections/diagnosis/virology/epidemiology/classification
*Papillomaviridae/classification/genetics/isolation & purification
Genotype
Male
Prevalence
China/epidemiology
Coinfection/virology/epidemiology

@article {pmid41219399,
year = {2025},
author = {Fyfe, I},
title = {Microglia response altered by ALS mutation.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41219399},
issn = {1759-4766},
}

@article {pmid41219095,
year = {2025},
author = {Pu, S and Sawyer, A and Levinson, C and Putrino, D and Kirke, DN},
title = {Exploring Voice Banking as an Alternative Augmentative Communication Strategy for Individuals with Dysphonia, Aphonia, and Dysarthria: A Scoping Review.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jvoice.2025.10.018},
pmid = {41219095},
issn = {1873-4588},
abstract = {OBJECTIVES: This scoping review sought to: (i) review studies involving people diagnosed with dysphonia, aphonia, and dysarthria who have used voice banking technology in a hospital or community setting, and (ii) understand the scope of research surrounding existing voice banking technology and software in the clinical setting.

METHODS: This scoping review was conducted according to the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews. An electronic search of databases, including Ovid MEDLINE(R), Embase (Ovid), APA PsycINFO (Ovid), and CINAHL was conducted. Title, abstract, and full text screening were completed using Covidence (Veritas Health Innovation, Melbourne, Australia) by two reviewers.

RESULTS: After deduplication, 1336 studies underwent title and abstract screening. Of these, the full texts of 65 studies were reviewed, and 23 were included. Three distinct topics were identified in the search: (i) message banking, in which discrete messages or phrases are recorded for later use, without the ability to create novel phrases outside of those previously recorded; (ii) voice banking, in which all the necessary phonemes in the target language are captured, with the goal of generating a personalized synthetic voice that can generate novel phrases; (iii) and voice conversion or voice reconstruction, in which pathologic voices or speech are "converted" into a personalized synthetic voices.

DISCUSSION AND CONCLUSION: This scoping review summarized the evidence for voice banking technology use in people diagnosed with dysphonia and dysarthria and sought to understand the research landscape of existing types of voice banking technology and software use in a clinical setting. The included papers were highly heterogeneous in terms of the population and type (research vs clinical program vs review/other). There is a pressing need for the publication of clinical programs and models facilitating the adoption of voice banking, especially within populations affected by conditions such as amyotrophic lateral sclerosis and laryngectomy, to address existing gaps and foster broader implementation and accessibility.},
}

@article {pmid41218638,
year = {2025},
author = {Wasicki, B and Zawistowski, P and Jankowiak, T and de Oliveira Pires, L and Fernandes, S and Bączyk, M},
title = {Acute Invasive Dorso-Ventral DCS Applied With a Ball Electrode Does Not Alter Spinal Motoneurons' Firing Characteristics in the SOD-1 G93A Mouse Model of ALS.},
journal = {The European journal of neuroscience},
volume = {62},
number = {9},
pages = {e70314},
doi = {10.1111/ejn.70314},
pmid = {41218638},
issn = {1460-9568},
support = {2017/26/D/NZ7/00728//Narodowe Centrum Nauki/ ; 2019/35/B/NZ4/02058//Narodowe Centrum Nauki/ ; 2022/04/Y/NZ4/00117//Narodowe Centrum Nauki/ ; 2024.00602.BD//Fundação para a Ciência e a Tecnologia/ ; JPND/0003/2022//Fundação para a Ciência e a Tecnologia/ ; UID/00645/2025//Fundação para a Ciência e a Tecnologia/ ; },
abstract = {In amyotrophic lateral sclerosis (ALS), alterations of spinal motoneurons' (MNs) excitability form the hallmark of their degeneration. Trans-spinal direct current stimulation (tsDCS) is based on the delivery of low-intensity DC to the spinal column in order to alter spinal circuit excitability. Recently, this technique was applied to the management of ALS in the SOD1 G93A mice and resulted in a reduction of disease biomarkers and extended mouse survival. While indirect evidence suggests that these effects can be linked to a decrease in MNs excitability following tsDCS, this has never been directly confirmed. Therefore, in this study, we have utilized in vivo sharp intracellular recordings of spinal MN to directly investigate the impact of DC on MN intrinsic excitability in SOD1 G93A mice. Electrophysiological properties of MNs recorded before DCS were compared to the properties of MNs recorded within 1 h after DCS application using linear mixed-effect models. We have found that direct DCS application significantly increases MN peak and plateau input resistance (by 31% and 35%, respectively); however, this was not linked to any significant change to MN threshold and firing properties. Both mathematical modelling and in vivo recordings of the electric field (EF) indicate that our results may be explained by the low density of the EF at the MN recording site. While our results indicate that invasive DCS is not efficient in modifying MN excitability, it may be effective in altering the excitability of afferent fibers traversing the dorsal column close to the DCS application site.},
}

@article {pmid41218158,
year = {2025},
author = {Silva Sousa, LD and Bertuzzi, A and Rodrigues Fiuza, TE and Leite, ER and Benito, P and Ferri, D and Zanchet, D and Beale, AM},
title = {Identification of Transient Intermediates and Active Species in Atomic CZA Catalysts for CO2 Hydrogenation to Methanol.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c08043},
pmid = {41218158},
issn = {1520-5126},
abstract = {Direct hydrogenation of carbon dioxide to methanol is a promising strategy for carbon capture and utilization (CCU). Copper-zinc-alumina (CZA) catalysts are widely used for this transformation, yet the nature of the active Cu and Zn species and the reaction intermediates remains debated due to their sensitivity to feed composition and temperature. This challenge is compounded by the high metal loading in conventional CZA catalysts, which obscures active species signals with background contributions from spectator species. To address this, we synthesized model CuZn/Al2O3 catalysts using bimetallic coordination complexes, achieving low metal loadings that yield small Cu clusters and Cu[+] single atoms adjacent to isolated Zn[2+] sites. In situ XANES and UV-vis data were analyzed using multivariate curve resolution-alternating least-squares (MCR-ALS), revealing that Cu dispersion and reagglomeration─phenomena suspected in industrial systems─also occur at low loadings. Operando and modulation excitation with phase sensitive detection DRIFTS (ME-PSD-DRIFTS) showed: (a) Cu clusters dissociate H2 and activate CO2 via monodentate formate; (b) Al2O3 stabilizes Cu[+] under reducing conditions, with Cu content correlating with methanol productivity via CO hydrogenation; and (c) Zn in ZnAl2O4 promotes CO2 activation through reactive carbonate formation and enhances oxygenate conversion kinetics. ZnAl2O4 also acts as a structural promoter, facilitating CO2 conversion via reverse water gas shift (RWGS) and CO hydrogenation. These findings reveal new structure-activity relationships, highlighting the role of the mixed-metal interface in stabilizing transient intermediates and providing some guidance in the rational design of improved catalysts for CO2 valorization.},
}

@article {pmid41218062,
year = {2025},
author = {Takeuchi, E and Yasumizu, Y and Morita, J and Ishikawa, M and Ogawa, K and Motooka, D and Okuzaki, D and Nagata, M and Ishihara, Y and Miyashita, Y and Asano, Y and Mori, K and Morii, E and Beck, G and Saito, Y and Murayama, S and Mochizuki, H and Nagano, S},
title = {Single-nucleus multiome shows motor neuron glutamate overactivation in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf426},
pmid = {41218062},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes motor neuron degeneration. However, the mechanisms underlying the selective vulnerability of motor neurons and the involvement of non-motor neuron cells in ALS remain unclear. To investigate ALS pathology at the cellular level, we performed a single-nucleus multiome analysis, including RNA sequencing and chromatin accessibility profiling, on motor cortex (75,583 nuclei) and spinal cord (62,711 nuclei) from patients with ALS (n=6) and controls (n=6). Our results revealed significant gene expression changes specifically in spinal motor neurons, including upregulation of a metabotropic glutamate receptor, GRM5, and enhanced glutamate signaling. By integrating genome-wide association study data, we identified ALS-associated SNPs in regulatory regions, suggesting cell-type-specific enrichment of risk, especially in microglia. These findings suggest that changes in spinal motor neurons and their surrounding environment, including glutamate signaling, may be involved in ALS pathology. The study also provides valuable resources for future research on the underlying mechanisms and potential therapeutic targets.},
}

@article {pmid41217159,
year = {2025},
author = {Maranges, HM and Timbs, CL},
title = {Operational and conceptual confusion in life history research necessitates the two-tiered model.},
journal = {The Behavioral and brain sciences},
volume = {48},
number = {},
pages = {e115},
doi = {10.1017/S0140525X25100940},
pmid = {41217159},
issn = {1469-1825},
abstract = {Our systematic analysis of operationalizations and conceptualizations of harshness (extrinsic mortality) and unpredictability in the (psychology) life history literature highlights that (1) employment of extremely diverse measures contributes to the confusion about the effect of harshness on life history traits and (2) few measures reflect energetic stress or ambient EM, such that Ellis et al.'s two-tiered model should motivate future research.},
}

@article {pmid41217141,
year = {2025},
author = {Sasson, I},
title = {Social inequalities as sources of extrinsic mortality: implications of the two-tiered model.},
journal = {The Behavioral and brain sciences},
volume = {48},
number = {},
pages = {e119},
doi = {10.1017/S0140525X25100861},
pmid = {41217141},
issn = {1469-1825},
mesh = {Humans ; *Mortality ; *Socioeconomic Factors ; *Bereavement ; },
abstract = {Ellis et al.'s two-tiered model compellingly integrates biological and psychosocial pathways through which extrinsic mortality shapes life history strategies. An understated, yet important, implication of their framework is the role of social inequalities in signaling mortality risk - particularly through differential exposure to bereavement - and how it may give rise to distinct life history strategies and outcomes.},
}

Humans
*Mortality
*Socioeconomic Factors
*Bereavement

@article {pmid41217139,
year = {2025},
author = {Komyaginskaya, E and Gallyamova, A and Grigoryev, D},
title = {Density slows, while pathogens and disasters accelerate life history within populations.},
journal = {The Behavioral and brain sciences},
volume = {48},
number = {},
pages = {e111},
doi = {10.1017/S0140525X25101106},
pmid = {41217139},
issn = {1469-1825},
abstract = {This commentary complements Ellis et al.'s two-tiered framework by using panel data and emphasizing the role of population density in decelerating life history (LH) strategy. We show that mortality cues and energetic constraints do not operate in isolation, demonstrating how density-dependent competition shapes LH strategies over time and underscoring the need for a dynamic, multifaceted approach to LH development.},
}

@article {pmid41217137,
year = {2025},
author = {Chen, BB},
title = {From shyness to attachment: social behaviors as adaptive responses to environmental stress.},
journal = {The Behavioral and brain sciences},
volume = {48},
number = {},
pages = {e103},
doi = {10.1017/S0140525X25101076},
pmid = {41217137},
issn = {1469-1825},
mesh = {Humans ; *Object Attachment ; *Shyness ; *Social Behavior ; *Adaptation, Psychological/physiology ; *Stress, Psychological/psychology ; },
abstract = {This commentary expands Ellis et al.'s 2-tiered life history (LH) model by integrating shyness and insecure attachment as mediators of environmental adaptation. Shyness balances survival-reproduction trade-offs with mixed LH outcomes. Avoidant attachment accelerates LH strategies under harsh conditions; anxious attachment delays reproduction under unpredictable conditions. Incorporating social behaviors, which are related to survival and safety, enhances the model's applicability across behavioral domains.},
}

Humans
*Object Attachment
*Shyness
*Social Behavior
*Adaptation, Psychological/physiology
*Stress, Psychological/psychology

