bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–02–08
99 papers selected by
Luca Bolliger, lxBio
  1. Short-term infusion of GDF11 after SCI attenuates pericytes loss and BSCB damage to promote recovery of spinal cord function.
  2. Methodological considerations in the analysis of survival data in amyotrophic lateral sclerosis.
  3. Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions.
  4. Long-acting nanomedicine for brain diseases.
  5. Current potential biomarkers for Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: review of literature.
  6. Translational roadmap of BBB-targeted nanoparticle strategies for neuroregenerative therapy in neurodegenerative diseases.
  7. Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.
  8. Stage-Based Communication Rehabilitation in Amyotrophic Lateral Sclerosis (ALS): A Review of Strategies for Enhancing Quality of Life.
  9. Compensatory scaling of modulatory neural populations in response to motor challenges.
  10. Axonal dying back of upper motor neurons in human ALS.
  11. Extracellular matrix remodeling therapeutic strategies to tackle central nervous system diseases.
  12. Characterization of Atypical Ebola Virus Disease in Ferrets.
  13. A national survey of pseudobulbar affect and symptomatic treatment in Amyotrophic Lateral Sclerosis.
  14. Organ-Brain Axis in Alzheimer's Disease: A Systemic Perspective on Pathogenesis and Progression.
  15. Microglial, astrocytic, oligodendrocyte, B-/T-cell and neutrophil dysregulation in neuroinflammation of Alzheimer's disease and related dementias.
  16. Nuclear membrane disruption in neurodegenerative diseases: Emerging perspectives.
  17. Circuit architecture and axonal branching in the efferent auditory system.
  18. Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.
  19. Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.
  20. Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.
  21. Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.
  22. Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
  23. Information, certainty, and learning.
  24. APP-C31 pathology as a target in neurodegenerative diseases.
  25. From origins to nomenclature: illuminating the landscape of CNS fibroblasts and fibroblast-like cells.
  26. Pain and the immune system.
  27. Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15.
  28. [Recurrent hypoglycemia and the structure of the choroid plexus of the lateral ventricles of the rat brain].
  29. What Is Uncertainty? A Grounded Theory of the Role of Uncertainty in Anxiety in Autism.
  30. Retinal biomarkers in schizophrenia spectrum disorders: evidence and implications for the neurodevelopmental and neurodegenerative models.
  31. An overview on central nervous system tuberculosis (CNS-TB) focusing on cognitive impairments.
  32. The potential role of COX-2/PGs signaling pathway in epileptogenesis and associated neuroinflammation: collusions or serendipity.
  33. Prosaposin in CNS health and disease, metabolic stress and exercise adaptation.
  34. Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.
  35. Safety of Intravenous Edaravone in Clinical Practice.
  36. Ligand content-dependent exocytosis governs the blood-brain barrier transcytosis of nanocarriers.
  37. Defining Safe and Effective Cefazolin Dosing Regimens for MSSA Infections in the CNS: Leveraging Sparse Real-World Data and PBPK Modeling.
  38. Focused Ultrasound for the Treatment of Circuit and Molecular Pathology in Parkinson's Disease.
  39. Drug & virus transport across biological barriers: interactions, diffusion, partitioning, permeability, and selectivity.
  40. Infection control in the brain and the eye.
  41. Morphological and transcriptomic change of brain pericytes by lipopolysaccharide treatment.
  42. The Pyridoxal-5'-Phosphate-Dependent Enzymes of Mycobacterium tuberculosis.
  43. Is there any relationship between the menopause transition and dizziness?
  44. "Unfolding Parkinson's Disease Through the Microbiome-Gut-Brain Axis".
  45. BioModelsRAG: A Biological Modeling Assistant Using RAG (Retrieval Augmented Generation).
  46. Messages to the future? Lesbian subversion of official categories in the 1921 UK census.
  47. Artificial Intelligence and Ocular Imaging in the Evaluation of Neurologic Disorders: The New Era of Neuro-Oculomics?
  48. A Personal Exploration of Oral Health in Amyotrophic Lateral Sclerosis (ALS) Through the Eyes of a Multifaceted Authority.
  49. Live Imaging and Characterization of Microglia Dynamics and Interactions with Synapses in Diseased Murine Retina.
  50. Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.
  51. On Francis Pasche's (1993) text "From the ambivalent superego to the impersonal superego": A brief introduction or Towards an impersonal and loving superego.
  52. Glutathione and neurodegenerative diseases: immunopharmacological implications.
  53. Empathic Disequilibrium as a Predictor of Nonsuicidal Self-Injury in Autistic and Nonautistic People.
  54. Enterovirus D68 VP1 and VP3 determine neurotropism in human spinal cord organoids.
  55. Roles of efferocytosis in wound repair: Process, cells, and signals.
  56. Study 19 (MCI186-19) Post Hoc Analyses.
  57. Parkinson's and Alzheimer's disease impairs temporal precision.
  58. FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.
  59. 2024 Year-in-Review: Scientific Highlights from Current Pharmaceutical Biotechnology.
  60. The regenerative period of somatosensory nerves is closed by a DCC signaling axis.
  61. Sensoriality and thought. In development and in psychopathology.
  62. Nose-to-brain axis: mechanistic links between nasal microbiome dysbiosis, neuroinflammation, and brain disorders.
  63. Effect of Pressure on Liquid-Phase Adsorption on a Solid Surface.
  64. Study of Royal Jelly effect on serum levels of IL-4, TNF- α, TGF-B, and IFN-γ in multiple sclerosis patients in comparison with Omega-3; A double-blind, randomized, clinical trial.
  65. Searching to Modulate for Cold-Start Recommendation.
  66. A gut-activated NHR-86-CYP pathway mediates the neuroprotective effects of Enterococcus faecium probiotics in a nematode model of amyotrophic lateral sclerosis.
  67. Panax notoginseng saponins ameliorate spinal cord injury by inhibiting JAK2/STAT3-mediated macrophage polarization: Enhanced delivery by ultrasound-targeted microbubble destruction.
  68. Explainable Artificial Intelligence to Decode the Blood-Brain Barrier Permeability of Gut Microbial Metabolites.
  69. Elements for a Phenomenology of Cultures: Cultural Existentials and the Dialectical Experiential Matrix.
  70. Current and Ongoing Clinical Studies.
  71. Generalizability of Edaravone Efficacy.
  72. IGF-like growth factors that couple food sensing to developmental decisions employ different release mechanisms in a single pair of C. elegans chemosensory neurons.
  73. Relationship between perturbation specificity and functional dispensability in yeast phosphoproteome.
  74. [Neuroendocrine regulation of the reproductive system: integration of research of neuropeptide and experimental pathophysiology of amenorrhea of different genesis (literature review)].
  75. Macrophage-targeted PEGylated liposomes ameliorate experimental autoimmune encephalomyelitis.
  76. Characteristics of muscle cramps as a prodromal symptom of sporadic amyotrophic lateral sclerosis.
  77. Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID.
  78. Neuroprotection via IGF-1 Neuronal Signaling Activation by Melatonin and Edaravone Synergy in Methylmercury-Induced ALS-like Neurotoxicity: Comprehensive Analysis of Brain Regions, Spinal Cord, CSF, and Blood Plasma.
  79. Sex-dependent disruption of affective behaviors by GBR 12909: relevance to bipolar disorders.
  80. The relation between children's shyness and their contingent dialogical actions when reacting to a social robot's instructions.
  81. Epilepsy-Induced Intestinal Barrier Disruption: Protective Effects of Rosa Canina Seed Oil on Duodenal Morphology and Junctional Integrity.
  82. Visualization of gadolinium transport across the blood-brain barrier along perivascular clearance pathways.
  83. Towards robust identification of Pleistocene adhesives: a critical review of current analytical approaches.
  84. Natural Variation Reveals Functional and Genetic Integration of a Polyphenism.
  85. Semantically Correct Policy Mining and Enforcement for Attribute based Access Control.
  86. Hierarchical Transit Compartment Model to Describe Absorption Delay in Orally Administered Drugs in Heterogeneous Populations.
  87. Progressive neuroinflammation and deficits in motor function in a mouse model with an Epg5 pathogenic variant of Vici syndrome.
  88. Current and emergent therapies targeting spinal cord injury.
  89. Variable partition of non-homogeneous ooplasm sets the stage for divergent potency of 2-cell stage blastomeres.
  90. Sphingosine-1-Phosphate Regulation to Alleviate Sickle Cell Disease Severity: A Promising Therapeutic Approach.
  91. TBK1 activity regulates the directionality of axonal transport of signalling endosomes.
  92. Zero-information limit of a collective olfactory search model.
  93. The power of the group: How neuroscience supports expanding the therapeutic dyad through group psychotherapy.
  94. Limited data capture on reproductive medicine use in amyotrophic lateral sclerosis: implications for monitoring access.
  95. Exploring the therapeutic potential of beta-3 adrenergic agonists in overactive bladder: A comprehensive review.
  96. Use of a human immortalized microglia cell line to study recognition, phagocytosis, and intracellular survival of Cryptococcus neoformans.
  97. [Features of bioenergetic metabolism in physiological and pathological conditions: focus on oncogenesis].
  98. Reducing Neuroinflammation via Inhibition of Fibrinogen Deposition and Microglial Activation as an Underlying Mechanism of Paning I Decoction in Ameliorating Parkinson's Disease Symptoms.
  99. A semi-automated modelling pipeline to predict the mechanics of multiple sclerosis lesion afflicted brains from magnetic resonance images.
  1. Neurochem Int. 2026 Feb 03. pii: S0197-0186(26)00015-X. [Epub ahead of print]193 106124
    Short-term infusion of GDF11 after SCI attenuates pericytes loss and BSCB damage to promote recovery of spinal cord function.
    Honghao Shen, Jiangtao Liu, Minghao Du, Geng Qin, Jiani Li, Yichen Lu, Hongqian Gao.
      To investigate the role of GDF11 in acute neural trauma, this study focused on the effects of GDF11 on pericytes and the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI). We established a mouse SCI model and administered GDF11 infusion for three consecutive days. Spinal cord samples were collected early after injury, and the integrity of the BSCB was evaluated using pathomorphological analysis, Western blotting, immunofluorescence, and transmission electron microscopy. The results demonstrated that GDF11 infusion significantly reduced BSCB damage at 7 days post-SCI, as evidenced by improved intercellular junction integrity and enhanced pericyte coverage. Since neurovascular communication is a critical function of the BSCB, we further assessed neuronal survival and myelin sheath integrity across different groups. In addition, we isolated primary central nervous system microvascular pericytes and simulated SCI through oxygen-glucose deprivation (OGD) culture, with and without GDF11 treatment and its critical receptor TGF-β receptor (TGFR) antagonist, ACE-536. The viability and migration ability of pericytes in each group were evaluated by flow cytometry and migration assays. We found that the GDF11/TGFR/SMAD3 signaling pathway mediates the beneficial effects of GDF11 on SCI. As functional recovery is a key measure of clinical outcome following SCI, behavioral assessments were performed at later stages. Our results showed that early GDF11 infusion significantly improved functional recovery, as demonstrated by enhanced gait performance and increased swimming scores. In conclusion, early post-SCI GDF11 infusion targeting pericytes to regulate BSCB integrity may offer a promising therapeutic approach for SCI recovery.
    Keywords:  Blood-spinal cord barrier; GDF 11; Pericytes; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.neuint.2026.106124
  2. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jan 31. 1-12
    Methodological considerations in the analysis of survival data in amyotrophic lateral sclerosis.
    Solmaz Yazdani, Christina Seitz, John Andersson, Caroline Ingre, Fang Fang, Anikó Lovik.
      Survival outcomes are commonly analyzed in studies with data from patients with progressive, neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Given the fast progression of ALS, survival analyses are, however, often difficult to perform and interpret. In this methodological article we demonstrate on real-world data how the choices we make in the study design, data collection, and analysis could influence the results. The factors we consider in this study are length of follow-up, sample size, timing of sample collection, and choice of covariables adjusted for in the models. We further discuss the importance of each of these contributing factors and about how to avoid mistakes in interpreting and reporting survival data in ALS and other rare, progressive diseases.
    Keywords:  Cox regression; methodology; statistical analysis; survival analysis; tutorial
    DOI:  https://doi.org/10.1080/21678421.2026.2615111
  3. Neural Regen Res. 2026 Jan 27.
    Amyotrophic lateral sclerosis: Neural repair strategies based on multi-target synchronous interventions.
    Jingjing Liu, Lijun Zhou, Youqing Deng, Renshi Xu.
       ABSTRACT: Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease that targets motor neurons in the cerebral cortex, medulla oblongata, and spinal cord. This review focuses on the current concepts in the aetiopathogenesis and diagnosis of amyotrophic lateral sclerosis, aiming to explore potential neural repair strategies (curative and/or progression-retarding therapeutics). Recent studies have highlighted that the complex pathogenesis of amyotrophic lateral sclerosis is related to its multifactorial aetiology, including proteostasis disruption, impaired RNA metabolism and DNA repair, cytoskeletal and axonal transport defects, excitotoxicity, neuroinflammation, mitochondrial dysfunction, oligodendrocyte dysfunction, nucleocytoplasmic transport deficits, lipid dyshomeostasis, and autophagy. Several approved drugs are currently used to treat patients with amyotrophic lateral sclerosis; however, their curative efficacy is limited. Thus, the search for effective therapeutic strategies for amyotrophic lateral sclerosis requires a comprehensive understanding of its pathogenesis. Current evidence indicates that a single drug cannot provide a satisfactory therapeutic effect. Additionally, multiple pathophysiological processes and related targets are involved in the pathogenesis of amyotrophic lateral sclerosis. Therefore, research on multi-target synchronous interventions may be the path forward for discovering and developing potential neural repair strategies.
    Keywords:  RNA; amyotrophic lateral sclerosis; axonal transport; endoplasmic reticulum stress; excitatory amino acids; lipid metabolism; mitochondrial dysfunction; neuroinflammation; oxidative stress; protein aggregates
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00221
  4. J Control Release. 2026 Jan 28. pii: S0168-3659(26)00066-0. [Epub ahead of print]392 114665
    Long-acting nanomedicine for brain diseases.
    Jun Liao, Qi Huang, Ruiyu Li, Lidong Gong, Tiancheng Li, Zhiqiang Lin.