@article {pmid41216790,
year = {2025},
author = {Strell, P and Waldron, MA and Johnson, ST and Shetty, A and Crane, AT and You, Y and Steer, CJ and Low, WC},
title = {Characterization of the intraspecies chimeric mouse brain at embryonic day 12.5.},
journal = {Cell transplantation},
volume = {34},
number = {},
pages = {9636897251384571},
doi = {10.1177/09636897251384571},
pmid = {41216790},
issn = {1555-3892},
abstract = {Incidence of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis have increased dramatically as life expectancy has risen year-over-year, and can lead to neurologic changes. Neurological changes within the central nervous system, specifically the brain, include cell loss and deterioration that impact motor function, memory, executive function, and mood. Available treatments are limited and often only address symptomatic manifestations of the disease rather than disease progression. Cell transplantation therapy has shown promise for treating neurodegenerative diseases, but a source of autologous cells is required. Blastocyst complementation provides an innovative method for generating autologous neural cells. By injecting mouse induced pluripotent stem cells into a wild type mouse blastocyst, we generated a chimeric mouse brain derived of both donor and host neuronal and non-neuronal cells. At embryonic day 12.5 (E12.5), automated image analysis of mouse-mouse chimeric brains showed the presence of GFP-labeled donor-derived dopaminergic and serotonergic neuronal precursors. GFP-labeled donor-derived cholinergic precursor neurons and non-neuronal microglia-like and macrophage-like cells were also observed using more conventional imaging analysis software. This work demonstrates that the generation of mouse-mouse chimeric neural cells is possible; and that characterization of early neuronal and non-neuronal precursors provides a first step toward utilizing these cells for cell transplantation therapies for neurodegenerative diseases.},
}

@article {pmid41216506,
year = {2026},
author = {Wei, Y and Snow, BA and Stevenson, CC and Miao, H and Kaur, J and Lee, SG and Kim, NC and Kim, WJ},
title = {Surface glia for modeling ALS-FTD-associated mutant C9orf72 toxicity in the nervous system of Drosophila.},
journal = {Genes & diseases},
volume = {13},
number = {2},
pages = {101629},
pmid = {41216506},
issn = {2352-3042},
}

@article {pmid41216140,
year = {2025},
author = {Spencer, BE and Xie, SX and Ohm, DT and Elman, L and Quinn, CC and Amado, DA and Baer, M and Lee, EB and Van Deerlin, VM and Dratch, L and Massimo, L and Irwin, DJ and McMillan, CT},
title = {Cumulative incidence of motor and cognitive features in the amyotrophic lateral sclerosis-frontotemporal degeneration spectrum.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf405},
pmid = {41216140},
issn = {2632-1297},
abstract = {In frontotemporal degeneration and amyotrophic lateral sclerosis, subsequent motor or cognitive-behavioural features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a C9orf72 expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with amyotrophic lateral sclerosis and frontotemporal degeneration. We performed a retrospective evaluation of the entire disease course of individuals with an initial clinical syndrome of amyotrophic lateral sclerosis or frontotemporal degeneration who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion. We examined the odds and hazard of subsequent feature development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. At autopsy, we evaluated the association between TDP-43 pathology burden in characteristic brain regions and features across this disease spectrum. For individuals with amyotrophic lateral sclerosis (n = 168) and frontotemporal degeneration (n = 73), binary logistic regression revealed increased odds (odds ratio = 3.49 [95% confidence interval 1.64-7.80], P = 0.002) and Cox proportional hazard analyses revealed an increased hazard (hazard ratio = 3.78 [95% confidence interval 1.86-7.65], P < 0.001) for developing subsequent features in those with a C9orf72 expansion compared to those without. Beyond C9orf72 expansion status, binary logistic regression revealed decreased odds (odds ratio = 0.25 [95% confidence interval 0.12-0.53], P < 0.001) and Cox proportional hazard analyses revealed a decreased hazard (hazard ratio = 0.48 [95% confidence interval 0.25-0.95], P = 0.03) for developing subsequent features in those with an initial amyotrophic lateral sclerosis clinical syndrome compared to those with an initial frontotemporal degeneration clinical syndrome. We observed a 94-month difference in the time after symptom onset of the initial clinical syndrome that a given person without a C9orf72 expansion reached the highest probability of developing subsequent features (0.12 [95% CI 0.03-0.19], 113.00 months) and a person with a C9orf72 expansion surpassed that probability (0.13 [95% CI 0.06-0.19], 19.00 months). The distribution of TDP-43 pathology across characteristic brain regions reflected both the initial clinical syndrome and subsequent features, with relatively preserved spinal cord only in frontotemporal degeneration cases without subsequent motor features (P < 0.0001) and relatively preserved neocortical regions only in amyotrophic lateral sclerosis cases without subsequent cognitive-behavioural features (P < 0.0001). These data highlight the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioural features in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.},
}

@article {pmid41215674,
year = {2025},
author = {Adeagbo, MJ and Kahler, J and Jones, D and Reisinger, HS and Swenson, A},
title = {'I want to be generous, but I only have limited energy': a qualitative study of amyotrophic lateral sclerosis patients' preferences for clinical trials participation.},
journal = {Annals of medicine},
volume = {57},
number = {1},
pages = {2586150},
doi = {10.1080/07853890.2025.2586150},
pmid = {41215674},
issn = {1365-2060},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Patient Preference/psychology ; Female ; Male ; Qualitative Research ; Middle Aged ; Aged ; *Clinical Trials as Topic/psychology ; Adult ; *Patient Participation/psychology ; Emotions ; },
abstract = {BACKGROUND AND OBJECTIVE: Research and decisions on health-related issues such as Amyotrophic Lateral Sclerosis (ALS) continue to evolve as the etiology of network degenerative disease remains indeterminate. Due to its heterogeneity, clinical trials (CTs) are continually being conducted for beneficial breakthroughs aimed at improving the lives of patients with ALS. However, there is a dearth of research on ALS patients' health-seeking decisions and preferences in CTs, particularly for patients living in rural areas. To bridge this important gap, we explored patients' subjective experiences and preferences in CT participation through their emotions.

MATERIALS AND METHODS: Seventeen participants (10 ALS patients, 6 healthcare professionals, and an advocacy group representative associated with ALS) affiliated with the University of Iowa ALS Multidisciplinary clinic were purposively selected and interviewed for the study. Qualitative descriptive data were analyzed using thematic content analysis to understand the patients' experiences and preferences.

RESULTS: Findings indicate key emotional and logistical challenges including fatigue, travel distance and constraints, limited trial availability, which are exacerbated by the disease's rapid progression and restrictive eligibility criteria. Participants' narratives highlighted frustration, anxiety, and fear as central emotional experiences influencing their health-seeking decisions. Conversely, expressions of hope and empathy emerged as significant motivators, with patients demonstrating a willingness to participate in CTs despite the known risk of limited personal benefits, while focusing on the need to benefit future ALS research. Patients prefer and desire more compensation, broader eligibility and inclusive criteria, trial availability and publicity, and access to telemedicine.

CONCLUSION: Given the multifaceted physical, and emotional challenges faced by ALS patients, this study recommends prioritizing patient preferences in future CTs and intervention designs, while advocating for targeted grants and sustained funding that supports ALS clinical trials. This will better align with the needs and expectations of ALS patients, thereby enhancing trial participation and overall patient satisfaction.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/therapy
*Patient Preference/psychology
Female
Male
Qualitative Research
Middle Aged
Aged
*Clinical Trials as Topic/psychology
Adult
*Patient Participation/psychology
Emotions

@article {pmid41214888,
year = {2025},
author = {Lin, H and Xie, X and Gao, R and Jing, Y and Chen, D and Zhang, J and Qiu, X and Zhang, J and Luo, L},
title = {Comparison of Ocular Biometry and Refractive Outcome between IOLMaster 700 and ZW-30.},
journal = {Journal of cataract and refractive surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/j.jcrs.0000000000001828},
pmid = {41214888},
issn = {1873-4502},
abstract = {PURPOSE: To compare the ocular biometry and refractive outcome between two optical biometers.

SETTING: Zhongshan ophthalmic center, Guangzhou, China.

DESIGN: Prospective observational study.

METHODS: A total of 953 cataract patients underwent preoperative biometry including ZW-30 sum-of-segments [SOS] method (ZWSM), ZW-30 composite method (ZWCM), and IOLMaster 700. Agreement of axial length (AL), with or without Cooke-modified AL (CMAL) adjustment, was analyzed using Bland-Altman 95% limits of agreement (LoA). Subgroup analysis were used based on ALs (Short eyes: AL<22mm; Normal eyes: 22mm≤AL<26mm; Long eyes: AL≥26mm). Refractive prediction accuracy was evaluated using Emmetropia verifying optical (EVO) 2.0 formula and its SOS-optimized version (EVO 2.0SOS).

RESULTS: In short and normal eyes, narrow 95%LoAs (<0.2mm) were identified among three ALs. However, AL obtained by ZWSM was lower compared with this obtained by ZWCM and IOLMaster 700 (95%LoA: -0.39 to 0.01mm; -0.38 to 0.04mm) in long eyes. CMAL adjustment enhanced the agreement of AL between ZWSM and ZWCM (95%LoA: -0.01mm to 0.02mm), ZWSM and IOLMaster 700 (95%LoA: -0.10mm to 0.07mm) in long eyes. Myopic prediction errors (PE) have been identified in the use of ocular biometric parameters obtained from ZWSM (Mean PE [ME]: EVO 2.0, -0.19D; EVO 2.0SOS, -0.18D). After adjusting ME to zero, no difference was observed in PE calculated using any combination of formulas based on biometric measurements from three devices.

CONCLUSIONS: This novel segmented biometer demonstrates excellent agreement with IOLMaster 700 in short and normal eyes. However, ALs obtained by IOLMaster 700 are not interchangeable with the SOS method and require CMAL adjustment in long eyes. The application of the SOS method's ocular biometric parameters in refractive prediction led to myopic errors, which suggest constant optimization.},
}

@article {pmid41214238,
year = {2025},
author = {Mushtaq, U and Ahmad, B and Khanday, FA and Ahmad, M},
title = {CHI3L1: An Emerging Player in Neuroinflammation and Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {23},
pmid = {41214238},
issn = {1559-1182},
abstract = {Neuroinflammation is now being identified as the major factor in the development of various neurological disorders. It is a vital process in neurons and the brain that maintains homeostasis under normal and healthy conditions. However, in hyperactivated states, neuroinflammation can also go awry when microglia and astrocytes enter a toxic, reactive state that can release chemicals that damage neurons. When innate immune cells encounter pathogens, infection, cell debris, or misfolded proteins, they release certain chemokines and cytokines to eliminate the intruding particles and protect the brain. However, persistent inflammatory reactions are harmful and can lead to neurodegeneration by continuously releasing toxic chemicals and proteins. Chitinase-3-like protein 1 (CHI3L1), a secretory protein, is emerging as a key inflammatory molecule that is strongly upregulated during neuroinflammation and has been implicated in the pathogenesis of many diseases. The brain's activated astrocytes are the main source of CHI3L1 and are a dependable biomarker for inflammatory pathologies affecting the central nervous system (CNS), including neurodegeneration and autoimmune diseases. The protein has been implicated in many neurological disorders, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and others, mediating neuroinflammation and neurodegeneration. CHI3L1 has contrasting functions in the CNS and other tissues. While the protein promotes cell proliferation and migration in various non-neuronal cancers, at the same time, it simultaneously promotes neurodegeneration and apoptosis in the CNS. This paper reviews the current developments in our knowledge of the pathogenic role of the CHI3L1 protein in various neurological disorders.},
}

@article {pmid41213972,
year = {2025},
author = {Chisholm, CG and Bartlett, R and Brown, ML and Proctor, EJ and Farrawell, NE and Gorman, J and Delerue, F and Ittner, LM and Vine-Perrow, KL and Ecroyd, H and Cashman, NR and Saunders, DN and McAlary, L and Lum, JS and Yerbury, JJ},
title = {Development of a targeted BioPROTAC degrader selective for misfolded SOD1.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9713},
pmid = {41213972},
issn = {2041-1723},
mesh = {Animals ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; Mice, Transgenic ; Mice ; Protein Folding ; Humans ; Disease Models, Animal ; Proteolysis ; Motor Neurons/metabolism/pathology ; Ubiquitin-Protein Ligases/metabolism/genetics ; CRISPR-Cas Systems ; Disease Progression ; HEK293 Cells ; },
abstract = {The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1[G93A] mouse model of ALS. Delayed disease progression is associated with protection of motor neurons, a reduction of insoluble SOD1 accumulation and preservation of innervated neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases.},
}