      Effective pharmacological management of neurological disorders is profoundly limited by the blood-brain barrier (BBB) and the short biological half-life of therapeutics, necessitating frequent and invasive administration. Long-acting drug delivery systems (LADDS) integrated with nanotechnology offer a transformative paradigm to overcome these challenges. This review discusses the key principles and nanoplatforms enabling sustained brain drug delivery to the central nervous system. Key release mechanisms are analyzed including diffusion, degradation, and stimuli-responsiveness which alongside a survey of major nanocarrier platforms, designed to achieve controlled pharmacokinetics and enhanced BBB penetration. Recent groundbreaking applications in preclinical models of ischemic stroke, Alzheimer's disease, glioma, and traumatic brain injury are highlighted, where LADDS provide continuous, localized neuroprotection and modulate chronic pathology. Finally, the significant translational challenges, including long-term biocompatibility, manufacturing scalability, and regulatory hurdles, are critically evaluated. LADDS are poised to redefine neuropharmacology, shifting the focus from transient symptom management to precise, durable, and restorative intervention for chronic brain diseases.
    Keywords:  Blood–brain barrier; Brain disease; Long-acting delivery; Sustained release
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114665
  5. Dialogues Clin Neurosci. 2026 Dec;28(1): 17-39
    Current potential biomarkers for Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: review of literature.
    Jiaman Peng, Ting Fan, Junling Wang, Youqing Deng, Renshi Xu.
       INTRODUCTION: Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are several common neurodegenerative diseases (NDs). At present, is the lack of effective diagnosis, progression, prognosis and therapeutic biomarkers. it is a urgent demand to search the relevant confident biomarkers.
    AREA COVERED: This review systematically analysed the potential biomarkers of blood, cerebrospinal fluid, neuroimaing and emerging non-invasive indicators, and synthesises current evidences on the biomarkers of AD, PD and ALS about diagnosis, progression, prognosis and therapeutic, especially diagnosis biomarkers.
    EXPERT COMMENTARY: In this review, we focus on discussing relevant diagnosis, progression, prognosis and therapeutic biomarkers for AD, PD and ALS in recent years, and prospecting the possible future directions of relevant biomarkers.
    Keywords:  Alzheimer’s disease; Neurodegenerative diseases; Parkinson’s disease; amyotrophic lateral sclerosis; biomarkers
    DOI:  https://doi.org/10.1080/19585969.2026.2622722
  6. Biomater Sci. 2026 Feb 06.
    Translational roadmap of BBB-targeted nanoparticle strategies for neuroregenerative therapy in neurodegenerative diseases.
    Sohui Lee, Jiyeon Lee, Kangwon Lee.
      Neuroregeneration has drawn scientific attention due to its therapeutic potential for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and traumatic brain injury (TBI). A major obstacle in delivering neuroregenerative and neuroprotective drugs is crossing the blood-brain barrier (BBB)-a selective, physiological barrier that protects the central nervous system (CNS) from circulating toxins and pathogens. While this protective role is essential for maintaining CNS homeostasis, it also limits therapeutic efficacy and increases the risk of systemic side effects due to off-target accumulation. To overcome these challenges, recent advances in nanoparticle engineering have focused on enhancing BBB transcytosis by employing biologically inspired surface modifications. In this review, we highlight three mechanistically distinct approaches: (1) transporter-mediated transcytosis (TMT), which uses glucose or amino acid conjugation; (2) receptor-mediated transcytosis (RMT) via ligands such as transferrin or angiopep-2; and (3) adsorptive-mediated transcytosis (AMT), utilizing cationic polymer coatings or cell-penetrating peptides (CPPs).
    DOI:  https://doi.org/10.1039/d5bm01582k
  7. Chembiochem. 2026 Jan;27(2): e202500774
    Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.
    Florian Malard.
      The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.
    Keywords:   O‐GlcNAc transferase; O‐GlcNAcylation; RNA therapeutics; alternative splicing; antisense oligonucleotide; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/cbic.202500774
  8. Arch Intern Med Res. 2025 ;8(4): 359-371
    Stage-Based Communication Rehabilitation in Amyotrophic Lateral Sclerosis (ALS): A Review of Strategies for Enhancing Quality of Life.
    Mark C Jackson, Rafaelle B Azarraga, Marcel P Fraix, Devendra K Agrawal.
      Amyotrophic Lateral Sclerosis (ALS) is an incurable progressive degenerative neuromuscular disease. One way ALS affects patients is through dysarthria significantly impacting a patient's quality of life by affecting their ability to communicate. This makes maintaining relationships, identity and autonomy difficult, all of which affect psychological wellbeing - a determinant of the quality of life. Dysarthria makes communication difficult, and because the regions affected by ALS first are different for each patient, creating strategies for rehabilitating communication can be challenging. In this review we explore the different communication rehabilitation options available and organize them based on if they are usable based on the onset of intelligibility and locked in state. Interventions before the onset of intelligibility in the early stage are proactive measures such as voice banking and education which empower patient autonomy and a sense of control. Interventions between onset of intelligibility and the locked-in state in the middle stage are alternative and augmentative communication strategies varied in accessibility and usability in patients based on their preferences and functional ability. Late-stage interventions which work after a patient with ALS has entered a locked-in state, are the most technologically advanced alternative and augmentative communication devices and rehabilitate function inaccessible by other methods in this disease stage. While assessing patient values and recommending interventions which meet patient needs is most important in rehabilitation of communication in patient with ALS, using a stage-based approach to evaluate and recommend the treatment of dysarthria and communication rehabilitation will optimize quality of life throughout the progression of disease.
    Keywords:  Alternative and Augmentative Communication (AAC); Amyotrophic Lateral Sclerosis (ALS); Brain-computer interface (BCI); Bulbar dysfunction; Communication; Dysarthria; Motor neuron disease; Quality of Life (QOL); Rehabilitation; Speech-language Pathologist (SLP); Staged based approach
    DOI:  https://doi.org/10.26502/aimr.0230
  9. Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2519741123
    Compensatory scaling of modulatory neural populations in response to motor challenges.
    Tyler L Wells, Melpomeni Galani, Reynaldo Popoli, Laskaro Zagoraiou, Turgay Akay.
      Precise and adaptable movements are achieved by well-regulated muscle contractions, which are mainly governed by the excitability of motor neurons. Several neuromodulatory systems originating in the motor cortex, brainstem, and spinal cord regulate motor neuron excitability via the release of neurotransmitters such as acetylcholine and serotonin. However, these systems can have seemingly similar effects on motor neuron output, raising questions about interaction during movement. To address this, we investigated two modulatory systems in mice: the cholinergic V0c interneurons in the spinal cord and the serotonergic system in the brainstem. Electromyographic and behavioral recordings revealed that, when compared to control mice, mice whose V0c interneuron cholinergic output was genetically inactivated failed to display speed-dependent modulation of the gastrocnemius muscle, and exhibited lower amplitude bursting in the gastrocnemius muscle during swimming. c-Fos expression in this population during locomotion also indicated that they are active in a speed-dependent manner. Relative to control mice, those mice whose V0c interneurons had their cholinergic output inactivated showed upregulated activity in motor-related serotonergic populations while trotting at higher speeds but not while walking at lower speeds, indicating that serotonin plays a compensatory role in the absence of functional V0c interneurons. Last, we observed a progressive recruitment of these two populations in mice with amyotrophic lateral sclerosis, and the recruitment of serotonergic neurons is hastened in those mice whose V0c interneurons had their cholinergic output inactivated. These findings highlight that modulatory systems scale their activity to match motor demand across various circumstances.
    Keywords:  ALS; C-boutons; V0c; locomotion; neuromodulation
    DOI:  https://doi.org/10.1073/pnas.2519741123
  10. Res Sq. 2026 Jan 12. pii: rs.3.rs-8545414. [Epub ahead of print]
    Axonal dying back of upper motor neurons in human ALS.
    Haley Cropper, Fozia Mir, Jianguo Liu, Vidushi Srivastava, Mohammed Ramizuddin, Kylie Kopecky, Ebony Mocanu, Fabien Dachet, Qin Li Jiang, Madhu Soni, Tibor Valyi-Nagy, Diana Mnatsakanova, Charles Abrams, Fei Song, Jeffrey Loeb.
      Patients with amyotrophic lateral sclerosis (ALS) present with arm, leg, or bulbar weakness with or without spasticity. While genetics plays a clear role in a subset of cases, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. Here, we examined the clinicopathological relationships between UMN and LMN disease in ten ALS patients. Detailed clinical assessments were obtained and tissues from the motor cortex, brainstem, and spinal cord were collected via a rapid autopsy protocol. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43. Total RNA-sequencing was performed in the medulla, cervical, and lumbar spinal cords from each patient to identify pathways enriched at sites of disease onset. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and spasticity, indicating both UMN and LMN involvement. Postmortem examination showed LMN degeneration and microglial activation were highest at sites of disease onset. In contrast, UMN degeneration of the corticospinal tract (CST) was present equally at all levels of the spinal cord up through the medulla, regardless of the site of disease onset. Surprisingly, there was no evidence of UMN degeneration of cortical motor neurons or their projecting axons above the brainstem. Similarly, while extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. Mechanistically, RNA-sequencing implicated inflammatory pathways, especially at sites of disease onset. Our findings suggest that many ALS patients without FTD have a dying back of UMN axons, independent of the site of disease onset, which stops in the brainstem with preservation of cortical motor neurons and their proximal axons. Our findings suggest that UMN axonal degeneration can be directly triggered by LMN degeneration and inflammation.
    DOI:  https://doi.org/10.21203/rs.3.rs-8545414/v1
  11. Neural Regen Res. 2026 Feb 05.
    Extracellular matrix remodeling therapeutic strategies to tackle central nervous system diseases.
    Daniel A Domingo-Lopez, Maria Rosa Aguilar de Armas, Sergio Martin-Saldaña.
       ABSTRACT: Neurodegenerative diseases are a global burden due to the increased life expectancy. Neuroinflammation is not only a result of neurodegeneration but a key player in the initiation and onset of it. Due to the inherent complexity of these diseases, there is a need for the development of better treatments, as well as the discovery of new therapeutic targets. In this sense, knowledge about extracellular matrix remodeling after injury in the central nervous system was overseen for a century, but it has blossomed in the last three decades. Nowadays, we possess strong evidence regarding the imbalance, over-synthesis, and changes in the organization of most key components of the extracellular matrix after neuroinflammation and neurodegeneration. Thus, hyaluronic acid, chondroitin sulphate proteoglycans, or fibronectin presented an impairment in their anabolism and catabolism, which could be a cause or a consequence of the inflammatory and degenerative process. Regardless, it is clear that extracellular matrix remodeling plays a pivotal role in the onset and resolution of inflammation-driven neurological disorders by creating a non-permissive niche for self-restoration of the neural homeostasis. Despite being an emerging area of study, extracellular matrix changes have been explored in the last decades in the central nervous system to shed light on their potential as diagnostic markers as well as therapeutic targets. The extracellular matrix fingerprint in diseases such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, or stroke has been described both in preclinical models and in post-mortem clinical samples. Herein, we provided an overview of the state of the art of extracellular matrix components and function in the central nervous system, both under homeostasis and in neurodegeneration. Then, we critically revise the therapeutic efforts targeting the extracellular matrix, aiming to tackle neurodegenerative disorders. Altogether, this review contextualizes the current understanding of extracellular matrix in the central nervous system and its remodeling after neuroinflammation, its role in disease onset and resolution, and how this knowledge is being applied to the development of new therapeutic approaches.
    Keywords:  central nervous system; chondroitin sulphate; chondroitinase ABC; extracellular matrix; extracellular matrix remodeling; fibronectin; heparan sulphate; hyaluronic acid; hyaluronidase; neurodegeneration; neuroinflammation; proteoglycan
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01562
  12. bioRxiv. 2026 Jan 20. pii: 2026.01.20.700506. [Epub ahead of print]
    Characterization of Atypical Ebola Virus Disease in Ferrets.
    Wenguang Cao, Shihua He, Helene Schulz, Jordan Wight, Michael Chan, Karla Emeterio, Guodong Liu, Jonathan Audet, Kevin Tierney, Kimberly Azaransky, Kathy Frost, Lilianne Gee, Peter McQueen, Patrick Chong, Stephanie Booth, Garrett Westmacott, Erica Ollmann Saphire, Xiankun Zeng, Logan Banadyga.
      Ebola virus (EBOV) typically results in a severe-and often lethal-acute disease. However, increasing evidence suggests that EBOV can persist in certain immune-privileged tissues, which may then serve as reservoirs for the later reemergence of EBOV and disease recrudescence. Here, we report atypical EVD recrudescence in a ferret model inoculated with an otherwise lethal dose of EBOV and treated with low doses of a highly potent monoclonal antibody cocktail. Among 32 antibody-treated ferrets, 14 animals survived, while 8 succumbed to acute EVD within about 5-8 days. The remaining 10 animals succumbed to atypical EVD between 12 and 18 days post-infection (DPI) despite having shown no, or very minor, signs of illness during the acute phase of disease. While viremia disappeared by 14 DPI in most animals that succumbed to atypical EVD, it rebounded modestly just prior to death. Unlike animals that died of acute EVD, those that died of atypical EVD showed only a moderate systemic inflammatory response and few signs of organ dysfunction, in line with low levels of virus in the liver and spleen. Interestingly, however, ferrets that died of atypical EVD showed high levels of virus in the brain, consistent with increased markers of inflammation in the central nervous system and significant pathological changes, including a breakdown in the blood-brain barrier and severe meningoencephalitis. Not only does this study shed important light on the atypical and underappreciated manifestations of EVD, but it also establishes the ferret as a valuable model of EBOV persistence and recrudescence.
    AUTHOR SUMMARY: Over the last several years, it has become increasingly apparent that Ebola virus is capable of persisting in survivors and, occasionally, reemerging to cause a recrudescent disease that is often distinct from the acute illness and characterized by neurological involvement. Since nearly all existing Ebola virus animal models are uniformly lethal, it has been difficult to understand the processes that lead to persistence and atypical manifestations of disease. In this study, we describe a late-onset, atypical Ebola virus disease in ferrets that was characterized by high levels of virus in the brain and significant markers of brain inflammation. Our comprehensive analysis of the pathogenic processes that contributed to this disease not only provides critical insight into Ebola virus persistence and recrudescence, but it also establishes the ferret as the first tractable model for investigating these atypical outcomes.
    DOI:  https://doi.org/10.64898/2026.01.20.700506
  13. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jan 30. 1-7
    A national survey of pseudobulbar affect and symptomatic treatment in Amyotrophic Lateral Sclerosis.
    Christian H Steenkjaer, Jesper H Storgaard, Lotte Levison, Jakob U Blicher.
       OBJECTIVE: We aimed to determine diagnostic prevalence and symptom burden of pseudobulbar affect (PBA) in patients with Amyotrophic Lateral Sclerosis (ALS) in Denmark and differences in ongoing symptomatic treatment.
    METHODS: In this national cross-sectional survey study, participants with ALS completed an online survey regarding PBA and PBA symptoms, which were quantified through the Center for Neurologic Study Lability Scale (CNS-LS). A CNS-LS score ≥ 13 served as a threshold indicative of PBA.
    RESULTS: 157 participants with ALS were recruited. 12.1% were diagnosed with PBA and were more likely to receive antidepressant medication compared to those not diagnosed with PBA (47.4% compared to 15.2%, p = 0.002). 30.6% scored ≥13 in the CNS-LS; however, the proportion of participants treated with antidepressants was similar compared to those scoring below the ≥13 threshold (25% compared to 16.5%, p = 0.27). Of those not diagnosed with PBA, 23.2% scored ≥13 in the CNS-LS. This PBA symptomatic, but undiagnosed group was less likely to receive symptomatic treatment compared to patients with diagnosed PBA (12.5% compared to 47.4%, p = 0.009). No differences were seen in CNS-LS score between these groups.
    CONCLUSIONS: The proportion of diagnosed PBA among the study population was low compared to previous studies; however, the proportion of patients with symptoms of possible PBA was markedly higher. Patients with known PBA were more likely to receive recommended symptomatic treatment compared to patients not diagnosed with PBA, despite symptoms indicative of PBA. These findings highlight the potential underrecognition of PBA in ALS and concurrent absence of symptomatic treatment.
    Keywords:  Amyotrophic Lateral Sclerosis; CNS-Lability scale; motor neuron disease; pathological crying and laughing; pseudobulbar affect
    DOI:  https://doi.org/10.1080/21678421.2026.2620448
  14. Aging Dis. 2026 Jan 28.
    Organ-Brain Axis in Alzheimer's Disease: A Systemic Perspective on Pathogenesis and Progression.
    Yebeen Kim, Jaewoon Jung, Asifiwe Clarisse Cirunduzi, Seonghyun Yoon, Seokyoung Bang, Seung-Hoon Yang.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and memory decline. Current therapeutic strategies largely provide symptomatic relief and remain limited in their capacity to halt or reverse disease progression. Accordingly, increasing efforts seek to reexamine AD pathophysiology from a systemic perspective and to identify novel therapeutic targets. Although classical AD research has focused primarily on intrinsic brain pathology, accumulating evidence indicates that disease progression reflects complex interactions among multiple cellular and systemic mechanisms. The central nervous system (CNS) is now recognized as functionally interconnected with peripheral organs through immune-mediated and neural communication networks. Within this framework, the concept of the organ-brain axis has emerged, proposing that organ-specific immune microenvironments and inflammation-derived mediators originating from peripheral tissues may modulate immune homeostasis in the brain, neuronal survival, and neurodegenerative processes. In patients with AD, immunological alterations are observed not only within the CNS but also in peripheral organs including the gut, lung, liver, and bladder, and these changes are associated with disease progression. Peripheral immune dysregulation extends beyond localized inflammatory responses, potentially contributing to sustained neuroinflammation, disruption of blood-brain barrier integrity, and pathological activation of microglia and astrocytes. Rather than viewing AD as a disorder confined to the brain, this review adopts a systemic perspective in which peripheral immune environments dynamically interact with central neuroinflammatory pathways. We comprehensively summarize immune cell alterations across major peripheral organs under AD pathology, their interactions with neuronal cells, and the potential signaling mechanisms that mediate organ-brain immune crosstalk.
    DOI:  https://doi.org/10.14336/AD.2025.1537
  15. J Psychiatr Res. 2026 Jan 30. pii: S0022-3956(26)00061-0. [Epub ahead of print]195 225-243
    Microglial, astrocytic, oligodendrocyte, B-/T-cell and neutrophil dysregulation in neuroinflammation of Alzheimer's disease and related dementias.
    Asem Surindro Singh, Afsar Raza Naqvi, Machathoibi Takhellambam Chanu.
      Wide number of basic, preclinical and clinical research have led to increase our knowledge on understanding the potential roles of neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD). In fact, neuroinflammation is considered as one of the key pathological factors of neuronal dysfunction leading to dementia in AD and other forms of dementias or related dementias (RD). Central nervous system (CNS) network communicates and control the immune system signaling pathways within the brain as well as peripheral part of the body. Hence, disturbance in the physiological immune system regulation is susceptible to the etiology or pathogenesis of the diseases. Microglia, astrocytes, oligodendrocytes, B-/T-cells and neutrophils are potential regulatory cells in keeping our immune system in balance. The imbalance in the regulatory function of these cells results to inflammatory consequences and has direct or indirect influence in the AD trajectory. In the brain, neuroinflammation is strongly linked to the accumulation of Aβ plaques and tau tangles which lead to pathogenesis underlying dementia of AD. Currently, neuroinflammation is considered as one of the pathological hallmarks of AD, alongside Aβ plaques and tau tangles. Various research and review articles have described the dysregulation of immune system cells leading to neuroinflammation in AD and RD pathogenesis. However, how these immune cells become coordinately imbalanced in the disease pathogenesis has been rarely reported, which is necessary for deeper understanding of the disease pathology and therapeutic development. In this review, we intend to highlight and discuss the neuroinflammatory pathways mediated via dysregulation of microglia, astrocyte, oligodendrocyte, neutrophil, B-cell and T-cell functions, which leads to neuronal dysfunction, dementia or cognitive decline in AD and RD. We believe that the narrative in this review will be helpful in the future basic/clinical research and therapeutic development for AD and RD.
    Keywords:  Alzheimer's disease; Astrocytic; Chemokines; Cognitive impairment; Cytokines; Dementia; Microglia; Neuroinflammation; Neutrophils; Oligodendrocyte; Other forms of dementia or related dementia; T cell and B cell
    DOI:  https://doi.org/10.1016/j.jpsychires.2026.01.050
  16. Neural Regen Res. 2026 Jan 27.
    Nuclear membrane disruption in neurodegenerative diseases: Emerging perspectives.
    Shuo Yuan, Nicholas Essepian, Qingbo Wang, Lulu Jiang.
       ABSTRACT: The nucleus, as the largest organelle within the cell, serves as the central hub for storing, replicating, and transcribing genetic information, thereby orchestrating vital cellular processes. In eukaryotic cells, the nuclear membrane is composed of several structural components: the outer and inner nuclear membranes, the nuclear pore complexes, and the underlying nuclear lamina, which together preserve the stability of the intracellular environment. Neurodegenerative disorders, such as Alzheimer's disease and related dementias, are characterized by the gradual degeneration and loss of neuronal structure and function in the central nervous system. Growing evidence suggests that alterations in nuclear envelope architecture are closely associated with the onset and progression of these diseases. This article summarizes the information, focusing on the regulators of the cell nuclear membrane, as well as its pathophysiological processes and regulatory mechanisms in neurodegenerative diseases. Moreover, this paper discusses related research advances that provide novel insights into a deeper understanding of the nuclear membrane in disease progression and its potential as a therapeutic target.
    Keywords:  Alzheimer’s disease; neurodegenerative disease; nuclear invagination; nuclear lamina; nuclear membrane disruption; nuclear pore complex; nucleocytoplasmic transport; nucleoporin
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01127
  17. Hear Res. 2026 Jan 30. pii: S0378-5955(26)00029-8. [Epub ahead of print]472 109553
    Circuit architecture and axonal branching in the efferent auditory system.
    Brett R Schofield.
      The auditory efferent system has been implicated in nearly all aspects of hearing, including adaptations to aging and response to damage or disease. The system encompasses a collection of descending neural pathways that are widespread, supporting modulation of auditory processing from the cochlea to the cortex. To understand efferent function at a cellular and circuit level, it is necessary to determine which of the inputs to a region contact which of the various output pathways. For both inputs and the outputs, the presence or absence of axonal branching has important implications for how these circuits function. Lack of branching can allow projections to two targets to be modulated independently. The presence of branching can allow for efficient delivery of information and coordinated neuronal processing in multiple targets. The present review considers the merits of several methods that have been used to assess branching. These methods reveal that axonal branching is prominent in some efferent pathways and minimal or absent in others.
    Keywords:  Auditory cortex; Collateral; Descending; Inferior colliculus; Modulation; Olivocochlear
    DOI:  https://doi.org/10.1016/j.heares.2026.109553
  18. J Toxicol Sci. 2026 ;51(2): 89-100
    Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.
    Allison Loan, Rochelle D'Mello, Yingxi Li, Tuana Nurkan, Zoran Minic, Jing Wang, Hing Man Chan.
      Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.
    Keywords:  Cerebellum; Disease latency; MeHg; Neurodegenerative disease; Prenatal; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.2131/jts.51.89
  19. Amino Acids. 2026 Feb 01. 58(1): 8
    Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.
    Abdilatif Aynaashe, Petri Kursula.
      Amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT) are two distinct neurodegenerative disorders. While ALS is characterised by rapidly progressive motor neuron degeneration, leading to severe complications and death, CMT as a peripheral neuropathy is less severe, and patients have a longer life span, although with a compromised quality of life. Despite their clinical differences, current knowledge suggests that familial ALS (fALS) and CMT may share common genetic and molecular mechanisms. We aimed to identify shared genes mutations and molecular pathways between fALS and CMT through a literature and database search. Thirteen genes were identified, involved in distinct cellular processes: axonal transport (DYNC1H1, KIF5A, SPG11, DCTN1), protein homeostasis (NEFH, VCP, SOD1), RNA metabolism (GARS, SETX), cellular stress response (HSPB1, FIG4), and mitochondrial function (MFN2, CHCHD10). While these linkages to the two diseases are rare for each gene, understanding possible mechanistic commonalities at the molecular level can initiate new research directions, help in identifying additional common genes between neurodegenerative disorders, and improve diagnostics.
    Keywords:  ALS; Axonal transport dysfunction; CMT; Mitochondrial dysfunction; Molecular mechanism; Neurodegeneration; Protein aggregation; RNA transport and metabolism; Stress response dysfunction
    DOI:  https://doi.org/10.1007/s00726-026-03500-w
  20. Ann Pharmacother. 2026 Feb 04. 10600280251408862
    Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.
    Michael Karros, Marissa DiFulco, Anna Nogid.
       OBJECTIVE: This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).
    DATA SOURCES: PubMed, MEDLINE, Google Scholar, and ClinicalTrials.gov were searched using the keywords: Qalsody, BIIB067, antisense oligonucleotides, SOD1, and amyotrophic lateral sclerosis. Articles published from inception to November 2025 were included.
    STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing the pharmacokinetics, pharmacology, efficacy, and safety of tofersen were included. Prescribing information and real-world evidence were also reviewed.
    DATA SYNTHESIS: Tofersen is an intrathecally administered antisense oligonucleotide targeting superoxide dismutase 1 (SOD1) mRNA. Early trials demonstrate dose-dependent reductions in cerebrospinal fluid (CSF) SOD1 protein levels of -33% and slower ALS Functional Rating Scale (ALSFRS-R) decline compared to placebo (-1.19 vs -5.63 points). In Phase 3 trials, tofersen reduced CSF SOD1 by 29% and plasma neurofilament light chain (NfL) by 60%, while biomarkers increased in the placebo group. There was no significant difference in ALSFRS-R decline between tofersen and placebo (-6.98 vs -8.14; P = 0.97). Real-world data show favorable patient-related outcomes and improvement in ALSFRS-R. Adverse effects are primarily lumbar puncture related with serious neurologic events documented in 7% of tofersen recipients.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:As the first Food and Drug Administration (FDA)-approved gene-directed therapy for SOD1 ALS, tofersen directly targets the underlying genetic cause. Barriers include the need for genetic confirmation and intrathecal administration.
    CONCLUSION: Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.
    Keywords:  ALS; SOD1; amyotrophic lateral sclerosis; antisense oligonucleotides; tofersen
    DOI:  https://doi.org/10.1177/10600280251408862
  21. Cell Mol Neurobiol. 2026 Feb 05.
    Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.
    Maitha M Alhajeri, Yara Abukhaled, Rayyah R Alkhanjari, Wesam Bassiouni, Hana Al-Ali, Amna Baig, Sara H Sembaij, Fatima A Al Muhairi, Zakia Dimassi, Hamdan Hamdan, Khaled S Abd-Elrahman.
      Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.
    Keywords:  Estrogen; Neurodegeneration; Neuroglia; Neuroinflammation; Sex hormones; Testosterone
    DOI:  https://doi.org/10.1007/s10571-026-01674-1
  22. J Neurochem. 2026 Feb;170(2): e70365
    Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
    Yubo Wang, Stuart A Lipton.
      Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.
    Keywords:  GWAS; S‐nitrosylation; neurodegenerative disease
    DOI:  https://doi.org/10.1111/jnc.70365
  23. Elife. 2026 Feb 02. pii: RP102155. [Epub ahead of print]13
    Information, certainty, and learning.
    Justin A Harris, Charles Randy Gallistel.
      More than four decades ago, Gibbon and Balsam (1981) showed that the acquisition of Pavlovian conditioning in pigeons is directly related to the informativeness of the conditioning stimulus (CS) about the unconditioned stimulus (US), where informativeness is defined as the ratio of the US-US interval (C) to the CS-US interval (T). However, the evidence for this relationship in other species has been equivocal. Here, we describe an experiment that measured the acquisition of appetitive Pavlovian conditioning in 14 groups of rats trained with different C/T ratios (ranging from 1.5 to 300) to establish how learning is related to informativeness. We show that the number of trials required for rats to start responding to the CS is determined by the C/T ratio, and the specific scalar relationship between the rate of learning and informativeness is similar to that previously obtained with pigeons. We also found that the response rate after extended conditioning is strongly related to T, with the terminal CS response rate being a scalar function of the CS reinforcement rate (1 /T). Moreover, this same scalar relationship extended to the rats' response rates during the inter-trial interval, which was directly proportional to the overall rate of reinforcement in the context (1 /C). The findings establish that animals encode rates of reinforcement, and that conditioning is directly related to how much information the CS provides about the US. The consistency of these observations across species, captured by a simple regression function, suggests a universal model of conditioning.
    Keywords:  Pavlovian; appetitive; conditioning; information; learning; neuroscience; rat; rate
    DOI:  https://doi.org/10.7554/eLife.102155
  24. J Biomed Sci. 2026 Feb 04. 33(1): 15
    APP-C31 pathology as a target in neurodegenerative diseases.
    King Chi Yip, Woon Fei Ho, Yang Liu, Gavin Stewart Dawe.
      Neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.) are caused by the progressive loss of neurons, which affects many people worldwide. Therefore, many efforts have focused on neurodegenerative disease mechanisms and therapeutic strategies. Moreover, amyloid precursor proteins and their cleaving products, including APP-C31, may play important roles in neurodegeneration. This review provides a comprehensive introduction to the structure, neurotoxicity, regulatory mechanism, and relevance of APP-C31 to clinical diseases and its therapeutic potential as a drug target. This work will bridge the gap in our understanding of the function of APP-C31, which provides an experimental basis for neurodegenerative disease therapeutics. Meanwhile, a hypothesis is postulated that the APP-C31 functions not merely as a byproduct of caspase cleavage, but as the critical "central executioner" bridging upstream triggers and downstream neurodegeneration. Diverse upstream stressors, initiate the cascade to generate APP-C31. Once generated, C31 acts as a multi-functional signalling hub driving four distinct pathogenic pathways. Consequently, APP-C31 is hypothesized to be the essential mediator that amplifies these molecular damages into macroscopic failures.
    Keywords:  APP-C31 fragments; Amyloid precursor protein (APP); Neurodegenerative diseases; Therapeutic target
    DOI:  https://doi.org/10.1186/s12929-026-01216-3
  25. Acta Neuropathol Commun. 2026 Jan 30.
    From origins to nomenclature: illuminating the landscape of CNS fibroblasts and fibroblast-like cells.
    Jianing Lin, Kuo Liao, Sebastian A Lewandowski.
      Fibroblasts are a group of stromal cells that contribute to the scarring process in many neurological conditions in the central nervous system (CNS). Recently, single-cell sequencing efforts allowed an in-depth understanding of their cell origins and subpopulation profiles. Meanwhile, vascular leptomeningeal cells and the "type A pericytes" were also proposed as CNS fibroblast-like cells in the last decade by histological, functional and transcriptomic analysis. While these cells share overlapping features with CNS fibroblasts, the inconsistent use of nomenclature and partially overlapping cell-type markers is likely to cause confusion within the growing field of neurobiology. In this review, we will delineate the current knowledge of subtypes and functions of CNS fibroblasts, with special focus on the source of PVFs during development and the nomenclature origins of other similar cell types. We aim to provide comprehensive insights into these cells with similar functions or transcriptomic profiles.
    Keywords:  Central nervous system; Fibroblasts; Perivascular fibroblasts; Type A pericytes; Vascular leptomeningeal cells
    DOI:  https://doi.org/10.1186/s40478-026-02236-8
  26. Musculoskelet Sci Pract. 2026 Jan 31. pii: S2468-7812(25)00232-2. [Epub ahead of print] 103484
    Pain and the immune system.
    Paul W Hodges, Nathan T Fiore, Linda R Watkins, David M Klyne, Michel W Coppieters, Peter M Grace.
      Although classically considered from a neuro-centric vantage point, is now well known that pain involves interaction between the immune and nervous systems. Neuro-immune interactions occur all along the pain axis from the tissues to the peripheral neurons, the dorsal root ganglia, the spinal cord and supraspinal centres. Immune cells from mast cells, macrophages, T cells and B cells, to the Schwann cells of neurons, and the glia cells in the spinal cord and brain, release diverse inflammatory mediators including cytokines and chemokines. Fundamental mechanisms underlying pain enhancement by immune cells are diverse and differ between nociceptive, neuropathic and nociplastic pain conditions. The involvement of the immune system in pain provides enormous potential for interventions to address pain by targeting these mechanisms. These interventions include pharmacological and genetic treatments, as well as non-pharmacological treatments with the potential to impact systemic and CNS immune activity, such as exercise, diet and treatments targeting psychosocial and behavioural features (e.g., sleep and stress). Logically, treatment efficacy should depend on matching the treatment to the relevant neuro-immune mechanism. The aim of this review is to provide a foundation to understand the relevance of neuro-immune interactions to the development and persistence of chronic pain, and its implications for treatment. We provide an overview of the role of neuroinflammation in pain, evidence that this contributes to human pain conditions, and how this can guide matching the right treatments to the right person.
    DOI:  https://doi.org/10.1016/j.msksp.2025.103484
  27. bioRxiv. 2026 Jan 12. pii: 2026.01.12.698957. [Epub ahead of print]
    Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15.
    Stephan Tetter, Nikhil R Varghese, Alexey G Murzin, Wouter De Coster, Marleen Van den Broeck, Sigrun Roeber, Jeffrey T Joseph, Kathy Newell, Rudolf Castellani, Sumit Das, Lee-Cyn Ang, Matthis Synofzik, Jochen Herms, Rosa Rademakers, Bernardino Ghetti, Tammaryn Lashley, Ian R A Mackenzie, Manuela Neumann, Benjamin Ryskeldi-Falcon.
      Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing's sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.
    DOI:  https://doi.org/10.64898/2026.01.12.698957
  28. Probl Endokrinol (Mosk). 2026 Jan 18. 71(6): 50-55
    [Recurrent hypoglycemia and the structure of the choroid plexus of the lateral ventricles of the rat brain].
    О A Fokanova, Т V Korableva, N B Medvedeva, P K Telushkin.
       BACKGROUND: Recurrent hypoglycemia occurs during insulin therapy in patients with diabetes mellitus and is a significant cause of brain dysfunction in these patients. The functioning of the hematocerebrospinal fluid barrier and the production of cerebrospinal fluid (CSF) are of great importance in ensuring brain activity. The main volume of CSF is formed by the choroid plexus of the lateral ventricles (LV) of the brain and the glymphatic system of the brain. The role of the choroid plexus in the development of brain dysfunction in hypoglycemia has not been sufficiently studied.
    OBJECTIVE: The aim of this work was to determine the structure of the choroid plexuses of the lateral ventricles of the brain during recurrent hypoglycemia.
    MATERIALS AND METHODS: The object of the study were rats that had undergone 9 hypoglycemic states after insulin administration (with an interval of 3 days, the blood glucose level of 1.4-1.8 mmol/L) and intact animals. The volume of the LV and volume fractions of the choroid plexuses in the LV were estimated: the relative volume and total fraction of vessels, fractions of cells and connective tissue. Morphological changes in the epithelium of the choroid plexus and nervous tissue of the periventricular spaces were also recorded.
    RESULTS: In animals that had undergone a series of hypoglycemias, the maximum cross-sectional area of the LV, the relative volume of the choroid plexuses of the LV and the volume fraction of vessels per volume of the choroid plexus of the LV increase. The volume fraction of cells per volume of the choroid plexus of the ventricles decreases in rats with recurrent hypoglycemia. Morphological examination of these animals reveals dystrophic changes in the epithelial cells of the choroid plexus and zones of dystrophic changes in the brain tissue surrounding the ventricles.
    CONCLUSION: Thus, recurrent hypoglycemia leads to an increase in the maximum cross-sectional area of the LV and the relative volume of the choroid plexuses, as well as dystrophic changes in the epithelial cells of the choroid plexuses and neurons of the periventricular spaces. Since hypoglycemia is repeatedly observed during the treatment of patients with diabetes mellitus, the identified changes may cause cognitive impairment and the development of dementia in these patients.
    DOI:  https://doi.org/10.14341/probl13579
  29. Autism Adulthood. 2025 Nov;7(6): 739-751
    What Is Uncertainty? A Grounded Theory of the Role of Uncertainty in Anxiety in Autism.
    Laura Lennuyeux-Comnene, Julia Yates, Sebastian B Gaigg.
       Background: Although previous qualitative work has identified the role of intolerance of uncertainty in the development of anxiety in autism, there has been little research on what uncertainty means exactly for autistic people and/or what types of uncertainties may be particularly anxiety provoking.
    Methods: Fifteen autistic adults (five women) took part in this qualitative interview study in which we probed their understanding and experiences of uncertainty and its links to feelings of anxiety. We applied a grounded theory approach to transcripts of the interviews, broadly following Charmaz's constructivist epistemology, to derive a theory of uncertainty as it is experienced by the autistic people we interviewed.
    Results: From the interviews, we derived a model of uncertainty, which identified three different levels of uncertainty, ranging from the certainty of the "known," through to the relatively manageable uncertainty of the "known unknown," to the anxiety-provoking "unknown unknown" or that which cannot be made known. We propose in this model that anxiety can be understood as resulting from difficulties with avoiding or controlling the latter types of uncertainty through planning or information gathering.
    Conclusion: Previous researchers had treated uncertainty as a unified construct. However, they may not have explored what uncertainty might mean for autistic people. We have shown in this study that not all uncertainties are experienced equally. We hope that this research will help develop a more nuanced understanding and that it constitutes the first step in disentangling anxiety from intolerance of uncertainty in autism.
    Keywords:  anxiety; autism; intolerance of uncertainty; uncertainty
    DOI:  https://doi.org/10.1089/aut.2022.0085
  30. Front Med (Lausanne). 2025 ;12 1697871
    Retinal biomarkers in schizophrenia spectrum disorders: evidence and implications for the neurodevelopmental and neurodegenerative models.
    Brittany A Blose, Steven M Silverstein.
      Retinal morphological and functional alterations, such as changes in the thickness and volume of the retinal neural layers, architecture of the microvasculature, and functioning of neurons, have been observed in schizophrenia and have been interpreted in terms of neurodegenerative aspects of the disorder. However, little consideration has been given to the issue of whether, and the extent to which, these retinal differences may reflect neurodevelopmental features of schizophrenia. There are also no current conceptualizations that integrate retinal alteration findings in schizophrenia across different stages of illness, thereby helping to integrate neurodevelopmental and neurodegenerative perspectives on pathophysiology. Therefore, the present review aims to organize evidence of retinal abnormalities in schizophrenia in terms of findings from clinical high-risk for psychosis (CHR), genetic risk, first-episode psychosis (FEP), and chronic schizophrenia samples, and to consider factors such as age and duration of illness. Our goal is to move toward a lifespan model that integrates and transcends prior neurodevelopmental and neurodegenerative viewpoints. Toward this end, we also review studies of retinal alterations among those with prenatal/perinatal insults, neurodevelopmental disorders, and neurological soft signs, as such data can inform what has been observed in schizophrenia. We also mention, where appropriate, relevant findings from neurodegenerative disorders. A better understanding of the trajectories of central nervous system differences throughout the lifespan in people with schizophrenia, as observed in the retina (often called "a window to the brain"), can aid in understanding brain dysfunction in the disorder, assist with characterizing heterogeneity in clinical course, and inform more targeted prevention, monitoring, and intervention efforts.
    Keywords:  neurodegeneration; neurodevelopment; optical coherence tomography (OCT); retina; schizophrenia
    DOI:  https://doi.org/10.3389/fmed.2025.1697871
  31. Braz J Med Biol Res. 2026 ;pii: S0100-879X2026000101401. [Epub ahead of print]59 e14570
    An overview on central nervous system tuberculosis (CNS-TB) focusing on cognitive impairments.
    G L Garcia, B Regis da Cunha, J D Herling, C M Gomes, F C R Zucchi.
      One of the most serious clinical manifestations of tuberculosis (TB) is the central nervous system (CNS) presentation, which results in neurological disorders and cognitive impairments that may lead to reduced social skills. Few studies have assessed TB neuropsychological symptoms after infection. This review article investigated the incidence and spectrum of cognitive impairment related to complications in patients with CNS-TB and compiled data on the pathophysiology, diagnosis, and treatment of the disease. An extensive literature review was performed, and a total of 286 published studies were selected for manual screening. For analysis purposes, 43 studies were included in this review. CNS-TB mainly affects young children and is fatal in over 50% of cases, with survivors showing high morbidity. The characteristics of this disease include meningitis and brain tissue granulomas. This leads to extensive neurological involvement, resulting in a complex mechanism that alters the structure and composition of cells in the brain including the cerebellum and spinal cord. It also impairs language development, reading, and learning complex tasks, and therefore affects the patient's social adjustment. The results of our review provide information connecting the basis of neuroscience and clinical medicine, especially childcare. Furthermore, early diagnosis is imperative to prevent serious cognitive consequences of TB in the developing CNS.
    DOI:  https://doi.org/10.1590/1414-431X2025e14570
  32. Neurol Sci. 2026 Feb 02. 47(2): 218
    The potential role of COX-2/PGs signaling pathway in epileptogenesis and associated neuroinflammation: collusions or serendipity.
    Bshra A Alsfouk, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Ahmed M Abdelaziz, Alaa Ismail, Luay M Alkazmi, Athanasios Alexiou, Marios Papadakis, Gaber El-Saber Batiha.
       BACKGROUND: Epilepsy is a neurological condition characterized by recurrent, spontaneous seizures stemming from sudden, abnormal synchronization of neuronal activity in specific brain regions, driven by structural or functional alterations. This disorder is preceded by epileptogenesis, a dynamic process marked by cellular and molecular changes that heighten brain excitability. Although anti-seizure medications (ASMs) remain the cornerstone of treatment, roughly 30% of patients develop refractory epilepsy, which resists ASMs therapy. Critically, ASMs do not prevent epileptogenesis, implying divergent mechanisms govern disease progression.
    METHODS: This review evaluates the pathway's contributions to neuroinflammation, epileptogenesis, and epilepsy, and explores the promise of COX-2 inhibitors in managing refractory epilepsy.
    RESULTS: Epileptogenesis continues even after seizures manifest and is strongly associated with drug-resistant forms such as temporal lobe epilepsy (TLE). Neuroinflammation, which develops subsequent to the epileptic seizure, aggravates refractory epilepsy by enhancing the extrusion of ASMs across the blood-brain barrier (BBB), reducing their therapeutic efficacy. Following epileptic seizures, cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin (PG) synthesis, is upregulated and activates the COX-2/PG pathway, leading to exacerbation of neuroinflammation and acceleration of epilepsy progression. Furthermore, by inducing neuronal hyperexcitability and epileptogenesis, elevated COX-2 and PG levels correlate with increased seizure severity and frequency.
    CONCLUSION: Consequently, targeting of the COX-2/PG axis has emerged as a potential therapeutic strategy.
    Keywords:  Cyclooxygenase 2; Cyclooxygenase 2 inhibitors; Epilepsy; Epileptogenesis; Neuroinflammation
    DOI:  https://doi.org/10.1007/s10072-025-08679-6
  33. J Mol Med (Berl). 2026 Feb 02. 104(1): 38
    Prosaposin in CNS health and disease, metabolic stress and exercise adaptation.
    Hash Brown Taha, Shirley Zhu, Eric Wang.