Animals
*Superoxide Dismutase-1/metabolism/genetics/chemistry
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy
Mice, Transgenic
Mice
Protein Folding
Humans
Disease Models, Animal
Proteolysis
Motor Neurons/metabolism/pathology
Ubiquitin-Protein Ligases/metabolism/genetics
CRISPR-Cas Systems
Disease Progression
HEK293 Cells

@article {pmid41213652,
year = {2025},
author = {Sundar Sah, S and Kumbhalwar, A},
title = {Letter to the Editor: Comment on Kuč et al.'s "Smoking and Risk of Uveitis: A Systematic Review and Meta-Analysis".},
journal = {Ocular immunology and inflammation},
volume = {},
number = {},
pages = {1-2},
doi = {10.1080/09273948.2025.2588218},
pmid = {41213652},
issn = {1744-5078},
}

@article {pmid41213329,
year = {2025},
author = {Adachi, M and Banno, H and Inoue, H},
title = {Drug discovery research with the iPSC models of neurodegenerative diseases.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104985},
doi = {10.1016/j.neures.2025.104985},
pmid = {41213329},
issn = {1872-8111},
abstract = {Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. Recently, it has become recognized that the use of iPSCs for screening can promote drug discovery research. Additionally, research is being conducted to develop high-quality models for drug discovery and to link translational research with clinical studies. The present work focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and broadly introduces the latest research using iPSCs, from disease mechanism studies to drug discovery research. In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI).},
}

@article {pmid41213224,
year = {2025},
author = {Hokkoku, K and Inoue, M and Yamada, S and Namba, H and Matsukura, K and Mukai, T and Chiba, T and Hatanaka, Y and Kobayashi, S and Sonoo, M},
title = {Clinically visible but often unperceived: Low awareness of fasciculations in amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {479},
number = {},
pages = {123764},
doi = {10.1016/j.jns.2025.123764},
pmid = {41213224},
issn = {1878-5883},
abstract = {BACKGROUND: Fasciculations are a key clinical sign of amyotrophic lateral sclerosis (ALS) but also occur in other conditions such as benign fasciculation syndrome. Patients often present with perceived twitching fearing ALS; however, the extent to which ALS patients themselves perceive fasciculations has not been systematically examined. We therefore aimed to clarify how often ALS patients are aware of fasciculations that are clinically visible.

METHODS: We prospectively studied 34 ALS patients. First, a structured questionnaire assessed initial symptoms, chief complaints, and awareness of twitching. Then, the frequency and concordance between objective fasciculations and subjective awareness of fasciculations (twitching) were analyzed across five body regions (bilateral upper and lower limbs and trunk) based on simultaneous visual observation and patient reports.

RESULTS: In the questionnaire, only one of the 34 patients (3 %) reported twitching as the initial symptom, and none presented with twitching as the chief complaint. More than half (19, 56 %) had never noticed twitching. In the fasciculation analysis, patients showing objective fasciculations without subjective awareness were most common (21/34, 62 %), whereas those with objective fasciculations accompanied by subjective awareness were fewer (10/34, 29 %), indicating relatively low concordance between visible fasciculations and patient awareness. No patient exhibited subjective awareness without objective fasciculations. These findings suggest that the majority of visible fasciculations in ALS are not perceived by patients.

CONCLUSION: Fasciculations in ALS are rarely the initial or presenting symptom and are often unperceived by patients despite being clinically visible.},
}

@article {pmid41213077,
year = {2025},
author = {Cai, S and Liu, Y and Liu, B and Liao, H and Li, K},
title = {Hexokinase as a Central Hub in Neurodegeneration: From Metabolic Dysfunction to Therapeutic Innovation.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0891},
pmid = {41213077},
issn = {2152-5250},
abstract = {Neurodegenerative diseases represent an escalating global health crisis affecting more than 55 million people worldwide; however, underlying mechanisms remain unclear, and therapeutic breakthroughs are elusive. Emerging evidence indicates that hexokinase (HK), the rate-limiting glycolytic enzyme, functions as a master regulator orchestrating neuronal survival through metabolic‒mitochondrial coupling. This review consolidates emerging paradigms revealing that HK maintains neuronal viability through its obligate interaction with mitochondrial VDAC1, forming a metabolic checkpoint that integrates energy status with survival signaling. Disease-specific HK dysfunction patterns precede clinical manifestations and drive pathological cascades across primary neurodegenerative conditions. Pathological proteins characteristic of neurodegeneration-amyloid-β in AD, α-synuclein in PD, mutant SOD1 in ALS, and huntingtin in HD-converge to disrupt the HK-VDAC1 axis through distinct molecular mechanisms, triggering mitochondrial permeabilization, bioenergetic collapse, and inflammatory activation. This uncoupling event promotes VDAC1 oligomerization, enabling the cytosolic release of mtDNA, which in turn activates the NLRP3 inflammasome while depleting antioxidant capacity, establishing self-perpetuating neuroinflammatory cycles. The literature reveals that HK functions as a molecular rheostat, determining neuronal fate through glucose-6-phosphate-mediated feedback control, modulation of growth factor signaling, and regulation of apoptosis/survival pathways. Therapeutic targeting of HK through peptide interventions, enzymatic modulation, and gene therapy demonstrates robust neuroprotective effects across multiple disease models. Meanwhile, combination strategies addressing metabolic-inflammatory networks show synergistic efficacy. These insights position HK as a convergent therapeutic nexus offering unprecedented opportunities for precision intervention in neurodegeneration, with potential for early diagnostic applications and preventive strategies that could transform treatment paradigms for conditions affecting millions worldwide.},
}

@article {pmid41212342,
year = {2025},
author = {Zhong, R and Yang, H and Li, X and Wang, F and Zhai, L and Gao, J},
title = {Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {354},
pmid = {41212342},
issn = {1573-6903},
support = {202403070986//Health Science and Technology Project of Shandong Province/ ; RZ1900011598//post-doctoral foundation of Qingdao University/ ; },
abstract = {Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.},
}

@article {pmid41211682,
year = {2025},
author = {},
title = {Correction to "Amyotrophic Lateral Sclerosis and Swim Training Affect Copper Metabolism in Skeletal Muscle in a Mouse Model of Disease".},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70053},
pmid = {41211682},
issn = {1097-4598},
}

@article {pmid41210976,
year = {2025},
author = {Thapa, R and Adhikari, N and Gautam, S and Sun, M and McOmie, S and Davydzenka, V and Smith, D and Syring, J and Kaligis, H and Kosmicki, JM and Chen, R and Li, Y},
title = {Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43.},
journal = {iScience},
volume = {28},
number = {11},
pages = {113745},
pmid = {41210976},
issn = {2589-0042},
abstract = {TDP-43 is an RNA-binding protein important for RNA processing, whose loss of function is involved in multiple neurodegenerative disorders, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). We performed single-nucleus RNA-sequencing to study the convergent and divergent molecular signatures of short-term and long-term TDP-43 depletion in the medial prefrontal cortex (mPFC) using Tdp-43 [F/F] mice, compared with that of 5xFAD mice, a well-established AD mouse model with β-amyloid plaque pathology. Our results demonstrated a significant loss of GABAergic neurons in the mPFC after short-term TDP-43 depletion. This was accompanied by a remarkable reactive gliosis in the mPFC. Our results revealed a strong GABAergic and glial involvement during early stages of TDP-43 loss of function, suggesting that the GABAergic system is vulnerable to TDP-43 pathology and could be considered a potential target for developing therapeutic strategies and biomarkers for early detection in TDP-43 linked AD-related dementia.},
}

@article {pmid41210444,
year = {2025},
author = {Khan, S and Wennberg, B and Hooda, F and Witkowska, M},
title = {Delayed treatment and diagnostic challenges in differentiating multifocal acquired demyelinating sensory and motor neuropathy from lupus: a case report and literature review.},
journal = {AME case reports},
volume = {9},
number = {},
pages = {111},
pmid = {41210444},
issn = {2523-1995},
abstract = {BACKGROUND: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is a rare autoimmune-mediated inflammatory response with negative antibodies which causes demyelination of multiple peripheral nerves in an asymmetric distribution with both motor and sensory deficits. Diagnosis for MADSAM can be clinically challenging, relies on a combination of clinical and electrodiagnostic studies, and symptoms can overlap with other neurological conditions such as systemic lupus erythematosus (SLE). MADSAM is typically asymmetric, demyelinating, and limited to peripheral nerves, whereas SLE is systemic, more commonly axonal, and has vasculitic features. SLE is treated with steroids and immunosuppressants while MADSAM is treated with intravenous immunoglobulin (IVIG), steroids, or plasmapheresis. There is a good short-term prognosis for MADSAM with early treatment, but prognosis can worsen with delayed or inappropriate therapy.

CASE DESCRIPTION: We describe a case of a woman in her 50s who presented with progressive generalized weakness, weight loss, muscle atrophy, and numbness. She was initially diagnosed with SLE, but deteriorated despite treatment. A broad differential was considered which included SLE, paraneoplastic syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Guillain-Barré syndrome. Serological studies, neuroimaging studies, nerve conduction studies, and electromyography (EMG) were performed. She was ultimately diagnosed with Lewis-Sumner syndrome, or MADSAM, a variant of CIDP.

CONCLUSIONS: The case highlights the importance of understanding the various causes of weakness and neuropathy, particularly with an atypical presentation, to pursue the correct diagnostic tests and treatment. The case particularly focuses on the difference between MADSAM and SLE. There is significant clinical overlap between the two, and a misdiagnosis can delay effective treatment and worsen outcomes by allowing progression to more debilitating stages of the illness.},
}

@article {pmid41209626,
year = {2025},
author = {Jensen, SHJ and Frumer, M and Connelly, EDS and Østgård, R and Glerup, H and Denby, K and Egsgaard, AL and Appel, CW},
title = {Integrated Rheumatology-Gastroenterology Clinic: An Innovative Organisation for Patients with Multiple Autoimmune Diseases.},
journal = {International journal of integrated care},
volume = {25},
number = {4},
pages = {9},
pmid = {41209626},
issn = {1568-4156},
abstract = {INTRODUCTION: Patients with multiple autoimmune diseases lack continuity of care due to increasing specialisation and siloed practice in healthcare. Despite improvements in quality, this organisation has led to fragmented patient pathways, as related diseases are treated separately. Limited research has investigated approaches to integrate care for patients with co-occurrent Inflammatory Joint Disease and Inflammatory Bowel Disease, with minimal emphasis on the patient perspective. The aim was to describe the Rheumatology-Gastroenterology Clinic (ReGa), characterise its population, and investigate patient experiences.

DESCRIPTION: A Danish outpatient clinic combining rheumatology and gastroenterology.

RESULTS: During the study period, 54 patients attended the ReGa clinic. Prior to integration, these patients had an average of 29.6 outpatient visits. With most working-age patients, this frequent attendance poses individual and societal challenges. Based on Haggerty et al.'s definition of continuity of care, relational elements emerged as particularly important for patients but not independent of informational and management factors.

CONCLUSION: The integrated approach was experienced to improve continuity of care for patients with multiple autoimmune diseases. The findings highlight the potential to bridge healthcare gaps and address challenges arising from organisational structures shaped by specialisation and compartmentalisation of knowledge. This approach may also benefit other patient groups with comorbid conditions.},
}

@article {pmid41209384,
year = {2025},
author = {Han, K and Yan, SG and Liu, F and Li, L and Zhou, D and Li, L and Liu, N and Dong, J},
title = {The Alterations in the Osteoimmune Microenvironment of STZ-Induced Type 2 Diabetic Mice:A Single-Cell RNA Sequencing Analysis.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {15309-15327},
pmid = {41209384},
issn = {1178-7031},
abstract = {BACKGROUND: This study aimed to delineate the single-cell transcriptome of bone marrow (BM) cells from wild-type (WT) and type 2 diabetic (T2D) mice, revealing distinct immune microenvironment features.

METHODS: Single high-throughput single-cell RNA sequencing dataset (GSE212726) from BM cells of WT and streptozotocin (STZ)-induced T2DM mice were analyzed. Uniform manifold approximation and projection (UMAP), pseudo-time analysis, gene enrichment studies, and CellphoneDB were employed to identify immune cell interactions within the osteoimmune microenvironment. Key gene expression was validated by quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: After filtering low-quality cells and doublets, 9,360 cells (WT) and 10,885 cells (T2DM) were retained and classified into 12 clusters. Proportional analysis revealed a significant decrease in BM-neutrophils (66.56% → 54.73%) and an increase in B cells (9.16% → 19.78%) in the DM group. The DM/WT ratio for BM-neutrophils/T cells, BM-neutrophils/DCs, and monocytes/T cells increased, while the ratio for BM-neutrophils/Naïve_B decreased. KEGG pathway analysis highlighted enrichment of neurodegeneration, protein processing in the endoplasmic reticulum, and amyotrophic lateral sclerosis pathways in BM-neutrophils. Intercellular communication analysis indicated reduced incoming and outgoing interaction strength for B cells and T cells, while the T2D group showed enhanced THBS, VISFATIN, CLEC, IL4, and IL6 signaling. Notably, CLEC was specific to outgoing signaling in T cells, and THBS was specific to both outgoing and incoming signaling in monocytes, MSCs, and BM-neutrophils.

CONCLUSION: Single-cell RNA sequencing provides a comprehensive profile of bone marrow immune cells in T2D mice and has highlighted their heterogeneity, population shifts, and intercellular interactions. These findings highlight critical alterations in immune cell functions that may contribute to T2D progression and suggest possible avenues for future therapeutic investigation. Future research should continue to leverage scRNA-seq technology to refine treatment strategies and enhance patient outcomes by addressing immune dysfunction and chronic inflammation.},
}

@article {pmid41208712,
year = {2025},
author = {Godrich, D and Pasteris, J and Martin, ER and Kunkle, B and Naj, AC and Hamilton, K and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, C and Mukherjee, S and Kofler, J and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Schellenberg, G and Pericak-Vance, MA and Cuccaro, M and Scott, WK and Rundek, T and Kukull, W and Montine, T and Beecham, GW and , },
title = {Genome-wide association studies of TDP-43 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70760},
pmid = {41208712},
issn = {1552-5279},
support = {R01-AG062695//Primary Funding includes (additional funding in Acknowledgements)/ ; AG074855//Primary Funding includes (additional funding in Acknowledgements)/ ; U01-AG016976//National Alzheimer's Coordinating Center (NACC)/ ; U24-AG21886//National Cell Repository for Alzheimer's Disease (NCRAD)/ ; U24-AG041689//National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS)/ ; U01-AG032984//Alzheimer's Disease Genetics Consortium (ADGC)/ ; RC2-AG036528//Alzheimer's Disease Genetics Consortium (ADGC)/ ; U24-AG074855//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; U01-AG068057//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; R01-AG059716//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; AG006781//Adult Changes in Thought (ACT)/ ; AG066567//Adult Changes in Thought (ACT)/ ; AG030653//University of Pittsburg/ ; AG041718//University of Pittsburg/ ; AG064877//University of Pittsburg/ ; P30-AG066468//University of Pittsburg/ ; P30-AG010161//Rush University (ROSMAP)/ ; R01-AG019085//Rush University (ROSMAP)/ ; R01-AG15819//Rush University (ROSMAP)/ ; R01-AG17917//Rush University (ROSMAP)/ ; R01-AG3014//Rush University (ROSMAP)/ ; },
abstract = {INTRODUCTION: Transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy has been linked to cognitive decline and often co-occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP-43 proteinopathy and HS, we performed genome-wide association studies (GWASs) of HS and TDP-43 inclusions.

METHODS: Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP-43: N = 4669). Statistical analyses included association analysis with HS and TDP-43 inclusions and meta-analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region.

RESULTS: Two regions achieved genome-wide significance with TDP-43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome-wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP-43 proteinopathy.

DISCUSSION: We identified associations with TDP-43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy.

HIGHLIGHTS: HS and TDP-43 contribute to dementia and often co-occur. The etiology and relationship of HS and TDP-43 remains unclear. HS and TDP-43 share genetic risk factors in the genes APOE and TMEM106B. Genes have direct effects on HS, with additional effects mediated through TDP-43.},
}

@article {pmid41207985,
year = {2025},
author = {Mei, J and Li, L and Ma, ZS},
title = {Unraveling the Ecological Mechanisms Influencing the Structure and Composition of Lung Cancer Microbiomes.},
journal = {Microbial ecology},
volume = {88},
number = {1},
pages = {119},
pmid = {41207985},
issn = {1432-184X},
abstract = {This study investigates the ecological mechanisms governing the structure and composition of lung microbiome communities within tumor tissue from lung cancer patients. While this field has attracted increasing research attention, the ecological and etiological mechanisms driving microbial community assembly in this environment remain poorly characterized. To address this gap, we applied Sloan's near neutral model, Ning et al.'s normalized stochasticity ratio framework and Harris et al.'s multi-site neutral model to evaluate the influences of stochastic and deterministic factors at species, community and metacommunity levels, respectively. Our findings include: (i) Stochastic drift exhibited predominant influence at both species and community levels in normal adjacent tissue (NT), exceeding its effects in LUAD (lung adenocarcinoma) and LUSC (lung squamous cell carcinoma). (ii) At the metacommunity level, neutrality was not rejected at the metacommunity or local community levels, which is consistent with the previous finding (i). (iii) Elevated metacommunity biodiversity (θ) and immigration rates (m) in LUAD/LUSC compared to NT (observed in ∼50% of cases) suggest that tumor occurrence/progression may actively promote microbial recruitment to tumor microenvironments. We propose three non-exclusive mechanistic interpretations: (i) Tumor-mediated immune modulation creates permissive ecological niches; (ii) structural remodeling of tissue enhances microbial colonization potential; (iii) selective enrichment of opportunistic taxa (e.g., Streptococcus) through tumor-specific microenvironmental changes. Our results demonstrate that LUAD and LUSC microbiomes are shaped by deterministic tumor-driven selection, in contrast to the predominantly stochastic assembly observed in NT microbiomes. These findings reveal substantial reorganization of tumor-associated microbial communities, warranting further biomedical investigation and clinical validation.},
}

@article {pmid41207946,
year = {2025},
author = {Kahana, GK and Codish, S},
title = {When the hospital becomes the battlefield: patients as stakeholders in mass casualty incidents.},
journal = {Israel journal of health policy research},
volume = {14},
number = {1},
pages = {64},
pmid = {41207946},
issn = {2045-4015},
abstract = {ABSTRACT: Hospitals are uniquely positioned during disasters, functioning as first-line responders and at risk themselves. While system preparedness and staff resilience have been widely studied, the experience and preparedness of patients admitted to hospitals during mass casualty incidents (MCIs) have received little attention. This commentary was prompted by the recent study of Wolff et al., which assessed inpatients’ knowledge of how to respond during an MCI and the barriers they perceived in such situations. Their work highlights gaps in patient awareness and preparedness, raising the question of whether and how inpatients should be involved in disaster response. Drawing on the experience of Soroka Medical Center during the June 2025 Israel–Iran conflict, we reflect on these findings in the context of a real-world missile strike on a major tertiary medical center. On June 19, 2025, Soroka was directly struck by a ballistic missile that destroyed a surgical inpatient building, rendering 562 beds unusable and necessitating mass evacuation and transfers. The event revealed the complexity of patient reactions—from acute fear and uncertainty to pragmatic acceptance of crowding in compromised conditions. Hospital leadership rapidly instituted patient education on air-raid protocols, relocated vulnerable patients, and implemented staff refresher training. Despite these efforts, challenges in communication, rumor control, and logistics significantly affected inpatients’ sense of safety and continuity of care.

CONCLUSIONS: Wolff et al.’s study and Soroka’s lived experience converge on a critical insight: patients cannot be passive bystanders in disasters. Their perceptions, behaviors, and resilience have a direct impact on hospital functionality. Future research should define the scope of patient roles in preparedness, assess the psychological impact of preparedness training, and inform scalable policies for integrating patients into hospital resilience frameworks. Incorporating patient preparedness into disaster planning is crucial, especially during times of heightened alert and in regions prone to conflict or natural disasters.},
}

@article {pmid41207217,
year = {2025},
author = {Wu, Y and Huang, S and Sha, Q and Yu, J},
title = {Emerging and Re-emerging viruses as triggers of human endogenous retrovirus activation: Implications for aging and age-related pathologies.},
journal = {Molecular aspects of medicine},
volume = {106},
number = {},
pages = {101422},
doi = {10.1016/j.mam.2025.101422},
pmid = {41207217},
issn = {1872-9452},
abstract = {The human genome contains a substantial legacy of ancient retroviral infections known as Human Endogenous Retroviruses (HERVs), composing 8 % of our DNA. In healthy young individuals, these elements are kept dormant by robust epigenetic mechanisms, primarily DNA methylation and repressive H3K9me3 histone marks. However, this epigenetic silencing deteriorates with age, leading to the reactivation of HERVs, particularly the youngest HERV-K subfamily. This report posits that this HERV awakening is not a passive byproduct of aging but an active, transmissible driver of pathology. The reactivation of HERVs leads to the production of retrovirus-like particles (RVLPs) that can induce senescence in healthy neighboring cells, propagating a contagious aging phenomenon. Furthermore, the accumulation of HERV-derived dsRNA and reverse-transcribed DNA triggers chronic innate immune responses through pathways including cGAS-STING and IFIH1-MAVS, fueling the systemic, low-grade inflammation characteristic of inflammaging, catalytically accelerated by exogenous viral infections. Pathogens such as SARS-CoV-2, Epstein-Barr Virus (EBV), and Herpes Simplex Virus (HSV-1) can directly transactivate HERVs via their own viral proteins, overwhelming the already compromised epigenetic controls in an aging host. This mechanistic link between viral triggers and endogenous retroviral activity is strongly implicated in a range of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS), where the HERV-K envelope protein is directly neurotoxic. It is also linked to autoimmune diseases like Multiple Sclerosis and various cancers. This report synthesizes these findings and identifies a novel mechanistic link between viral activity, chronic inflammation, and the onset of age-related diseases.},
}

@article {pmid41206819,
year = {2025},
author = {Buonocore, J and Fratto, E and Arcuri, F and Vescio, B and Calomino, C and Talarico, M and Cristiani, CM and Quattrone, A and Quattrone, A},
title = {Plasma NfL and GFAP in the preclinical stages of neurodegenerative diseases: insights from the UK Biobank.},
journal = {Journal of neurology},
volume = {272},
number = {12},
pages = {755},
pmid = {41206819},
issn = {1432-1459},
abstract = {BACKGROUND: Plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising blood-based biomarkers of neuroaxonal injury and astrocytic activation, relevant in neurodegeneration. We investigated their pre-diagnostic profiles across common neurodegenerative diseases, including Parkinson's disease (PD), atypical parkinsonian disorders (APD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS).

METHODS: Forty-eight thousand five hundred and twenty-four UK Biobank participants with baseline plasma proteomic data for NfL and GFAP were included. Incident diagnoses of PD, APD, AD, and ALS were identified through ICD-10-coded health records, after careful inclusion/exclusion procedures. Baseline plasma NfL and GFAP concentrations were standardized as z-scores adjusted for relevant covariates. The hazard ratio (HR) for incident neurodegenerative diseases was estimated using Cox regression models adjusted for demographic, clinical, socioeconomic and genetic factors.