      Prosaposin (PSAP), a highly conserved lysosomal protein and precursor of saposins A-D, has emerged as a key regulator of cellular and central nervous system (CNS) homeostasis. Disrupted PSAP trafficking may lead to amyloid protein aggregation with implications for neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), PSAP shows altered expression patterns and pathological co-localization with amyloid aggregates. PSAP variants are linked to multiple neurodegenerative diseases, including synucleinopathies, Gaucher's disease, and metachromatic leukodystrophy. Its levels are elevated in blood and cerebrospinal fluid in some individuals with AD or PD and are upregulated by stress conditions such as nerve injury and cold adaptation, but not by exercise. Prosaptides, short peptides derived from PSAP, show protective effects in models of oxidative stress, CNS injury, and metabolic disorders. Pharmacological stabilization of PSAP interactions with progranulin has shown promise in neurodegenerative disease models. These findings suggest PSAP plays an important role in maintaining brain health and may hold therapeutic potential. Here, we provide a comprehensive overview of PSAP's role in CNS health and disease, metabolic stress, and exercise adaptation.
    Keywords:  Alpha-synuclein; Alzheimer’s disease; Amyloid beta; Exerkine; Metabolism; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s00109-026-02643-3
  34. Neurobiol Dis. 2026 Feb 04. pii: S0969-9961(26)00053-7. [Epub ahead of print] 107309
    Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.
    Brianna Hnath, Srinivasan Ekambaram, Nikolay V Dokholyan.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2-3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.
    Keywords:  ALS; Aggregation; Extracellular vesicles; Oligomer; SOD1; Spreading
    DOI:  https://doi.org/10.1016/j.nbd.2026.107309
  35. Muscle Nerve. 2026 Feb;73 Suppl 1 S13-S15
    Safety of Intravenous Edaravone in Clinical Practice.
    Angela Genge, Stephen Apple.
      This article summarizes the post-marketing pharmacovigilance safety data of intravenous (IV) edaravone during the 1- and 3-year periods following its launch for amyotrophic lateral sclerosis (ALS) in the United States. The most frequently reported adverse events (AEs) and serious AEs (SAEs) included those consistent with ALS disease progression, such as fatigue and muscular weakness, and were not qualitatively different from those reported in previous ALS trials. There were AEs and SAEs associated with IV administration, such as administration site reactions, and five non-fatal anaphylaxis SAEs were reported. No new safety signals were identified, and IV edaravone continues to demonstrate a favorable safety profile. These insights are especially useful as treatment transitions to edaravone oral suspension, which avoids IV-related complications. These findings underscore the importance of ongoing clinical safety assessments in informing ALS treatment decisions.
    Keywords:  amyotrophic lateral sclerosis; clinical; edaravone; pharmacovigilance; safety
    DOI:  https://doi.org/10.1002/mus.70038
  36. Nanoscale. 2026 Feb 05.
    Ligand content-dependent exocytosis governs the blood-brain barrier transcytosis of nanocarriers.
    Xinyue Zhang, Yanan Xu, Caixia Wang, Zhihong Liu.
      The blood-brain barrier (BBB) penetration efficiency of nanocarriers is restricted by limited exocytosis to the brain parenchyma. This study demonstrates that exocytosis efficiency initially increases and subsequently decreases with increasing ligand content. Therefore, optimizing ligand content in brain-targeted nanocarriers is crucial to enhance exocytosis and transcytosis across the BBB.
    DOI:  https://doi.org/10.1039/d5nr05008a
  37. Eur J Drug Metab Pharmacokinet. 2026 Feb 05.
    Defining Safe and Effective Cefazolin Dosing Regimens for MSSA Infections in the CNS: Leveraging Sparse Real-World Data and PBPK Modeling.
    Samuel Dubinsky, Mark McIntyre, Min-Soo Kim, Laura Hawryluk, Andrea Edginton.
       BACKGROUND AND OBJECTIVE: Infections in the central nervous system (CNS) are serious and carry a significant risk of morbidity and mortality. Though commonly used as prophylaxis for neurosurgical interventions, cefazolin as a treatment for CNS infections due to methicillin-susceptible Staphylococcus aureus (MSSA) has been debated owing to the perceived inability to achieve adequate concentrations at the site of infection. The objective of the current study was to evaluate the dose-exposure-response relationship of cefazolin in the CNS.
    METHODS: To leverage sparse data of cefazolin in the cerebrospinal fluid (CSF) and derive an understanding of the dose-exposure-response profile in the CNS, a physiologically-based pharmacokinetic (PBPK) model was created in PK-Sim. Simulations were performed using standard cefazolin dosing of 2000 mg every 8 h and alternative regimens to maximize the probability of target attainment (PTA). The pharmacodynamic target used was 100% fT > MIC (100% of free drug concentrations above the minimum inhibitory concentration). Furthermore, a neurotoxicity threshold of ≥ 300 mg/L and ≥ 30 mg/L for trough concentrations was set as the safety indicator in plasma and CSF, respectively.
    RESULTS: The cefazolin CSF-PBPK model was successfully validated such that predicted CSF:plasma ratios were within a 1.5-fold error compared with the observed values. In addition, the median predicted CSF:epidemiological cut-off (ECOFF) concentration ratio was 2.52, compared with an observed value of 2.8. In silico simulations demonstrate that intermittent doses of 2000 mg every 6 h or a continuous infusion of 8-10 g/day may be required to ensure 90% PTA for MSSA to a MIC ≤ 2 mg/L. Predicted plasma and CSF concentrations were well below concentrations associated with neurotoxicity.
    CONCLUSIONS: This study is the first to use sparse observed CNS data to develop a mechanistic model to describe the pharmacokinetics of cefazolin in the CSF. This work supports existing research on the viability of cefazolin as a therapeutic alternative for CNS infections attributed to MSSA and can be used for future clinical trial planning.
    DOI:  https://doi.org/10.1007/s13318-025-00981-0
  38. Mov Disord. 2026 Feb 03.
    Focused Ultrasound for the Treatment of Circuit and Molecular Pathology in Parkinson's Disease.
    Rikke Hahn Kofoed, Victor Schwartz Hvingelby, Jose A Pineda-Pardo, Javier Blesa, Steffen Paschen, Anurag Tandon, Juho Joutsa, Andreas Nørgaard Glud.
      Focused ultrasound is rapidly emerging as a novel technology for the development of symptomatic therapies and supporting disease-modifying treatments for Parkinson's disease (PD). At the forefront of this development is thermoablation using high-intensity focused ultrasound, an incisionless treatment that has been extensively tested in clinical trials and so far has received clinical approval for the treatment of essential tremor and PD patients. At the other end of the spectrum, low-intensity focused ultrasound has been demonstrated in both neuromodulation and blood-brain barrier opening to allow the entry of therapeutic molecules into the central nervous system. The aim of this review is both to provide an overview of the current and future roles of focused ultrasound in disease-modifying treatments for PD with a special focus on outlining the full complexity of the disease beyond dopaminergic cell loss and to bridge clinical and preclinical research. First, we establish PD as a disease including both circuit dysfunctions and molecular pathology. Second, we discuss focused ultrasound state-of-the-art clinically and when relevant in relation to other similar treatment strategies (ie, deep brain stimulation). Third, we highlight preclinical advances and the potential of focused ultrasound to become a disease-modifying treatment. Understanding the therapeutic effects of focused ultrasound in a complex disease like PD is necessary to harness the full potential of the technology. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Parkinson's disease; circuit dysfunctions; focused ultrasound; molecular pathology; neuromodulation; therapy delivery
    DOI:  https://doi.org/10.1002/mds.70156
  39. Soft Matter. 2026 Feb 06.
    Drug & virus transport across biological barriers: interactions, diffusion, partitioning, permeability, and selectivity.
    Mikael O Ellingson, Michael A Bevan.
      Biological barriers protect the human body by selectively blocking foreign material. Designing particles with coatings that efficiently transport across these barriers can increase the effectiveness and feasibility of advanced therapeutics. In particular, the mucus barrier protects the intestines, lungs, eyes, etc., complicating oral, inhaled, or ocular drug delivery. Heuristics for particle design are currently limited to the rate of diffusion within the barrier. Relying on first-principles theories for colloidal scale interactions, a cohesive model of the transport of particles through biological barriers is developed based on the barrier permeability, which incorporates essential contributions from both partitioning and diffusion. Analytical models are developed to predict partition coefficients based on particle-pore interaction potentials. Particle-pore hydrodynamics are considered to predict average diffusivities within mucus barriers. We show that kT-scale attractive interactions, that are either specific or non-specific, can yield optimal delivery of larger particles, to increase the mass flux across mucus barriers by an order of magnitude, and enable delivery of macromolecular cargo, due to enhanced partitioning. Our model indicates drug particle design rules to achieve transport rates comparable to or exceeding what is possible by viruses with highly evolved chemical and physical characteristics.
    DOI:  https://doi.org/10.1039/d5sm01176k
  40. Acta Ophthalmol. 2026 Feb 07.
    Infection control in the brain and the eye.
    John V Forrester, Paul G McMenamin, Samantha J Dando.
      The Central Nervous System (CNS), comprising the brain and the eye, is considered to have a 'privileged' mechanism for dealing with immunological challenge (immune privilege, IP). CNS IP has been revealed through experiments using foreign protein antigens and cell and tissue alloantigens (grafts), but evidence for a role for IP in modulating host-pathogen interactions in the CNS is limited. However, the low frequency of CNS infection in the face of widespread systemic exposure to CNS-tropic infectious agents, together with the high incidence of CNS infection in immunocompromised individuals, suggests that in healthy individuals, the CNS has tightly controlled regulatory mechanisms to protect against infectious agents. Although the naïve healthy brain and retina parenchyma largely lack adaptive immune cells, their border tissues (meninges, uveal tract) contain a full complement of resident immune cells, including CNS-specific regulatory T cells (Tregs), which have a fundamental role in controlling infection in the brain parenchyma. Tregs also underpin ocular IP, particularly of the neural retina. Recent studies report that Tregs are transcriptionally 'customised' to the CNS and function at a distance; that is, are located in niches/hubs around the venous sinuses of the border tissues. T cells resident in the uveal tract probably play a similar role. We propose that Tregs are key drivers of CNS IP and do so by promoting latency of infectious agents.
    Keywords:  CNS; immune privilege; infection; latency
    DOI:  https://doi.org/10.1111/aos.70071
  41. Front Neural Circuits. 2026 ;20 1725431
    Morphological and transcriptomic change of brain pericytes by lipopolysaccharide treatment.
    Taiki Asai, Yoshino Yonezu, Akiko Uyeda, Haruki Watanabe, Tatsunori Suzuki, Hidemi Misawa, Rieko Muramatsu.
      Brain pericytes play essential roles in vascular homeostasis, including capillary stabilization and maintenance of the blood-brain barrier. Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is known to trigger inflammatory responses not only systemically but also within the central nervous system. In this study, we investigated the effects of LPS on the phenotype and transcriptome of brain vascular pericytes. LPS promoted bromodeoxyuridine incorporation in the primary culture of human brain pericytes as well as increased the number of Ki67-positive cells, indicating enhanced pericyte proliferation. Morphological analysis revealed that LPS decreased the cellular aspect ratio, suggesting altered cellular elongation. Transcriptomic profiling showed that LPS-induced differentially expressed genes were enriched for terms related to cell proliferation, angiogenesis, and blood-brain barrier function. Because pericytes critically regulate neurovascular coupling and metabolic support for active neurons, these LPS-induced alterations may ultimately perturb the microvascular control of neural circuits. These results suggest that LPS has the potential to regulate brain vascular function by inducing morphological and functional changes in pericytes.
    Keywords:  central nervous system; development; human; lipopolysaccharide; neurovascular unit; pericyte; repair
    DOI:  https://doi.org/10.3389/fncir.2026.1725431
  42. ACS Infect Dis. 2026 Jan 30.
    The Pyridoxal-5'-Phosphate-Dependent Enzymes of Mycobacterium tuberculosis.
    Alessio Peracchi, Bienyameen Baker.
      Enzymes that depend on the cofactor pyridoxal 5'-phosphate (PLP) catalyze a remarkable variety of biochemical reactions in all organisms. In particular, the genome of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), encodes 45 bona fide PLP-dependent enzymes plus a few related proteins that presumably do not have enzymic function. The large majority of the 45 enzymes have been characterized in terms of catalytic activity and structure. Several of them have been shown to be central to the bacterium's survival and pathogenicity, while some of these enzymes are targets of an extant drug (d-cycloserine). Herein, the annotated catalog of the PLP-dependent enzymes in M. tuberculosis is presented and analyzed with three main goals in mind. The first will be to assess the specific aspects of mycobacterial metabolism that rely most on PLP-dependent enzymes. A second goal will be to signal those enzymes whose function is still uncertain and whose functional characterization may help to further understand the biology of M. tuberculosis. Finally, we will examine the potential and limitations of targeting the PLP-dependent enzymes for the development of new antimycobacterial drugs.
    Keywords:  Mycobacterium tuberculosis; PLPome; drug targets; essential enzymes; functional annotation; sulfur metabolism
    DOI:  https://doi.org/10.1021/acsinfecdis.5c00996
  43. Braz J Otorhinolaryngol. 2026 Feb 05. pii: S1808-8694(26)00012-1. [Epub ahead of print]92(3): 101763
    Is there any relationship between the menopause transition and dizziness?
    Lucas Resende Lucinda Mangia, Roseli Saraiva Moreira Bittar.
       OBJECTIVES: This review aims to study the impact of menopause transition on the vestibular system.
    METHODS: A broad systematic search of biomedical databases was performed. Papers investigating the effects of changes in female sex hormones on the vestibular physiology or the relationship between these changes in midlife women and vestibular manifestations were reviewed. Data from basic science, epidemiological studies and clinical investigations were organized and elaborated. The authors also addressed the gaps and limitations of current literature.
    RESULTS: Hormonal modifications during menopause transition seem to affect the vestibular system. Accordingly, epidemiological investigations describe a remarkable prevalence of vestibular disorders in climacteric women. However, clinical studies exploring this relationship are scarce, and little is known about the clinical and pathophysiological aspects of these diseases. The predisposition to vestibular disturbances during the menopause transition might be the result of an intricate combination of hormonal effects in the nervous system. These effects encompass changes in energy metabolism, immune and inflammatory regulation, modulation of several neurotransmitter systems, integrity of microcirculation and neuroprotection and neuroplasticity pathways. As a result, structural consequences within the inner ear, changes in the transduction and modulation of peripheral signals and dysregulation of central vestibular circuits may occur. Additionally, patients may present with signs of disturbances in sensory processing or difficulties in recovering from functional damages to the vestibular system. These events may contribute to the manifestation of individual vulnerabilities, causing sensory complaints, and the onset or worsening of vestibular problems. Preliminary data also corroborate the impact of menopause transition in specific vestibular diseases.
    CONCLUSION: There is a theoretical basis for understanding the menopause transition as a facilitating condition for vestibular symptoms and diseases. However, clinical studies addressing these issues are scarce. Exploring them is a promising field of investigation that could lead to improvement in care for vestibular patients.