RESULTS: The final sample included 1196 cases (505 PD, 26 APD, 476 AD, 189 ALS) and 44,107 control subjects. In Cox regression models, NfL was associated with higher risk of incident ALS (HR 1.69; 95% CI, 1.58-1.80, p < 0.001), APD (HR 1.51; 95% CI, 1.22-1.87, p < 0.001), AD (HR 1.31; 95% CI, 1.22-1.41, p < 0.001), and PD (HR 1.14; 95% CI, 1.05-1.23, p < 0.001). GFAP was independently associated with incident AD only (HR 1.72; 95% CI, 1.63-1.82, p < 0.001).

CONCLUSION: Plasma NfL and GFAP showed distinct pre-diagnostic profiles. NfL was associated with incident diagnosis of several neurodegenerative diseases, while GFAP was specific to AD, reinforcing its role in dementia. These results may help optimize the identification of target populations at risk of neurodegenerative diseases for future neuroprotective treatments.},
}

@article {pmid41206134,
year = {2025},
author = {Allel, K and Palmer, T and Abou Jaoude, GJ and Korotych, O and Yedilbayev, A and Vilc, V and Corloteanu, A and Macari, M and Evghenia, C and Laticevschi, D and Shakhimurat-Shaimovich, I and Anar-Saduakasovna, R and Gulzhan-Elbrusovna, T and Anatolievna-Ryazanet, D and Shahrizada-Yergalymovna, A and Yatskevich, N and Skrahina, A and Zhurkin, D and Avaliani, Z and Kiria, N and Lomtadze, N and Kiria, N and Avaliani, T and Khonelidze, I and Danelia, M and Maxim, C and Haghparast-Bidgoli, H and Skordis, J},
title = {Cost-effectiveness of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis in Belarus, Georgia, Kazakhstan and the Republic of Moldova.},
journal = {BMJ global health},
volume = {10},
number = {11},
pages = {},
doi = {10.1136/bmjgh-2024-018099},
pmid = {41206134},
issn = {2059-7908},
abstract = {INTRODUCTION: Prior to 2020, treatment options for multidrug-resistant tuberculosis (MDR-TB) were limited and typically involved long treatment durations and high financial burdens. In the eastern European and central Asian (EECA) region, traditional inpatient tuberculosis (TB) care models, alongside high MDR-TB rates, escalate nosocomial transmission risks and treatment costs. Modified, fully oral, shorter treatment regimens (mSTR) implemented in the WHO European Region under operational research conditions offered a potential reduction in the burden of MDR-TB treatment for both patients and health systems.

METHODS: We conducted the first regional evaluation of the cost-effectiveness of the novel mSTR treatment regimen compared with the standard of care (SOC) in Belarus, Georgia, Kazakhstan and Republic of Moldova. We used cohort data on mSTR efficacy and WHO data on SOC in patients with MDR-TB. We used a Markov model, with treatment costs calculated from the provider perspective. Outcomes were measured in quality-adjusted life years (QALYs), with incremental cost-effectiveness ratios (ICER) calculated per QALY gained in each country. An annual 3% discount rate was used for both costs and outcomes. We performed univariate and probabilistic sensitivity analysis (PSA) to assess the robustness of our cost-effectiveness calculations under varying assumptions. Finally, we estimated potential cost savings if mSTR was implemented nationally and we evaluated the incremental net monetary benefit (iNMB) and willingness-to-pay (WTP) thresholds based on Wood et al's country-level cost-effectiveness thresholds. All costs were reported in 2022 USD.

RESULTS: We estimated that mSTR can reduce TB treatment costs by between 23% and 47% and drug costs by 39% to 74%, compared with SOC in the countries studied. mSTR resulted in cost savings of between $3596 and $8174 per patient and offered additional health gains of between 0.56 to 2.69 QALYs per patient. mSTR remained cost-effective (iNMB>0) compared with SOC in 78%, 85%, 91% and 92% of PSA simulations in Belarus, Georgia, Kazakhstan and Republic of Moldova, respectively, when compared with their country-level WTP threshold. Implementing mSTR in up to 80% of MDR/rifampicin-resistant TB patients may result in cost savings of $20.5, 2.5, 0.7 and 0.2 million in Kazakhstan, Belarus, Republic of Moldova and Georgia; equivalent to 17%, 3%, 4% and 1% of their national TB budgets, respectively.

CONCLUSIONS: Compared with SOC, mSTR is a more cost-effective treatment option for MDR/RR-TB, which should be considered by policymakers in the EECA region. Using insights from current implementations to scale up, plan operational changes and reallocate savings from mSTR could greatly enhance TB services and patient care.},
}

@article {pmid41205880,
year = {2025},
author = {Cho, H and Lee, B and Son, C and Choi, J and Eom, S and Park, J},
title = {ERLIN1: A central regulator of protein quality control, lipid homeostasis, and cellular signaling at the endoplasmic reticulum.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112224},
doi = {10.1016/j.cellsig.2025.112224},
pmid = {41205880},
issn = {1873-3913},
abstract = {Endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) is an endoplasmic reticulum (ER)-resident stomatin/prohibitin/flotillin/HflK/C (SPFH) family protein that assembles into oligomeric complexes within detergent-resistant membrane domains. ERLIN1 regulates multiple cellular functions, including protein quality control, calcium signaling, and lipid metabolism. Together with ERLIN2, it forms ER-associated degradation (ERAD) nanodomains through interactions with RING finger protein 170 (RNF170) and transmembrane and ubiquitin-like domain-containing 1 (TMUB1). These specialized domains facilitate the degradation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R) via the ERAD pathway. ERLIN1 also controls cholesterol metabolism by inhibiting sterol regulatory element-binding protein (SREBP) activation and promoting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) degradation. In addition, it blocks cholesterol esterification, thereby enhancing cholesterol transport to the Golgi apparatus. ERLIN1 further regulates cell fate by promoting autophagy and suppressing apoptosis; in complex with ERLIN2, it interacts with activating molecule in Beclin 1-regulated autophagy protein 1 (AMBRA1) at mitochondria-associated membranes to initiate autophagy and binds phosphatidylinositol 3-phosphate to stabilize autophagy signaling. Its overexpression enhances tumor progression, whereas silencing triggers apoptosis in colorectal cancer. Mutations in ERLIN1 are linked to neurodegenerative diseases such as hereditary spastic paraplegia type 62 and atypical amyotrophic lateral sclerosis. The ERLIN1/2 complex also influences immune responses and viral replication through cholesterol regulation. Collectively, these diverse and integrated functions highlight the potential of ERLIN1 as a therapeutic target in cancer, metabolic, neurodegenerative, and infectious diseases.},
}

@article {pmid41205804,
year = {2025},
author = {Akan, T and Alp, S and Aishwarya, R and Xing, DG and Dicharry, D and Bhuiyan, MS and Bhuiyan, MAN},
title = {PathViT: Automated disease classification from skeletal muscle histopathology.},
journal = {The American journal of pathology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajpath.2025.10.009},
pmid = {41205804},
issn = {1525-2191},
abstract = {Analyzing skeletal muscle pathology from histological images is a labor-intensive process prone to inter- and intra-user variability influencing diagnosis accuracy and consistency-conventional techniques, such as ImageJ-based tools, demand manual cell counting, segmentation, and thresholding. As a result, they are time-consuming and create different results. To address these difficulties, we developed PathViT, a transformer-based deep learning model for automated classification of pathological images. Skeletal muscle pathology is characterized by changes in myofiber cross-sectional area, increased central nuclei, and structural disruptions in sarcomeres. To investigate these changes in myofiber size, we utilized Wheat Germ Agglutinin (WGA) stained histopathological images of different skeletal muscles (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus) to classify amyotrophic lateral sclerosis (ALS), diabetes, and healthy controls. PathVit can automatically distinguish between healthy and diseased muscle fibers, reducing human intervention, minimizing subjectivity and variability, and significantly decreasing analysis time compared to traditional manual methods. We evaluated PathViT against state-of-the-art deep learning models using WGA-stained skeletal muscle images from wild-type and disease models (G93A*SOD1 for ALS and Akita for Type 1 diabetes). PathViT classified healthy and diseased muscle fibers with 96% accuracy, outperforming all other models. Compared to manual methods, PathVit reduces human intervention, subjectivity, variability, and analysis time. This approach enhances scalability, diagnostic accuracy, and variability, making PathViT a powerful biomedical research and clinical tool.},
}

@article {pmid41205733,
year = {2025},
author = {Hendricus Maes, KJ and Briedé, JJ},
title = {Repurposing immunomodulatory drugs targeting microglia for amyotrophic lateral sclerosis.},
journal = {Brain research},
volume = {},
number = {},
pages = {150032},
doi = {10.1016/j.brainres.2025.150032},
pmid = {41205733},
issn = {1872-6240},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that progressively affects upper and lower motor neurons, leading to symptoms including dysarthria, muscle weakness, and paralysis. The disease is multifactorial, with a variety of contributing pathways, including excitotoxicity, oxidative stress, and neuroinflammation. Current treatments target only two of these pathways with limited efficacy, highlighting the need for alternative approaches. Increasing evidence highlights the involvement of immune dysregulation, particularly microglial-mediated neuroinflammation, in ALS pathology. Fortunately, many immunomodulatory drugs acting on microglia are already available for other diseases, indicating promising opportunities for drug repurposing. This literature review provides an overview of existing drugs under investigation for ALS, including those that have failed, and highlights new microglia-targeting candidates with repurposing potential. Compounds such as ibudilast, fingolimod, and modafinil have shown encouraging initial clinical results, whereas others were well-tolerated but underpowered or failed to demonstrate efficacy. New candidates, such as azithromycin, naltrexone, montelukast, doxycycline, tofacitinib, quercetin, belinostat, and several kinase inhibitors, have demonstrated positive preclinical results, supporting their advancement toward clinical evaluation. Overall, these findings emphasize the potential of microglia-targeting therapies for ALS. To realize this potential, future studies must include larger cohorts, assess effects across disease stages and patient subgroups, and examine sex differences. This is essential to address patient heterogeneity and improve personalized treatment in ALS.},
}

@article {pmid41204694,
year = {2025},
author = {Scirocco, E and Luppino, SD and Allen, MD and Giacomelli, E and Gelevski, D and Higgins, M and Scalia, JL and McCaffrey, AC and Sanders, DL and Ho, DT and Quarles, B and Dalamagas, H and Heintzman, S and Paganoni, S},
title = {Amyotrophic Lateral Sclerosis Clinical Research Site Operations: Emerging Challenges and Potential Solutions From Multiple Sites in the US.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70054},
pmid = {41204694},
issn = {1097-4598},
abstract = {As the amyotrophic lateral sclerosis (ALS) clinical trial landscape continues to grow and evolve, optimization of research site efficiency is essential. Herein, we outline results from a formal discussion among multiple ALS research sites in the US to help establish and maintain efficient research site infrastructure. Ten ALS site managers collaborated over a 6-month period to develop a framework of operational strategies to support ALS clinical research sites. To address the evolving ALS research landscape, it was agreed that the traditional site operational model requires continuous evaluation and adaptation. Challenges, particularly affecting staff recruitment and retention (such as salary, burnout, and limited opportunities for professional growth for certain positions), were discussed. The group identified challenges related to increased burden to maintain staff training, evolving outcome measures, and limitations in available space. Sites agreed on the importance of well-trained and experienced site personnel, and the emergence of site research nurses and nurse practitioners as trial leaders. Successful strategies to address staffing barriers were discussed, recognizing the need for ongoing improvements and increased funding to support the research team. A centralized organizational approach, consisting of multiple specialized study teams supported by an overarching site operations infrastructure, was identified as a key driver to optimize staff performance, accelerate trial conduct, and streamline workflow. Future initiatives should include refining strategies to continuously enhance site operations, identify key metrics to quantify efficiency and ensure financial sustainability.},
}

@article {pmid41204026,
year = {2025},
author = {Seemikeri, C and Menon, D and Nashi, S and Arshad, F and Srijithesh, PR and Alladi, S},
title = {Facial onset sensory and motor neuronopathy: a diagnostic challenge.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41204026},
issn = {2240-2993},
abstract = {Facial onset sensory and motor neuronopathy (FOSMN) is a rare neurological disorder that combines features of both sensory neuropathy and motor neuron disease. Its clinical resemblance to trigeminal neuralgia and amyotrophic lateral sclerosis (ALS) often leads to delayed or incorrect diagnosis. Recent evidence suggests that FOSMN may represent a sensory-onset variant within the ALS spectrum, characterised by the addition of cranial and limb sensory involvement. The present report highlights this diagnostic challenge and emphasises that FOSMN can occur with prominent sensory symptoms and cranial nerve dysfunction even in the absence of significant bulbar features. Recognising this pattern broadens the classical understanding of motor neuron diseases, which are traditionally viewed as purely motor disorders. Awareness of such presentations and the use of targeted neurophysiological tests, particularly blink reflex studies, are essential for accurate diagnosis and better characterisation of this rare and evolving disease spectrum.},
}

@article {pmid41203507,
year = {2025},
author = {Zhang, YP and Kedia, S and Klenerman, D},
title = {Rethinking neurodegeneration through a co-proteinopathy lens.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.10.006},
pmid = {41203507},
issn = {1878-108X},
abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.},
}

@article {pmid41202295,
year = {2025},
author = {Sales de Campos, P and Smith-Hublou, M and Olsen, WL and Souza Leite, W and Wymer, JP and Napoli, NJ and Vose, AK and Pulley, MT and Mitchell, GS and Smith, BK},
title = {Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e76105},
doi = {10.2196/76105},
pmid = {41202295},
issn = {1929-0748},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/therapy ; Double-Blind Method ; *Hypoxia/physiopathology ; Purines/therapeutic use/pharmacology ; *Respiration/drug effects ; *Neuronal Plasticity/drug effects ; *Purinergic P1 Receptor Antagonists/therapeutic use ; Randomized Controlled Trials as Topic ; Male ; Adult ; Middle Aged ; Female ; },
abstract = {BACKGROUND: Respiratory impairment is a major concern in amyotrophic lateral sclerosis (ALS), shortening survival and lowering quality of life. One therapy with promise to delay respiratory decline in ALS is acute intermittent hypoxia (AIH), consisting of alternating periods of breathing mildly hypoxic (9%-12% O2) and normoxic (21% O2) gas. AIH stimulates spinal, serotonin-dependent neuroplasticity in rodent models, conferring functional benefits in diverse physiological systems without detectable pathology. However, in rodent models, AIH-induced neuroplasticity is constrained by distinct signaling cascades initiated by spinal adenosine.

OBJECTIVE: We propose to investigate a therapeutic strategy to delay breathing compromise in those living with ALS by combining a selective adenosine 2A (A2A) receptor inhibitor (istradefylline) with AIH. The fundamental hypothesis guiding this proposal is that a single AIH trial after pretreatment with istradefylline enhances respiratory neuroplasticity versus AIH or sham intervention.

METHODS: We propose to evaluate resting breathing, respiratory strength, and participant-reported symptoms in adults living with ALS after combined istradefylline plus AIH. A mixed within- and between-participant study design incorporates 4 test sessions, separated by approximately 2 weeks (±5 days). Testing conditions include single sessions of AIH + istradefylline, AIH + placebo, sham AIH (ie, normoxia) + placebo, and sham AIH + istradefylline. Safety and feasibility will be characterized using the rate of adverse events, changes in vital signs, and participant-reported breathing sensations (Aim 1). Neuroplasticity of breathing and motor function will be evaluated as changes in resting breathing, voluntary respiratory strength, respiratory control, and maximal pinch force (Aim 2).

RESULTS: As of January 2025, with a target sample of 16 participants in each group, 10 participants with ALS and 5 control participants completed study procedures. Recruiting is ongoing, and the final participant will complete the study by December 2025. Publication of results is expected by the end of 2026.

CONCLUSIONS: These aims will provide crucial data regarding the preliminary safety and feasibility of this paired intervention and help optimize therapeutic AIH as a rehabilitation strategy, thereby guiding further research concerning this novel treatment for ALS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05377424; https://clinicaltrials.gov/study/NCT05377424.

DERR1-10.2196/76105.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/therapy
Double-Blind Method
*Hypoxia/physiopathology
Purines/therapeutic use/pharmacology
*Respiration/drug effects
*Neuronal Plasticity/drug effects
*Purinergic P1 Receptor Antagonists/therapeutic use
Randomized Controlled Trials as Topic
Male
Adult
Middle Aged
Female

@article {pmid41202020,
year = {2025},
author = {Senior, E and Clarke, A and Wilson-Menzfeld, G},
title = {Living with a loved one's mental health issue: Recognizing the Lived Experiences of Military Spouses.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336295},
pmid = {41202020},
issn = {1932-6203},
mesh = {Humans ; *Spouses/psychology ; Female ; Male ; *Military Personnel/psychology ; *Mental Health ; Adult ; Middle Aged ; Qualitative Research ; *Mental Disorders/psychology ; },
abstract = {Limited evidence surrounds the lived experiences of military spouses whose partner has mental health issues. This lack of evidence may be due to factors such as global austerity, underfunding of armed forces, and inadequate healthcare systems. As a result, family members-especially spouses-often end up being the primary caregivers for their military partners with mental health issues. The study used a qualitative, biographical methodology, collecting data through life stories. Two face-to-face semi-structured interviews took place with nine military spouse recruited through military spouse networks and snowballing. Lieblich et al.'s (1998) framework provided analytical pluralism, which allowed for both narrative and thematic analysis. Stories are presented in the stages 'in the beginning', changing times' and 'this is me'. Thematic analysis identified six overarching categories; Living with disruption, living in the midst of it all, It isn't enough, seeking support, Diagnosis and treatment, Living alongside. Whilst the first of its kind in the UK, this biographical study advances both national and global understanding of military spouse experiences in the context of mental health. Both the stories and the categories indicate that living with a serving partner who has mental health issues is a complex journey marked by both struggle and growth. A uniqueness arising from this study highlights the period leading up to a mental health diagnosis, emphasising the prolonged emotional and psychological strain experienced by military spouses before any formal recognition of mental illness in their serving partner. The study adds a new dimension to understanding the emotional toll on military spouses and underscores the importance of early recognition and support. While participants faced emotional detachment and feelings of invisibility, they also identified gains in resilience and strengthened relationships. Through the convergence of the narrative and thematic analysis the participants experience throughout their partners mental health issue is conceptualised in a Relationship Trajectory model. It illustrates the positive, early relational strength, superseded by relationship decline followed with relationship reinvention.},
}

Humans
*Spouses/psychology
Female
Male
*Military Personnel/psychology
*Mental Health
Adult
Middle Aged
Qualitative Research
*Mental Disorders/psychology

@article {pmid41201719,
year = {2025},
author = {Gautam, P and Vishwakarma, RK and Nath, M and Nath, G and Pathak, A},
title = {Microbiota Dysbiosis in Amyotrophic Lateral Sclerosis: A Systematic Review of Human Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {10},
pmid = {41201719},
issn = {1559-1182},
mesh = {*Amyotrophic Lateral Sclerosis/microbiology/complications ; Humans ; *Dysbiosis/microbiology/complications ; *Gastrointestinal Microbiome/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Despite intensive research, its pathogenesis remains poorly understood. Recent insights suggest a pivotal role of the gut microbiota in modulating neuroinflammation and neurodegeneration via the gut-brain axis. This systematic review aims to synthesize clinical evidence on gut microbiota dysbiosis in ALS, exploring microbial and metabolic alterations and their associations with disease progression and severity. A comprehensive literature search was conducted across PubMed, Embase, Scopus, Web of Science, and other databases up to May 10, 2024, adhering to PRISMA 2020 guidelines. Eighteen eligible human studies were selected based on predefined inclusion criteria. Data on microbial diversity, taxonomic shifts, metabolite profiles, and clinical correlations were extracted and assessed using a modified Newcastle-Ottawa Scale. Most studies reported altered microbial diversity, reduced butyrate-producing bacteria (e.g., Faecalibacterium, Roseburia), and increased pro-inflammatory taxa (e.g., Escherichia coli, Bacteroides) in ALS. Integrated microbiome-metabolome analyses revealed disruptions in SCFAs, bile acids, and lipid metabolism, some correlating with ALSFRS-R scores and cognitive impairment. Although some studies showed minimal or no differences, the overall evidence supports a link between dysbiosis and ALS pathophysiology. Probiotic trials demonstrated limited efficacy, highlighting the need for targeted, patient-specific interventions. Gut microbiota dysbiosis is increasingly recognized as a contributor to ALS progression. However, methodological variability, small sample sizes, and limited longitudinal data restrict definitive conclusions. Future research should employ standardized, multi-omics approaches and larger cohorts to clarify causal links and develop microbiome-informed diagnostics and therapies for ALS.},
}

*Amyotrophic Lateral Sclerosis/microbiology/complications
Humans
*Dysbiosis/microbiology/complications
*Gastrointestinal Microbiome/physiology

@article {pmid41201375,
year = {2025},
author = {Tomlinson, J and Roberson, E and Klee, V and Ma, J and Roggenbuck, J},
title = {A study of patient recall and comprehension of genetic testing results in amyotrophic lateral sclerosis (ALS).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2025.2582829},
pmid = {41201375},
issn = {2167-9223},
abstract = {Objective: Assess the accuracy of ALS patient recall of genetic testing results and evaluate comprehension of key implications of results. Methods: Participants were recruited from the Center for Disease Control's National ALS Registry. A survey collected participant demographics, their recollection of their genetic test result, and their understanding of the implications of their result. Comprehension was scored based on responses to key questions. Whenever possible, patient-reported test results were confirmed by review of their test report. Results: Most participants (n = 246) were white (n = 238, 96.7%) with high health literacy. Among participants whose self-reported result could be validated, most 93/98 (94.9%) accurately recalled whether they received a positive, negative, or uncertain result. Among participants who reported positive results, 32/50 (64.0%) demonstrated understanding that their genetic testing results explained their ALS, while 38/50 (76.0%) accurately characterized the risk that first degree relatives carried the same variant. Among participants who reported negative results, 100/142 (70.4%) incorrectly indicated that their result ruled out a genetic cause. When asked about the risk for family members to develop ALS, 98/142 (69.0%) correctly characterized this residual risk. However, only 12/142 (8.5%), answered both questions correctly. Overall, participants who saw a genetic counselor were more likely to demonstrate high comprehension (p = 0.022). Conclusions: The majority of participants demonstrated accurate recall of their ALS genetic testing result. However, deficits in understanding of key implications were identified, particularly among those with negative results. Participants who saw a genetic counselor had significantly better comprehension of their test results than those who did not.},
}

@article {pmid41201205,
year = {2025},
author = {Canosa, A and Callegaro, S and Manera, U and Vasta, R and Cabras, S and Di Pede, F and De Mattei, F and Palumbo, F and Iazzolino, B and Giudici, AD and Matteoni, E and Zocco, G and Minerva, E and Maccabeo, A and Pellegrino, G and Pascariu, D and Grassano, M and Ciresi, F and Testa, M and Polverari, G and Salamone, P and De Marco, G and Paolantonio, C and Marchese, G and Moglia, C and Calvo, A and Chiò, A and Pagani, M},
title = {Cognitive Reserve in Amyotrophic Lateral Sclerosis: A 2-[[18]F]FDG-PET Study on Sex-Related Differences.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70412},
pmid = {41201205},
issn = {1468-1331},
support = {PRIN 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran/ ; RF-2016-02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; GA101017598//Horizon 2020 Framework Programme/ ; 101137074//Horizon 2020 Framework Programme/ ; //A.S.D. Polisportiva U.I.C.I Torino Onlus/ ; //Ministry of Education, University and Research of Italy/ ; //Ministry of Health/ ; },
mesh = {Humans ; *Cognitive Reserve/physiology ; Male ; Female ; Positron-Emission Tomography ; Fluorodeoxyglucose F18 ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/psychology/complications ; Middle Aged ; Aged ; *Brain/diagnostic imaging/metabolism ; *Sex Characteristics ; Radiopharmaceuticals ; },
abstract = {BACKGROUND: Cognitive reserve (CR) applies to ALS-related cognitive impairment and education is a CR proxy. The influence of sex on CR in ALS is unclear.