    Keywords:  Climacteric; Dizziness; Labyrinth diseases; Menopause; Vestibular diseases
    DOI:  https://doi.org/10.1016/j.bjorl.2026.101763
  44. J Mol Neurosci. 2026 Feb 05. 76(1): 25
    "Unfolding Parkinson's Disease Through the Microbiome-Gut-Brain Axis".
    Ramana Kamatchi Shenthilvel, Thangavelu Arumugam Umashankar, Deenathayalan Uvarajan, Mohana Mathuraj, Manish Ravikumar.
      Parkinson's disease (PD) is a progressive and multifactorial neurodegenerative disorder primarily caused by the loss of dopaminergic neurons in the substantia nigra. This neuronal loss leads to characteristic motor symptoms such as tremors, rigidity, and slowness of movement. Although PD has long been regarded as a disorder originating in the brain, recent findings suggest that the gut-brain axis, the intricate communication network between the gastrointestinal tract and the central nervous system also plays an important role in the development and progression of PD. Interestingly, early non-motor symptoms such as constipation and other bowel irregularities often appear several years before the onset of motor symptoms, indicating that changes in gut function may precede and even contribute to neurodegeneration. The gut microbiota influences neuronal signaling, immune activity, and metabolic balance through neuroactive molecules such as neurotransmitters, short-chain fatty acids (SCFAs), and cytokines. In PD, microbial imbalance, intestinal barrier dysfunction, and chronic inflammation are closely linked to the misfolding and accumulation of α-synuclein (α-syn), which can spread from the gut to the brain through the vagus nerve in a prion-like manner. Current therapeutic approaches are increasingly exploring ways to restore gut microbial balance using probiotics, prebiotics, dietary interventions, fecal microbiota transplantation (FMT), and SCFA supplementation. These strategies not only aim to relieve symptoms but may also have the potential to slow disease progression. This review discusses the mechanisms through which the gut-brain axis contributes to PD, summarizes key clinical and preclinical findings, and highlights emerging gut-targeted therapeutic approaches.
    Keywords:  Gut microbiota; Gut-brain axis; Neuroinflammation; Parkinson’s disease; α-Synuclein pathology
    DOI:  https://doi.org/10.1007/s12031-025-02462-0
  45. ArXiv. 2026 Jan 30. pii: arXiv:2601.22684v1. [Epub ahead of print]
    BioModelsRAG: A Biological Modeling Assistant Using RAG (Retrieval Augmented Generation).
    Bhavyahshree Navaneetha Krishnan, Adel Heydarabadipour, Herbert Sauro.
      The BioModels database is one of the premier databases for computational models in systems biology. The database contains over 1000 curated models and an even larger number of non-curated models. All the models are stored in the machine-readable format, SBML. Although SBML can be translated into the human readable Antimony format, analyzing the models can still be time consuming. In order to bridge this gap, a LLM (large language model) assistant was created to analyze the BioModels and allow interaction between the user and the model using natural language. By doing so, a user can easily and rapidly extract the salient points in a given model. Our analysis workflow involved 'chunking' BioModels and converting them to plain text using llama3, and then embedding them in a ChromaDB database. The user-provided query was also embedded, and a similarity search was performed between the query and the BioModels in ChromaDB to extract the most relevant BioModels. The BioModels were then used as context to create the most accurate output in the chat between the user and the LLM. This approach greatly minimized the chance of hallucination and kept the LLM focused on the problem at hand.
  46. J Lesbian Stud. 2026 Feb 01. 1-15
    Messages to the future? Lesbian subversion of official categories in the 1921 UK census.
    Caroline Derry.
      This article considers how Britain's 1921 census can be a source for histories of lesbian activism. It explores evidence that the census returns were a site of lesbian resistance and considers the implications for our own histories and understandings of activism. It asks whether these official forms can be considered as messages from our forebears to the future, and what that means for our activism today: The 1921 census form required everyone present in a household on the night of 19 June to be recorded, and their relationship to its 'head' to be stated: a process of categorization which reified patriarchal family relations. However, a small number of women - some known to have been in committed relationships with each other - rejected the official directions in favor of their own relationship categories including 'joint head' or 'joint occupier'. They did so in a context where their relationships were legally unspeakable, hierarchies of gender were intimately entwined with those of sexuality and race, and the heteronormative family was positioned as central to the survival of the nation.
    Their rebellions are both a form of activism and an archive within an archive, allowing historians to capture experiences which might otherwise be unrecorded. In a time where patriarchal hierarchies are being reasserted, listening to these messages from the past has taken on new urgency.
    Keywords:  Census; activism; heteronormativity; household; joint occupiers
    DOI:  https://doi.org/10.1080/10894160.2026.2622097
  47. Semin Neurol. 2026 Feb 02.
    Artificial Intelligence and Ocular Imaging in the Evaluation of Neurologic Disorders: The New Era of Neuro-Oculomics?
    Fiona Costello, Gemma C Norman.
      Links between the eye and the central nervous system (CNS) have been recognized since the origins of the ophthalmoscope. Owing to the elegant topography of the afferent visual pathway and its close embryonic, anatomical, and physiological connections to the brain, it is possible to capture structural effects of CNS injury in the retina. The availability of large-scale, high-quality retinal imaging datasets and ongoing advances in artificial intelligence (AI) have paved the way for Oculomics, a field in which ocular measures act as biomarkers for systemic diseases. Similarly, ocular images have been used in AI models to provide critical insights about neurologic disorders in the fledgling discipline of what might be considered Neuro-Oculomics. In this review, we will describe key ocular imaging techniques and highlight emerging roles for AI in the diagnosis and management of important neurological conditions.
    DOI:  https://doi.org/10.1055/a-2792-8597
  48. J Oral Rehabil. 2026 Jan 30.
    A Personal Exploration of Oral Health in Amyotrophic Lateral Sclerosis (ALS) Through the Eyes of a Multifaceted Authority.
    Merel C Verhoeff, Maurits K A van Selms, Frank Lobbezoo.
       BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that impairs motor function, including oral musculature, complicating oral hygiene and care. Despite its impact, oral health in ALS patients remains under-addressed. This personal scoping review explores oral health in ALS through the dual lens of Dr. Maurits K.A. van Selms-a dental researcher and ALS patient-highlighting care, research, and education priorities.
    METHODS: Semi-structured interviews were conducted via email with Dr. van Selms, using a topic guide adapted from a prior personal scoping review. The interview covered personal experiences and professional insights into oral health care, research, and education in ALS. Responses were analysed and synthesised into thematic agendas.
    RESULTS: Dr. van Selms emphasised the neglect of oral hygiene in ALS care. He advocated for patient-informed, tailored guidelines based on functional capacity, interdisciplinary collaboration, and improved accessibility to dental services. In research, he called for ethically sensitive, patient-centered studies that reduce the burden of oral care. Educationally, he stressed the need for inclusive training across disciplines and stakeholder levels, promoting self-advocacy and awareness. Instructional materials, such as videos, were recommended to support caregivers and patients.
    CONCLUSION: This personal scoping review underscores the importance of integrating oral health into ALS management. Dr. van Selms' unique perspective reveals gaps in care delivery, research ethics, and education, advocating for interdisciplinary collaboration and proactive guideline development. His insights offer a roadmap for improving oral health outcomes and quality of life in ALS and similar neurodegenerative conditions.
    Keywords:  amyotrophic lateral sclerosis; oral health; personal scoping review
    DOI:  https://doi.org/10.1111/joor.70157
  49. J Vis Exp. 2026 Jan 16.
    Live Imaging and Characterization of Microglia Dynamics and Interactions with Synapses in Diseased Murine Retina.
    Camille Fang, Subramanian Dharmarajan, Colin Germer, Jeanette Hyer, Yvonne Ou.
      Microglia are the resident macrophages of the central nervous system (CNS) that respond to tissue infection and injury. In addition to their role in inflammation, microglia play a developmental role in circuit refinement through synaptic pruning. However, the mechanisms of synaptic pruning in neuroinflammation and neurodegeneration remain unknown. In this protocol, we use a mouse retina explant model to study microglia dynamics ex vivo. To examine microglia motility and their interactions with postsynaptic proteins, we label synapses with AAV-PSD95-RFP and record timelapse videos of motile microglia colocalized with postsynaptic proteins using spinning disk confocal microscopy. We then create surface and spot reconstructions of microglia and PSD95 using image analysis software. Data such as microglia displacement length, process speed, and contact with postsynaptic puncta can then be extracted from these surfaces to understand microglia behavior both in homeostatic states and after neuronal injury. This protocol can be useful in examining the role of microglia in synaptic pruning in retinal neurodegenerative diseases.
    DOI:  https://doi.org/10.3791/68420
  50. J Cell Mol Med. 2026 Feb;30(3): e71045
    Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.
    Madeeha Shahzad Lodhi, Muhammad Maisam, Muhammad Tahir Khan, Amina Bibi, Dongqing Wei, Kejie Mou.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood-brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%-90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.
    Keywords:  Alzheimer's disease; WGX50; curcumin; gold nanoparticles; insulin; miRNA‐146a‐5p; targeted drug delivery
    DOI:  https://doi.org/10.1111/jcmm.71045
  51. Int J Psychoanal. 2025 Dec;106(6): 1211-1219
    On Francis Pasche's (1993) text "From the ambivalent superego to the impersonal superego": A brief introduction or Towards an impersonal and loving superego.
    Nathalie Zilkha.
      This paper revisits Francis Pasche's 1993 seminal essay From the Ambivalent Superego to the Impersonal Superego. Particular emphasis is given to Pasche's view on the specific verticality in the relation between the ego and superego, and on its evolution. Pasche conceptualises the transformation of this relation from primary admiration and idealization towards an impersonal superego, which he describes as apophatic - defined by what it is not. In doing so, Pasche outlines an ethical horizon that is central to his conception of psychoanalysis, and more specifically of the analyst's inner stance. These ideas are discussed more precisely in reference to some of his other papers. Beyond Pasche's concepts, further reflection is given to the relationship between the ego and the superego and to the way it evolves, notably through processes of de-identification.
    Keywords:  Francis Pasche; ego-superego relations; psychoanalytic ethic
    DOI:  https://doi.org/10.1080/00207578.2025.2577100
  52. Front Pharmacol. 2025 ;16 1737199
    Glutathione and neurodegenerative diseases: immunopharmacological implications.
    Ethan Knudsen, Jaxson Tadje, Carter Coggins, Vishwanath Venketaraman.
      Neurodegenerative diseases are characterized by progressive neuronal dysfunction, often accompanied by chronic inflammatory states and redox imbalance within the central nervous system (CNS). Glutathione (GSH), a key regulator of oxidative stress and cellular immunity, has a critical role in modulating the functional states of CNS-resident and infiltrating immune cell subsets. This review aims to synthesize emerging evidence on how GSH depletion contributes to impaired immune and antioxidant activity in neurodegenerative diseases, such as Parkinson's Disease (PD), Alzheimer's Disease (AD), and multiple sclerosis (MS). By exploring how redox signaling via GSH influences inflammatory immune phenotypes across different disease states, we will isolate possible therapeutic interventions for treatment of these conditions. By characterizing GSH's function and designating it as a special regulator of immune cell behavior, this review highlights its potential as both a therapeutic agent and biomarker for patients with neurodegenerative conditions.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; glutathione; multiple sclerosis; redox imbalance
    DOI:  https://doi.org/10.3389/fphar.2025.1737199
  53. Autism Adulthood. 2025 Nov;7(6): 724-738
    Empathic Disequilibrium as a Predictor of Nonsuicidal Self-Injury in Autistic and Nonautistic People.
    Rachel Moseley, Ido Shalev, Nicola Gregory, Florina Uzefovsky.
       Background: Nonsuicidal self-injury (NSSI) affects many autistic individuals, and has been linked to suicidality in this group. It has been closely linked to difficulties with intrapersonal emotion regulation, but a role of interpersonal emotion regulation processes in NSSI has been underexplored. Empathic disequilibrium is a state of imbalance between a person's cognitive empathy (CE) and emotional empathy (EE). We recently found that autistic people exhibit heightened EE relative to CE, consistent with their firsthand reports of hypersensitivity to the emotions of others. Because this kind of empathic imbalance is associated with hyperarousal and emotional reactivity, we hypothesized that it might increase the risk of NSSI, which often occurs as a means of trying to regulate overwhelming or distressing emotions.
    Methods: We measured CE, EE, emotional reactivity, and NSSI behaviors in 304 autistic and 289 nonautistic participants, and used polynomial regression with response surface analysis to examine empathic disequilibrium as a predictor of emotional reactivity and engagement in NSSI.
    Results: Replicating previous research, individuals with an autism diagnosis were more likely to show a pattern of EE-dominance (OR = 4.51 [2.66, 7.63], p < 0.001), although they did not differ significantly in overall empathy levels. While empathic disequilibrium was associated with NSSI in autistic and nonautistic people, the nature of these pathways differed between groups. In autistic people, empathic disequilibrium toward EE-dominance was associated with a higher incidence of NSSI through emotional reactivity. In contrast, for nonautistic individuals, the incidence of NSSI was associated with overall empathy and, when accounting for emotional reactivity, with empathic disequilibrium toward CE dominance.
    Conclusions: While future studies should investigate the direction of relationships with longitudinal designs, these findings highlight different mechanisms for NSSI in autistic and nonautistic people. They corroborate growing evidence that the relative imbalance between empathic abilities may be relevant for meaningful outcomes, such as psychopathology.
    Keywords:  NSSI; empathic disequilibrium; empathy; self-harm; self-injury
    DOI:  https://doi.org/10.1089/aut.2023.0134
  54. bioRxiv. 2026 Jan 25. pii: 2026.01.25.701582. [Epub ahead of print]
    Enterovirus D68 VP1 and VP3 determine neurotropism in human spinal cord organoids.
    Jessica E Packard, Jennifer E Jones, Gal Yovel, Megan Culler Freeman.
      Enterovirus D68 (EV-D68) is a non-polio enterovirus that can cause a polio-like paralysis condition, acute flaccid myelitis (AFM). EV-D68 associated AFM cases waned in the US after 2018 and the reasons for this are unknown. It has recently been demonstrated that EV-D68 containing point mutations in viral structural proteins VP1 and VP3 resulted in decreased paralysis in different neonatal mouse models. However, phenotypes of these mutations in a human multicellular central nervous system (CNS) model are unknown. We hypothesized that mutations in VP1 and VP3 will similarly direct neurotropism in human spinal cord organoids (hSCO). To investigate this, we recreated viruses with mutations in VP3 (I88V) or VP1 (L1I/N2D/T98A/E283K or L1P/V148A/K282R) and infected hSCOs. We found that VP3 I88V and VP1 L1I/N2D/T98A/E283K resulted in decreased titer and viral protein staining, consistent with attenuated neurovirulence in previously published murine models. When these mutations were combined, their effects on neurotropism were not additive. Sequence analysis of recently circulating EV-D68 strains reveals that VP3 I88 and VP1 E283 have remained the dominant amino acid residues since 2014, whereas VP1 sites 1, 2, and 98 have higher population diversity, indicating that these residues may be contributing to newly reduced neurovirulence after 2018.