METHODS: We compared brain 2-[[18]F]FDG-PET metabolism of male (m-ALS, n = 95) and female (f-ALS, n = 95) patients, matched for age, education, onset, and King's stage, with no significant difference in ECAS scores. In each group, clusters showing a negative/positive correlation with education were used as seed regions in an interregional correlation analysis (IRCA) to evaluate connectivity. We identified the seed regions including age, onset, King's stage and ECAS as covariates.

RESULTS: M-ALS showed a relative hypometabolism compared to f-ALS in bilateral frontotemporal regions. In f-ALS brain metabolism positively correlated with education in the left fusiform gyrus, cerebellum and pons. The IRCA showed a positive correlation of the seed region with the cerebellum, pons, right fusiform gyrus and cuneus, and the left precuneus, and a negative correlation with the frontal lobes and caudate nuclei. In m-ALS brain metabolism negatively correlated with education in the left frontotemporal and insular cortices. The IRCA showed a positive correlation of the seed region with bilateral frontotemporal and cingulate cortices, and the right parietal cortex, and a negative correlation with bilateral cerebellum and motor cortex, and the left lingual gyrus.

CONCLUSIONS: M-ALS showed relative frontotemporal hypometabolism compared to f-ALS, suggesting a male prevalence of CR. In m-ALS the negative correlation of education with left frontotemporal and insular metabolism supports the CR hypothesis. In f-ALS the positive correlation of cerebellar metabolism with education suggests compensatory mechanisms, also supported by the IRCA.},
}

Humans
*Cognitive Reserve/physiology
Male
Female
Positron-Emission Tomography
Fluorodeoxyglucose F18
*Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/psychology/complications
Middle Aged
Aged
*Brain/diagnostic imaging/metabolism
*Sex Characteristics
Radiopharmaceuticals

@article {pmid41201192,
year = {2025},
author = {Kumar, S and Kumar, A and Sufiyan, M and Shashi, },
title = {Factor Structure and Measurement Invariance of SDO7 Scale in India.},
journal = {Journal of personality assessment},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/00223891.2025.2583443},
pmid = {41201192},
issn = {1532-7752},
abstract = {Social dominance orientation (SDO) is the generalized preference for hierarchy across groups. It is currently measured through the two-dimensional (i.e., physical dominance and anti-egalitarianism) SDO7 scale. However, a complete testing of its factor structure across varied populations is highly required. A caste-based society perhaps reflects a stronger socio-cultural expression of social dominance theory. In the present study, we examined the factor structure of the SDO7 scale in such a society, using exploratory and confirmatory factor analyses on a sample of 1,020 participants (age: M = 19.5, SD = 2.07 years). The results reported that Ho et al.'s two-factor model was one of the best good-fit models. The SDO7 scale was strongly invariant across gender, caste, religion, and region. Moreover, men and higher caste had higher SDO. The present study shows that the asymmetrical expression of the method effect across dimensions is a possible problem in the SDO conceptualizations. It supports the cross-cultural validity of SDO, suggests new ideas on its factor structure, and partially establishes a reliable and valid Hindi version of the SDO7 scale. Relevance to social dominance theory and interventions has been discussed.},
}

@article {pmid41200140,
year = {2025},
author = {Bourke, CA},
title = {Decreased purine ingestion, increased molybdenum ingestion, and the decline in amyotrophic lateral sclerosis on Guam.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1618834},
pmid = {41200140},
issn = {2296-861X},
}

@article {pmid39505721,
year = {2025},
author = {Lu, GN},
title = {Invited Commentary on: Gossett et al.'s "Lower Lip Fascia Lata Repositioning in Flaccid Facial Paralysis".},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {27},
number = {6},
pages = {504-505},
doi = {10.1089/fpsam.2024.0256},
pmid = {39505721},
issn = {2689-3622},
}

@article {pmid41199620,
year = {2025},
author = {Zelikovich, AS and Ackrivo, J},
title = {Acoustic Features in ALS: Taking a Pause to Appreciate a Novel Remote Respiratory Monitoring Strategy.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70056},
pmid = {41199620},
issn = {1097-4598},
support = {HT9425-25-1-0154//Department of Defense ALS research program/ ; K23 HL-151879/HL/NHLBI NIH HHS/United States ; },
}

@article {pmid41199372,
year = {2025},
author = {Xu, L and Huang, B and Zhou, Y and Liao, X and Chen, T and He, H},
title = {Multi-omics-based decoding of circulating biomarkers in amyotrophic lateral sclerosis and risks in environmental toxins.},
journal = {BMC pharmacology & toxicology},
volume = {26},
number = {1},
pages = {186},
pmid = {41199372},
issn = {2050-6511},
support = {2024Y389//Scientific Research Foundation of Yunnan Provincial Education Department/ ; 2024Y392//Scientific Research Foundation of Yunnan Provincial Education Department/ ; 2024JJ7319//Natural Science Foundation of Hunan Province/ ; 2025JJ70442//Natural Science Foundation of Hunan Province/ ; 2025JJ70465//Natural Science Foundation of Hunan Province/ ; 202412//Doctoral research project initiation fund at Hunan University of Medicine/ ; 202401001789//Reform Project of Hunan Provincial Education Department/ ; 2541STC72898//International Cooperative Project of Traditional Chinese Medicine/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Humans ; Biomarkers/blood ; Proteomics ; Genome-Wide Association Study ; Transcriptome ; *Environmental Pollutants/toxicity ; Machine Learning ; Mendelian Randomization Analysis ; Multiomics ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the interplay of genetic and environmental factors, and currently, there there is a lack of effective diagnostic or therapeutic strategies available. This study aims to identify circulating biomarkers for ALS and investigate their interactions with environmental toxins.

METHODS: This research utilizes plasma proteomic genome-wide association study (GWAS) data and whole blood transcriptomic data from ALS patients to screen for potential circulating biomarkers through Mendelian randomization (MR). Subsequently, functional enrichment analysis and immune infiltration analysis were performed. An integrated machine learning approach will be used to construct a diagnostic model, with hub genes selected based on SHAP values. The model's performance will be validated using receiver operating characteristic (ROC) curves, nomogram, and decision curve analysis (DCA). Finally, reverse network toxicology will be used to explore the interaction mechanisms between hub genes and environmental toxins.

RESULTS: Based on a MR analysis of plasma proteomics, we identified 68 plasma proteins significantly associated with the risk of ALS. By integrating differentially expressed genes (DEGs) from whole blood transcriptomics (1,116 DEGs), we selected four potential circulating biomarkers: FCRL3, HTATIP2, RNASE6, and SF3B4. Functional enrichment analysis indicated that the pathogenesis of ALS is closely related to autophagy, apoptosis, the endoplasmic reticulum unfolded protein response, and the NF-κB signaling pathway. Immune infiltration analysis revealed a disruption of the immune microenvironment mediated by T cells/myeloid cells in ALS patients. Validation through 113 machine learning algorithms showed that the random forest model exhibited the best diagnostic performance (AUC = 0.786), while SHAP analysis confirmed the contribution ranking of hub biomarkers: RNASE6 > FCRL3 > HTATIP2 > SF3B4. Further validation of their diagnostic value was performed using ROC curves, nomograms, and DCA. Environmental toxins analysis revealed that substances such as benzo(a)pyrene exhibit significant neurotoxicity, and molecular docking confirmed that they can interfere with the function of hub biomarkers through strong binding (∆G < -5 kcal·mol⁻¹), suggesting potential environmental pathogenic mechanisms in ALS.

CONCLUSIONS: This study not only highlights the value of FCRL3, HTATIP2, RNASE6, and SF3B4 as potential diagnostic biomarkers and therapeutic targets for ALS but also provides new evidence for the involvement of environmental toxins, particularly benzo(a)pyrene, in the pathogenesis of ALS through gene-environment interactions.},
}

*Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis
Humans
Biomarkers/blood
Proteomics
Genome-Wide Association Study
Transcriptome
*Environmental Pollutants/toxicity
Machine Learning
Mendelian Randomization Analysis
Multiomics

@article {pmid41198658,
year = {2025},
author = {Volik, PI and Kopeina, GS and Zhivotovsky, B and Zamaraev, AV},
title = {p62-dependent caspase-2 activation governs TDP-43 clearance and neuronal fate in ALS.},
journal = {Cell death & disease},
volume = {16},
number = {1},
pages = {801},
pmid = {41198658},
issn = {2041-4889},
support = {222013//Cancerfonden (Swedish Cancer Society)/ ; 181301//Radiumhemmets Forskningsfonder (Cancer Research Foundations of Radiumhemmet)/ ; 23-74-30006//Russian Science Foundation (RSF)/ ; },
}

@article {pmid41198497,
year = {2025},
author = {Xue, Y and Tao, L},
title = {Letter to the Editor: Exploring venous thromboembolism (VTE) risk in patients with acute spinal cord injury (SCI).},
journal = {Injury},
volume = {},
number = {},
pages = {112868},
doi = {10.1016/j.injury.2025.112868},
pmid = {41198497},
issn = {1879-0267},
abstract = {We commend Bassa et al.'s study on VTE risk in acute SCI patients. We propose further exploring rehabilitation strategies, genetic polymorphisms (e.g., factor V Leiden), and inflammatory markers (e.g., CRP, IL-6) to refine personalized VTE prophylaxis and management in this population.},
}

@article {pmid41196652,
year = {2025},
author = {Lang, C and Guillot, SJ and Lule, D and Balz, LT and Knehr, A and Weydt, P and Dorst, J and Kandler, K and Müller, HP and Kassubek, J and Wassermann, L and Da Cruz, S and Roselli, F and Ludolph, AC and Bolborea, M and Dupuis, L},
title = {Early brain-wide disruption of sleep microarchitecture in Amyotrophic Lateral Sclerosis.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI194555},
pmid = {41196652},
issn = {1558-8238},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, is preceded by an early period unrelated to motor symptoms, including altered sleep, with increased wakefulness and decreased deep NREM. Whether these alterations in sleep macroarchitecture are associated with, or even precede abnormalities in sleep-related EEG features remains unknown.

METHODS: Here, we characterised sleep microarchitecture using polysomnography in patients with ALS (n=33) and controls (n=32), and in asymptomatic carriers of SOD1 or C9ORF72 mutations (n=57) and non-carrier controls (n=30). Patients and controls with factors that could confound sleep structure, including respiratory insufficiency, were prospectively excluded. Results were complemented in three ALS mouse models (Sod1G86R , Fus∆NLS/+ and TDP-43Q331K).

RESULTS: We observed a brain-wide reduction in the density of sleep spindles, slow oscillations and K-complexes in both early-stage ALS patients and presymptomatic gene carriers. These defects in sleep spindles and slow oscillations correlate with cognitive performance in both cohorts, particularly with scores on memory, verbal fluency and language function. Alterations in sleep microarchitecture were replicated in three mouse models and decreases in sleep spindles were rescued following intracerebroventricular supplementation of MCH or by the oral administration of a dual orexin receptor antagonist.

CONCLUSION: Sleep microarchitecture is associated with cognitive deficits and is causally linked to aberrant MCH and orexin signalling in ALS.