    DOI:  https://doi.org/10.64898/2026.01.25.701582
  55. Genes Dis. 2026 May;13(3): 101937
    Roles of efferocytosis in wound repair: Process, cells, and signals.
    Yilin Sun, Haiying Guo, Yang Bai, Jin Chen, Yuhong Li.
      Efficient clearance of apoptotic cells, termed efferocytosis, is essential for resolving excessive inflammation, promoting wound repair, and maintaining homeostasis. Defective clearance results in the accumulation of dead cells and other metabolites, which are responsible for chronic inflammation, nonhealing of wounds, and tissue regeneration. Emerging evidence shows that the failure to resolve inflammation and defective phagocytosis or efferocytosis increases the possibility of several diseases involving diabetic wounds and damage to the gastrointestinal mucosa in patients with inflammatory bowel disease, which is a focus of medical development and the public eye. Thus, gaining deeper insight into the molecular and cellular mechanisms of efferocytosis may be useful for inflammation resolution. This review describes the mechanism of efferocytosis and wound repair and the roles of professionals (macrophages and dendritic cells) and amateur phagocytes (e.g., epithelial cells, endothelial cells, and fibroblasts) in both processes, which may provide insight into how efferocytosis affects wound repair. Because there may be many inflammatory cells recruited to the injury area, the aim of efferocytosis is to clear these cells and release proinflammatory and anti-inflammatory mediators to promote repair. Here, we review the effects of cell-mediated efferocytosis on the timely efferocytosis of neutrophils and M1 macrophages and the relationship between M2 polarization and efferocytosis. In addition, the molecular mechanisms involved are discussed, which may further our understanding of the effects of efferocytosis. Finally, these signals also provide potential targets for tissue repair intervention.
    Keywords:  Cells; Efferocytosis; Inflammation; Signals; Wound repair
    DOI:  https://doi.org/10.1016/j.gendis.2025.101937
  56. Muscle Nerve. 2026 Feb;73 Suppl 1 S19-S22
    Study 19 (MCI186-19) Post Hoc Analyses.
    Benjamin Rix Brooks, Jeremy Shefner, Stephen Apple.
      While randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of therapies in amyotrophic lateral sclerosis (ALS), post hoc analyses can provide critical insights into clinical effectiveness, treatment durability, and subpopulation responses. Several post hoc analyses of Study MCI186-19 (Study 19), the pivotal phase 3 RCT that supported the United States Food and Drug Administration approval of intravenous edaravone, have been performed to explore the broader clinical impact of this therapy. These analyses assessed the long-term treatment efficacy, changes in individual ALS Functional Rating Scale-Revised item scores, survival and additional milestone events, and the impact of edaravone in patient subgroups defined by disease progression trajectories using latent class analysis. Collectively, these findings reinforce the long-term clinical benefit of edaravone and demonstrate that edaravone may offer benefits across a spectrum of ALS disease trajectories, beyond those defined in the original study criteria. These studies help address questions not captured in the original RCT and may inform future trial design and treatment decisions.
    Keywords:  ALS; Study 19; amyotrophic lateral sclerosis; clinical; edaravone; efficacy; post hoc
    DOI:  https://doi.org/10.1002/mus.70039
  57. Res Sq. 2026 Jan 20. pii: rs.3.rs-8628264. [Epub ahead of print]
    Parkinson's and Alzheimer's disease impairs temporal precision.
    Matthew A Weber, Christopher M Hunter, Nandakumar S Narayanan.
      Several studies have reported temporal processing deficits in neurodegenerative diseases such as Parkinson's and Alzheimer's disease. These deficits can be quantified by interval timing paradigms that require participants to estimate or produce an interval of several seconds and require working memory for temporal rules as well as attention to time. Timing performance can be quantified by a variety of measures; however, two relatively universal metrics include: 1) temporal accuracy, defined as the mean temporal estimate and 2) temporal precision, reflected by the variability of temporal estimates. We examined temporal accuracy and precision in a meta-analysis of 14 studies in patients with Parkinson's disease and 10 studies in patients with Alzheimer's disease. Strikingly, in both diseases, temporal precision was reliably impaired across studies, while temporal accuracy was not. Our meta-analysis suggests that despite the diversity of interval timing paradigms and the complexity of Parkinson's and Alzheimer's disease, temporal precision is consistently impaired in these diseases. These results advance interval timing as a reliable assay to study cognitive dysfunction in Parkinson's and Alzheimer's disease and may extend to other neurological and psychiatric disorders.
    DOI:  https://doi.org/10.21203/rs.3.rs-8628264/v1
  58. BMC Biol. 2026 Feb 06.
    FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.
    Donovan W McDonald, Nikita Chugh, Rares Sava, Martin L Duennwald.
       BACKGROUND: Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models.
    RESULTS: Using optimized low-expression FUS and TDP-43 yeast models, we demonstrate that chronological ageing antagonizes proteostasis, the steady state levels and solubility of molecular chaperones, and aggregation of FUS and TDP-43. In addition, mistranslation caused by tRNA variants further antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity.
    CONCLUSIONS: Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.
    Keywords:  ALS; Ageing; FUS; Mistranslation; Mitochondria; Molecular chaperone; Protein aggregation; Protein misfolding; TDP-43
    DOI:  https://doi.org/10.1186/s12915-026-02537-3
  59. Curr Pharm Biotechnol. 2026 Jan 29.
    2024 Year-in-Review: Scientific Highlights from Current Pharmaceutical Biotechnology.
    Nikolaos E Labrou.
      This 2024 year-in-review article provides a comprehensive overview of the most cited articles published in Current Pharmaceutical Biotechnology (CPB) during the year across six key thematic areas: cancer, nanotechnology, antimicrobial agents, drug delivery, neurodegenerative diseases, and herbal and natural products. A total of twenty-nine high-impact studies have been selected and examined, each contributing meaningful advancements to the respective fields. The review highlights the application of phytochemicals in oncology, the versatility of nanomaterials in targeted therapies, innovations in antimicrobial strategies against resistant pathogens, intelligent drug delivery platforms, novel therapeutic approaches for neurodegenerative disorders, and the evolving role of botanicals in modern biopharmaceuticals. Through a narrative synthesis, the review illustrates how CPB has served as a vital platform for translational research, bridging molecular science and clinical innovation.
    Keywords:  Cancer; antimicrobial agents; drug delivery; herbal natural products.; nanotechnology; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/0113892010429526251026152322
  60. PLoS Genet. 2026 Feb 02. 22(2): e1012033
    The regenerative period of somatosensory nerves is closed by a DCC signaling axis.
    Jacob Hammer, Cody J Smith.
      Tissues and organs have periods of plasticity that close with age. While period closures can lock in tissue architecture and prevent aberrant cellular interactions, they also limit regenerative capacity. These regenerative periods - a timeframe with regeneration capacity - are defined, but the underlying genetic mechanisms that close specific regenerative periods remains critical knowledge that needs expanding. Here, we established zebrafish larvae as a model to study the genetic basis of regenerative period closure. We demonstrated that laser axotomy of the centrally-projecting axons of dorsal root ganglia (DRG) neurons exhibit a robust regenerative period that is closed by 3 days post fertilization (dpf). The closure of the regenerative period corresponds with the rearrangement of glia that express netrin, introducing the idea that changes in the DCC-mediated signaling axis could be a genetic and molecular basis closing the regenerative period. To test this hypothesis, we manipulated dcc, cAMP, and Rac1 in transgenic animals that label axons and the actin cytoskeleton. Combined with genetic epistasis analysis, we show that altering DCC signaling can re-open the regenerative period, allowing severed axons to regrow into the spinal cord. We show that this increased capacity to reinvade the spinal cord is mediated by growth cone invadopodia. Using calcium reporters and behavioral analysis, we demonstrate that re-opening the regenerative period by manipulating the DCC signaling axis restores the sensory circuit and sensory-specific behaviors. By introducing this genetic basis for regenerative period closure, these results reveal an active suppression process that keeps regenerative periods closed and establishes a new model for future dissection of such periods.
    DOI:  https://doi.org/10.1371/journal.pgen.1012033
  61. Int J Psychoanal. 2025 Dec;106(6): 1127-1145
    Sensoriality and thought. In development and in psychopathology.
    Franco De Masi, Gabriella Giustino.
      This paper addresses certain aspects of the role of sensoriality in psychic functioning and, in particular, seeks to compare child sensoriality - a natural component of development that precedes the ability to think - and the perceptual-sensorial distortion that occurs in certain pathological conditions. In the course of severe psychic disorders such as psychosis, and in other respects in post-traumatic conditions, the mind is invaded by sensorial perceptions that block its functioning as an organ of knowledge. In the case of trauma, the intrusive mental phenomena are more limited and related to untransformed traumatic anxiety. Instead, the psychotic transformation of the mind is most radical; it develops into psychic retreat that shatters the ability to think and perceive psychic reality. In this instance, the mind's sensorial mode of functioning is so extreme that these patients are immersed in a newly created sensorial reality; they do not think but rather see their own thoughts or perceive sounds or voices that do not exist.
    Keywords:  Sensoriality; development; trauma
    DOI:  https://doi.org/10.1080/00207578.2025.2518086
  62. Neuroscience. 2026 Jan 29. pii: S0306-4522(26)00076-X. [Epub ahead of print]598 19-28
    Nose-to-brain axis: mechanistic links between nasal microbiome dysbiosis, neuroinflammation, and brain disorders.
    Khiany Mathias, Fabricia Petronilho, Lucineia Gainski Danielski.
      The nasal microbiome has emerged as a previously underrecognized modulator of neuroinflammation and central nervous system (CNS) homeostasis. Beyond its role in respiratory host defense, this microbial niche is anatomically positioned to directly influence brain physiology through olfactory neuronal pathways, systemic immune signaling, and inter-organ communication within the gut-lung-brain axis. Accumulating evidence indicates that nasal microbiome dysbiosis contributes to blood-brain barrier (BBB) dysfunction, microglial activation, and propagation of neurotoxic protein aggregates, processes implicated in neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and major depressive disorder. This review synthesizes experimental and clinical studies elucidating key mechanisms by which nasal microbial imbalance may impact CNS pathology, including microbial translocation along olfactory neurons, release of pathogen-associated molecular patterns and inflammatory mediators, extracellular vesicle-mediated signaling, and peripheral immune crosstalk. We further highlight clinical observations linking nasal microbiome signatures with olfactory dysfunction, cognitive decline, and altered inflammatory profiles, particularly in systemic conditions such as sepsis. Despite rapid advances in this field, significant knowledge gaps persist, including the limited availability of longitudinal human cohorts capable of establishing causality, incomplete mechanistic validation in translational models, and insufficient characterization of how environmental exposures and aging reshape the nasal microbiome-brain interface. By integrating current evidence and defining these unmet needs, this review positions the nasal microbiome as a promising source of diagnostic biomarkers and a therapeutic target for modulating neuroinflammation and mitigating neurodegenerative progression.
    Keywords:  Human nasal microbiome; Neurodegeneration; Neuroinflammation; Psychiatric diseases
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.01.039
  63. Langmuir. 2026 Feb 02.
    Effect of Pressure on Liquid-Phase Adsorption on a Solid Surface.
    Maria Incoronata Sciancalepore, Stuart M Clarke, Philip J Camp.
      The effect of pressure on gas-phase adsorption on a solid surface has been well-known since the time of Irving Langmuir, but the situation is less clear for the adsorption of a solute from a liquid solution at high pressure. This could be important in solutions of surface-active molecules for applications under high pressure, such as lubricants in engines, motors, and wind turbines in which gigapascal pressures are possible, and the adsorption of additives on moving parts or dispersed particles is linked to performance. Pressure affects the chemical potentials of the solute and solvent in both the liquid solution and the adsorbed layer. Inspired by a recent experimental study [Sharifi, N.; J. Phys. Chem. B 2023, 127, 5141-5149], the effect on liquid-solution thermodynamics is explored, and it is shown that the volume of mixing of the solution, and its gradient with respect to the solute mole fraction, strongly influence whether adsorption increases or decreases with an increase in pressure. Dilute solutions with positive (negative) volumes of mixing show increased (decreased) adsorption. Concrete predictions are made using a Langmuir-type model expressed as surface coverage as a function of solute mole fraction. Key thermodynamic relationships are illustrated with molecular-dynamics simulations of a simple model of nonideal solutions, and numerical estimates of the pressure effect are given. Finally, volume-of-mixing data for real solutions are analyzed, and it is shown that gigapascal pressures are enough to change the adsorption constant by at least an order of magnitude.
    DOI:  https://doi.org/10.1021/acs.langmuir.5c06132
  64. Avicenna J Phytomed. 2026 ;16(1): 122-129
    Study of Royal Jelly effect on serum levels of IL-4, TNF- α, TGF-B, and IFN-γ in multiple sclerosis patients in comparison with Omega-3; A double-blind, randomized, clinical trial.
    Nastaran Majdinasab, Ali Aghaei, Amir Siahpoosh, Rezvan Motamedi, Seyed Ahmad Hosseini, Alireza Malayeri.
       Objective: Multiple sclerosis (MS) is a debilitating disorder related to damage to the central nervous system (CNS). MS incidence in about 2.3 million people worldwide. Royal jelly (RJ) is a white material with many medicinal properties. Omega-3 (ω-3) is a natural substance that its beneficial effects were demonstrated in several studies performed on MS patients.
    Materials and Methods: 60 patients referring to the MS Society of Iran were randomly divided into two groups (1:1 ratio) receiving 1-gram RJ and 1-gram ω-3 capsule 1 gr capsules of RJ and 1 gr ω-3 daily in addition to receiving their daily treatment. Then, their information was recorded. Blood samples of all subjects were collected to evaluate the level of IL-4, INF-Y, TGF-B, and TNF-α with Enzyme-linked immunosorbent assay (ELISA) method twice; first, before the intervention and then, received supplements for one month. The duration of treatment was one month, and the patients returned to the center.
    Results: The results indicated that RJ, similar to ω-3, could improve the cytokines levels in MS patients. RJ significantly improved TNF-α (p<0.05), and ω-3 significantly decreased TGF-β levels (p<0.05). Both decreased IFN-γ and increased IL-4, but it was more in the group receiving RJ.