FUNDING: This work was funded by Agence Nationale de la Recherche (ANR-24-CE37-4064, ANR-10-IDEX-0002, ANR-20-SFRI-0012), Fondation Thierry Latran, Association Francaise de Recherche sur la sclérose latérale amyotrophique, Association Française contre les Myopathies (#28944), TargetALS and JPND.},
}

@article {pmid41196279,
year = {2025},
author = {Han, J and Xu, X and Zhao, Y and Xiao, Y and Huang, F and Zhou, J and Huang, H and Wang, G},
title = {Tui Na Acupressure Modulates Treg Immunosuppression via FoxP3/mTORC1 Signalling in ALS Mice.},
journal = {Immunology},
volume = {},
number = {},
pages = {},
doi = {10.1111/imm.70052},
pmid = {41196279},
issn = {1365-2567},
support = {//Hubei Provincial Natural Science Foundation's Innovation/ ; 2023AFD171//Development Joint Fund Project/ ; 2023AFD128//Development Joint Fund Project/ ; 2023AFD170//Development Joint Fund Project/ ; 2025AFD535//Development Joint Fund Project/ ; GZY-KJS-2025-008//Science and Technology Special Project of the State Administration of Traditional Chinese Medicine/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease driven by neuroinflammation, where regulatory T cell (Treg) dysfunction exacerbates immune imbalance. This study explores whether Tui Na acupressure, a traditional Chinese therapy, can restore Treg immunosuppressive function through the FoxP3/mTORC1 signalling pathway to mitigate ALS pathology. In SOD1G93A ALS mice, Tui Na was applied at the Shenshu acupoint, with motor and cognitive functions assessed via rotarod, tail suspension, novel object recognition, and Y-maze tests. Multi-omics (transcriptomics, proteomics), flow cytometry, ELISA, and Western blot analysed Treg proportions, cytokine profiles, and pathway activation. In vitro assays evaluated Treg proliferation and immunosuppression. Tui Na significantly enhanced motor and cognitive performance, increased Treg proportions in spleen, lymph nodes, and blood, and elevated anti-inflammatory cytokines (IL-10, TGF-β) while reducing pro-inflammatory markers (IL-6, TNF-α). Transcriptomic and proteomic analyses revealed upregulated FoxP3, Mtor, and Raptor, with enhanced Treg proliferation and immunosuppression confirmed in vitro. Pathway inhibitors (GSK126, rapamycin) reversed these effects, confirming FoxP3/mTORC1 dependency. Tui Na also reduced apoptosis and oxidative stress, supporting immune regulation. These findings highlight Tui Na's potential to restore Treg-mediated immune balance in ALS, offering a non-pharmacological therapeutic strategy. This study provides novel immunological insights into Tui Na's mechanisms, advocating its clinical evaluation for ALS and related immune-driven disorders.},
}

@article {pmid41196223,
year = {2025},
author = {Beck, J and O'Hara, K and van der Schaaf, M and O'Brien, BC},
title = {How supervisors leverage stress to facilitate trainee learning in clinical settings: A six-element model.},
journal = {Medical education},
volume = {},
number = {},
pages = {},
doi = {10.1111/medu.70084},
pmid = {41196223},
issn = {1365-2923},
support = {//WGEA mini-grant proposal/ ; },
abstract = {BACKGROUND: Excessive stress can hinder learning, whereas moderate stress may enhance it by boosting motivation, memory and cognitive processing. Rudland et al. proposed a theoretical stress-learning pathway in which supervisors play a central role in shaping how stress influences learning. While this pathway offers a valuable high-level framework, the specific ways supervisors enact this role in clinical settings remain underexplored. Our study addresses this gap by examining how supervisors leverage stress to enhance trainee learning in clinical settings.

METHODS: In this constructivist grounded theory study, we interviewed supervisors (senior residents and attending physicians) whom paediatric residents identified as effectively leveraging stress to facilitate learning. We recorded and transcribed semi-structured interviews, which we analysed iteratively throughout the data collection period using constant comparative techniques. We created a model that extends Rudland et al.'s pathway by detailing specific ways that supervisors harness stress to facilitate learning.

RESULTS: We interviewed 23 supervisors (10 senior paediatric residents and 13 attending physicians), all of whom conceptualised stress as a dynamic, individualised experience that can promote learning and prepare trainees for unsupervised practice. Supervisors both introduced stressors and modulated naturally occurring stressors (e.g. delivering difficult news or managing a decompensating patient) as they supported trainees in challenging situations. Attending physicians, more than senior residents, reported difficulty gauging trainee stress, citing power dynamics as a barrier. Our analysis produced a six-element model explaining how supervisors use stress to support learning: setting the stage, assessing baseline stress, introducing or modulating stressors, re-assessing, and debriefing.

CONCLUSIONS: Our findings suggest supervisors leverage stress to enhance learning in inpatient clinical environments but do so cautiously to ensure stress does not reach a level that impedes learning. Through a proactive approach, supervisors introduce and modulate stressors-thereby creating individualised learning experiences that they expect to prepare trainees for the demands of independent practice.},
}

@article {pmid41196070,
year = {2025},
author = {Kartanou, C and Kontogeorgiou, Z and Loupis, T and Vrachnos, DM and Ragazos, N and Spyropoulou, I and Petraki, M and Koniari, C and Aristeidou, S and Koropouli, E and Daponte, A and Rentzos, M and Kapaki, E and Panas, M and Makrythanasis, P and Stefanis, L and Koutsis, G and Karadima, G},
title = {Unraveling the genetic landscape of ALS in Greece: identification of known and novel causative variants in a 353-patient cohort.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2582828},
pmid = {41196070},
issn = {2167-9223},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, fatal neurodegenerative disorder characterized by progressive loss of motor neurons. Approximately 15% of individuals diagnosed with ALS have a known genetic variant that contributes to disease. Herein, we present clinical and genetic data of a large Greek ALS cohort.

PATIENTS AND METHODS: The cohort consisted of 353 Greek consecutive index patients with ALS, including 16 patients with related motor neuron disease (MND) subtypes (nine with PLS, four with PBP, and three with PMA). Next generation sequencing raw data (obtained from the NYGC ALS Consortium) were further analyzed and used to screen for causative variants in known implicated genes. Repeat expansions in C9ORF72 and ATXN2 were investigated using ExpansionHunter software, repeat-primed PCR and fragment analysis.

RESULTS: Pathogenic repeat expansions in C9ORF72 were detected in 41 patients (11.6%). In addition, 30 patients (8.5%) carried a causative variant in one of the genes studied. Known causative variants were identified in 27 cases (nine in SQSTM1, seven in TARDBP, five in SOD1, three in NEK1 and one each in SETX, VCP, FUS), whereas novel causative variants were identified in three cases (SOD1, FIG4, TBK1). In total, 71 cases received a molecular genetic diagnosis (20.1%). Additionally, seven cases (2.0%) carried an intermediate repeat expansion (30-33 CAG) in ATXN2.

CONCLUSION: Our results reveal the distinct genetic profile of Greek ALS patients. These findings will have an impact on genetic counseling, the design of diagnostic gene panels for the Greek population and on genotype-specific therapeutic interventions. Understanding the genetic causes of ALS in different populations is becoming increasingly important, especially with the advent of personalized medicine.},
}

@article {pmid41196032,
year = {2025},
author = {Mansoor, N and Heiman-Patterson, T and Feldman, EL and Wicks, P and Benatar, M and Vieira, F and Glass, J and Levine, T and Bertorini, T and Barkhaus, P and Mascias Cadavid, J and Jackson, C and Jhooty, S and Brown, A and Pattee, G and Sane, H and Mcdermott, CJ and Carter, G and Beauchamp, M and Wang, O and Ratner, D and Bedlack, R and Li, X},
title = {ALSUntangled #81: Pyridostigmine (mestinon[®]).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/21678421.2025.2582830},
pmid = {41196032},
issn = {2167-9223},
abstract = {Pyridostigmine (Mestinon[®], Bausch Health, Canada Inc.) increases acetylcholine availability at the neuromuscular junction, enhancing transmission. Preclinical studies suggest that neuromuscular junction dysfunction develops early in ALS, and pyridostigmine may temporarily improve neuromuscular transmission. However, altered neuromuscular junction transmission has uncertain benefits in ALS progression. Pyridostigmine does not have other plausible mechanisms that truly modify ALS pathophysiology. People with ALS (PALS) who have positive acetylcholine receptor autoantibodies and no myasthenia symptoms are unlikely to respond to pyridostigmine treatment. Clinical trials on pyridostigmine in PALS are lacking, but two clinical trials of other similar anticholinesterase agents did not effectively slow ALS progression. Muscarinic cholinergic side effects, including gastrointestinal symptoms, are common. Given the lack of mechanistic plausibility and efficacy, we do not support the use of pyridostigmine for slowing ALS progression.},
}

@article {pmid41196018,
year = {2025},
author = {Magara, J and Suzuki, T and Yoshihara, M and Onuki, W and Sasa, A and Tsujimura, T and Inoue, M},
title = {Lingual pressure as a physiological indicator for dysphagia in amyotrophic lateral sclerosis and multiple system atrophy.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2025.2580876},
pmid = {41196018},
issn = {1758-2032},
abstract = {BACKGROUND: This study aimed to characterize lingual pressure (LP) and clarify its association with dysphagia in patients with amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA).

METHODS: We examined 52 patients with ALS (Spinal-onset, 39; bulbar-onset, 13) and 36 patients with MSA (MSA-C, 26; MSA-P, 10). LP was measured using a balloon-type instrument during isometric contractions. Maximum LP (MLP) and 80% endurance of LP (ELP; duration above 80% of MLP during 7 seconds) were analyzed against videofluoroscopic findings of dysphagia.

RESULTS: Both parameters significantly correlated with food intake scales, especially in ALS. Liquid aspiration was predicted in ALS with 80.8% accuracy (AUC = 0.794, p < 0.001) using MLP cutoff of 20.5 kPa, and in MSA with 75.0% accuracy (AUC = 0.786, p < 0.01) using an ELP cutoff of 1.68 second. Predictive accuracy improved in spinal-onset ALS and MSA-C.

CONCLUSION: LP thus may represent a physiological indicator for dysphagia detection and management.},
}

@article {pmid41195301,
year = {2025},
author = {Dijkstra, JIR and Hulsman, M and Waterink, L and Holstege, H and Teunissen, CE and Christiaansen, WFL and de Jong, BA and Kochunov, P and Donohue, B and Zwan, MD and den Braber, A and Vermunt, L and van der Lee, SJ},
title = {Heritability and shared environmental effects of brain diseases in 12,040 extended families.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {34},
pmid = {41195301},
issn = {3005-1940},
abstract = {Brain diseases have complex patterns of genetic and environmental risk factors, and better understanding of these risks is required for more effective prevention strategies. Participants of the Dutch Brain Research Registry provided detailed information on family structure and occurrence of brain diseases. A total of 12,040 participants (73% female, aged 64.9 ± 11 years) provided information on 101,379 family members (53% female, aged 62 ± 25 years). We estimated heritability (h [2]) of the nine most common brain diseases using polygenic modeling in SOLAR and assessed variations in h [2] through bootstrapping; Alzheimer's disease (AD) (h [2] = 73, range 53-86, P fdr < 0.001), ALS (h [2] = 72, range 10-98, P fdr = 0.030), frontotemporal dementia (FTD) (h [2] = 48, range 0-97, P fdr = 0.132), vascular dementia (VaD) (h [2] = 41, range 7-64, P = 0.003), Lewy Body dementia (h [2] = 34, range 0-58, P = 0.132), iCVA (h [2] = 27, 6-59, P fdr = 0.013), hCVA (h [2] = 29, 8-57, P fdr = 0.007), Parkinson's disease (PD) (h [2] = 38, 6-66, P fdr = 0.013), and multiple sclerosis (h [2] = 10, 10-97, P fdr < 0.001). Shared environmental effects could be estimated for AD (c [2] = 5.8%, P fdr = 0.011), VaD (c [2] = 9.0%, P fdr = 0.021), FTD (c [2] = 9.7%, P fdr = 0.33), iCVA (c [2] = 15.9%, P fdr < 0.001), hCVA (c [2] = 14.9%, P fdr = 0.005), and PD (c [2] = 7.5%, P fdr = 0.25). These findings underscore the significance of genetic contribution to most brain diseases and the important role of shared environments in AD and vascular-related conditions, highlighting initiatives to mitigate modifiable risk factors.},
}

@article {pmid41195023,
year = {2025},
author = {Furuya, K and Itoh, N},
title = {Red urine in a 68-year-old man with amyotrophic lateral sclerosis.},
journal = {Journal of general and family medicine},
volume = {26},
number = {6},
pages = {659-660},
pmid = {41195023},
issn = {2189-7948},
}