    Conclusion: According to the findings, it is hoped that using RJ and ω-3 could be helpful in MS patients.
    Keywords:  IFN-γ; IL-4; Multiple sclerosis; Omega 3; Royal Jelly; TGF-β; TNF- α
    DOI:  https://doi.org/10.22038/ajp.2025.26210
  65. IEEE Trans Pattern Anal Mach Intell. 2026 Feb 03. PP
    Searching to Modulate for Cold-Start Recommendation.
    Shiguang Wu, Yaqing Wang, Quanming Yao.
      Making personalized recommendation for cold-start users, who only have a few interaction histories, is a challenging problem in recommendation systems. Recent works leverage hypernetworks to directly map interaction histories to user-specific parameters, which are then used to modulate predictor by certain modulation structure. These works obtain the state-of-the-art performance. However, there lacks a general approach to design the modulation structure. Instead of using a fixed modulation function and deciding modulation position by expertise, we propose to determine proper modulation structure, including function and position, via neural architecture search. We propose two approaches. We first design a symbolic search space which covers broad models and theoretically prove that this search space can be transformed to a much smaller space, enabling an efficient and robust one-shot search algorithm, called ColdNAS. Since recommendation systems are a special case of bipartite matching problems, the proposed methods can be generalized to a wide range of cold-start tasks, such as disease-gene association prediction for emerging diseases. However, diverse scenarios introduce new challenges in both the flexibility of the search algorithm and the search space. To address these limitations, we further propose ColdNAS$_+$, where we employ neural networks to model modulation functions to extend search space and design a two-stage decoupled stochastic search algorithm to enable non-differentiable targets in continuous spaces. Extensive experimental results on benchmark datasets show that modulation structures obtained by ColdNAS and ColdNAS$_+$ consistently outperform hand-designed cold-start techniques for recommending items for new users and predicting associated genes for new disease. We observe that different modulation functions lead to the best performance on different datasets or under different metrics, which validates the necessity of designing the modulation structure in a data-driven way.
    DOI:  https://doi.org/10.1109/TPAMI.2026.3653806
  66. PLoS Biol. 2026 Jan;24(1): e3003627
    A gut-activated NHR-86-CYP pathway mediates the neuroprotective effects of Enterococcus faecium probiotics in a nematode model of amyotrophic lateral sclerosis.
    Yu Sang, Jie Ren, Alejandro Aballay.
      Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen species (ROS) levels. We identified the conserved nuclear hormone receptor NHR-86 as a key regulator of cyp gene expression and neuroprotection. Loss of nhr-86 abolished the probiotic's protective benefits, while transgenic expression of nhr-86 restored cyp induction and neuronal resilience. Importantly, intestinal expression of NHR-86 was sufficient to restore CYP induction and neuronal resilience, whereas neuronal knockdown had no effect, indicating that gut NHR-86 activity is essential for this protective pathway. These findings reveal a previously uncharacterized NHR-CYP regulatory axis activated by an intestinal probiotic, highlighting a mechanistic link between microbial signals and host neuroprotection.
    DOI:  https://doi.org/10.1371/journal.pbio.3003627
  67. Phytomedicine. 2026 Jan 20. pii: S0944-7113(26)00096-6. [Epub ahead of print]152 157856
    Panax notoginseng saponins ameliorate spinal cord injury by inhibiting JAK2/STAT3-mediated macrophage polarization: Enhanced delivery by ultrasound-targeted microbubble destruction.
    Yin Shi, Xuelian Chen, Shu Luo, Anjie Chen, Keyu Xie, Miao Fang, Jiaojiao Zhou.
       BACKGROUND: Spinal cord injury (SCI) causes abnormal macrophage polarization, worsening inflammation and neuronal apoptosis, with current therapies showing limited efficacy. Panax Notoginseng Saponins (PNS) has anti-inflammatory and neuroprotective potential but is limited by low bioavailability. Ultrasound-targeted microbubble destruction (UTMD) can open the blood-spinal cord barrier to improve drug delivery.
    AIM: To clarify the role of PNS and molecular mechanisms in regulating macrophage polarization for SCI and explore the effect of UTMD on enhancing PNS efficacy.
    METHODS: RAW264.7 macrophages and rat SCI models were used. Flow cytometry, RT-qPCR, Western blotting (WB), TUNEL staining, BBB scoring, and MRI were applied to detect polarization markers, JAK2/STAT3 pathway proteins, neuronal apoptosis, and neurological recovery.
    RESULTS: PNS dose-dependently promoted macrophage M2 polarization, inhibited the JAK2/STAT3 pathway, and reduced neuronal apoptosis. These effects were enhanced by the JAK2/STAT3 inhibitor AG490, while PNS also antagonized the pro-apoptotic action of the pathway activator colivelin. UTMD strengthened PNS's effects in vitro. In rats, compared with the SCI-only group, the SCI+PNS group already showed therapeutic effects, with improved BBB scores, less M1 infiltration, suppressed JAK2/STAT3, and reduced apoptosis and cyst areas. Notably, the SCI+UTMD+PNS group exhibited even more pronounced improvements in these aspects and superior efficacy to both the SCI and SCI+PNS groups.
    CONCLUSION: PNS inhibits JAK2/STAT3 to promote M2 polarization and reduce apoptosis. UTMD amplifies PNS's efficacy, providing a novel SCI therapy strategy.
    Keywords:  Blood-spinal cord barrier; JAK2/STAT3; Macrophage polarization; Panax notoginseng saponins; Spinal cord injury; Ultrasound-targeted microbubble destruction
    DOI:  https://doi.org/10.1016/j.phymed.2026.157856
  68. Biochemistry. 2026 Feb 04.
    Explainable Artificial Intelligence to Decode the Blood-Brain Barrier Permeability of Gut Microbial Metabolites.
    Chunyi Yang, Lan Yang, Yuyang Song, Mengxuan Du, Zhenyu Ma, Yuwen Xu, Min Xiao, Chang Liu, Xukai Jiang.
      Modulation of the nervous system by gut microbiota through metabolic pathways is a key mechanism of communication within the gut-brain axis. A critical factor determining whether gut microbial metabolites can exert functional effects in the brain is their ability to cross the blood-brain barrier (BBB). However, current methods for assessing BBB permeability lack systematic, standardized approaches and advanced predictive technologies. Traditional experimental techniques are often costly and time-consuming compared to computational methods. To address these limitations, we developed an automated molecular simulation workflow to generate a high-quality data set of gut microbial metabolites annotated with thermodynamic features related to BBB permeability. Based on this data set, we constructed an interpretable thermodynamic evaluation framework capable of accurately identifying key factors that influence transmembrane transport. The robustness and predictive power of our models were validated using two authoritative benchmark data sets, confirming their ability to reliably distinguish BBB-permeable from nonpermeable compounds. Furthermore, our findings highlight the substantial potential of gut microbiota metabolism to influence BBB permeability via metabolic pathways. Overall, this study provides a powerful tool for identifying gut microbiota-derived metabolites with potential biological activity in the brain and introduces a novel paradigm for the intelligent prediction of BBB permeability.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00647
  69. Psychopathology. 2026 Feb 02. 1-16
    Elements for a Phenomenology of Cultures: Cultural Existentials and the Dialectical Experiential Matrix.
    Riccardo Poggioli, Giovanni Stanghellini.
      This paper proposes a critical expansion of phenomenological psychopathology of the individual to explicitly integrate the collective dimension. In order to accurately describe the scenario of collective life, and its relationship with the psychology and psychopathology of individual existences, we propose two moves: (1) A shift of focus from society (which denotes an organized aggregate of individuals) to culture (a transversal symbolic system, capable of extending beyond the boundaries of the original social group), since in the context of advanced globalization the conception of stable social aggregates has been replaced by models of fluid and changing "cultural flows". (2) To phenomenologically describe these cultural flows that traverse the contemporary world, we introduce the concept of "cultural existentials" (time, space, body, and others) as a priori conditions of experience derived from the analysis of the fundamental structures of individual lifeworlds, as employed in phenomenology. These cultural existentials are integrated into a Dialectical Experiential Matrix (DEM), designed to overcome the reductionism of both structuralism and subjectivist individualism. The DEM frames the patient's experience as a dynamic interplay between individual freedom (the capacity for self-positioning) and cultural influence. An illustrative application analyzing the convergence between "pornographic culture" and the "homo œconomicus" anthropological type is provided to demonstrate how cultural existentials offer a collective model for specific narcissistic vulnerabilities and dysregulations of alterity, providing a crucial diagnostic device for the clinician.
    DOI:  https://doi.org/10.1159/000550835
  70. Muscle Nerve. 2026 Feb;73 Suppl 1 S26-S28
    Current and Ongoing Clinical Studies.
    Agessandro Abrahao, Lorne Zinman, Stephen Apple.
      This article provides a comprehensive overview of current and ongoing studies evaluating intravenous (IV) edaravone and edaravone oral suspension in the treatment of amyotrophic lateral sclerosis (ALS). In addition to data from clinical practice and post hoc analyses, multiple observational and interventional studies are underway to better understand the efficacy, safety, and biological impact of edaravone in clinical settings. Key studies include SUNRISE Japan, a long-term postmarketing surveillance study of IV edaravone in Japanese patients with ALS; the ALS/Motor Neuron Disease Natural History Study, a longitudinal registry designed to inform clinical trial design and track ALS progression; and the REFINE-ALS study, which is actively collecting biomarker data to elucidate the pathophysiologic mechanisms influenced by edaravone. For edaravone oral suspension, United States Food and Drug Administration approval was supported by Study MT-1186-A01, a phase 3 trial assessing safety and tolerability over 48 weeks, with extension Study MT-1186-A03. Study MT-1186-A02, conducted as an FDA postmarketing commitment, and its extension, Study MT-1186-A04, evaluated whether investigational once daily dosing showed superior efficacy vs. the approved on/off dosing regimen. Collectively, these studies contribute to a growing body of evidence supporting the use of edaravone as a therapeutic option for ALS. They also underscore the importance of continued data collection from both clinical trials and clinical settings to inform optimal treatment strategies and combination therapy approaches as more agents become available in an evolving ALS treatment landscape.
    Keywords:  ALS; amyotrophic lateral sclerosis; clinical; clinical trials; edaravone
    DOI:  https://doi.org/10.1002/mus.70040
  71. Muscle Nerve. 2026 Feb;73 Suppl 1 S16-S18
    Generalizability of Edaravone Efficacy.
    Benjamin Rix Brooks, David L Ennist, Danielle Beaulieu, Stephen Apple.
      The pivotal phase 3 trial MCI186-19 (Study 19) demonstrated the efficacy of intravenous edaravone in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS), leading to United States Food and Drug Administration approval. Study 19 utilized a targeted enrollment enrichment strategy based on post hoc analyses from earlier trials, selecting patients with higher baseline function, more rapid disease progression, and better respiratory status. To evaluate the generalizability of Study 19 results, subsequent post hoc analyses assessed the efficacy of edaravone in broader ALS populations. One machine learning-based analysis retrospectively applied a validated model to Study 16 data, stratifying patients by predicted risk of respiratory decline. This detectable effect cluster analysis suggested that up to 70% of Study 16 participants may have benefited from edaravone. A second analysis investigated edaravone efficacy in patients from Study 19 with forced vital capacity (FVC) < 80% predicted (%p) at the start of treatment, since FVC ≥ 80%p was one of the Study 19 inclusion criteria. Both high- and low-FVC subgroups demonstrated reduced ALS functional rating scale-revised decline at 48 weeks when treated continuously with edaravone. These findings support the potential benefit of edaravone in a wider range of patients with ALS than those enrolled in Study 19, providing important insights into how clinical trial enrichment strategies may influence perceived efficacy, and underscoring the need for future prospective studies in more diverse ALS populations.
    Keywords:  Study 19; amyotrophic lateral sclerosis; edaravone; efficacy; respiratory function
    DOI:  https://doi.org/10.1002/mus.70042
  72. bioRxiv. 2026 Jan 25. pii: 2026.01.23.701173. [Epub ahead of print]
    IGF-like growth factors that couple food sensing to developmental decisions employ different release mechanisms in a single pair of C. elegans chemosensory neurons.
    Julia M Perhacs, Lauren Klabonski, Mingjie Ying, Yair Argon, Tali Gidalevitz.
      Sensory neurons modulate organismal physiology and behavior in part by releasing neuropeptides and neurotrophins or growth factors, via the dense core vesicle (DCV) pathway. The precise matching of the sensory input to the identity of released vesicle cargo, and the timing and location of its release, is necessary to ensure appropriate responses. In some neurons, several neuropeptides or growth factors can be co-produced simultaneously, but found in distinct populations of vesicles. While this may permit their release independently of each other, in response to different stimuli, the responsible molecular pathways are not well understood. In C. elegans , the chemosensory ASI neuron pair expresses multiple neuropeptides and growth factors, including the structurally homologous C. elegans IGF-like growth factors DAF-28, INS-6, and INS-4, whose release in young larvae couples food sensing to the commitment to reproductive development. We find that these growth factors require separate molecular pathways for their release. While the axonal release of INS-6 protein required the Calcium-dependent Activator Protein for Secretion (CAPS/UNC-31), the release of DAF-28 was CAPS-independent. Consequently, the function of endogenous daf-28 , but not that of ins-6 and ins-4 , is independent of unc-31 . This difference is unexpected, as CAPS/UNC-31 is thought to control the regulated pre-synaptic/axonal release of DCV cargoes in C. elegans neurons, and demonstrates a divergence in vesicle release mechanisms. In addition, we find that mechanisms for delivering vesicles to the axons are also divergent: while neuropeptide NLP-21 was dependent on the clathrin adaptor AP-3 for its selective localization to axons, four insulin/IGF-like growth factors tested - DAF-28, INS-6, INS-4, and INS-22, were AP-3-independent for either axonal localization or function. Our data uncover molecular divergence in the pathways controlling axonal localization and release of neuropeptides and growth factors, including in a single neuron. These divergent vesicle pathways provide new means for the immediate and tunable changes in neuronal outputs, in addition to the known, less immediate mechanism of differential transcriptional regulation of DCV cargoes. Future delineation of the molecular composition of these pathways is necessary to understand how neurons match organismal responses to specific sensory inputs.
    DOI:  https://doi.org/10.64898/2026.01.23.701173
  73. Biophys J. 2026 Jan 30. pii: S0006-3495(26)00087-1. [Epub ahead of print]
    Relationship between perturbation specificity and functional dispensability in yeast phosphoproteome.
    Yilun Han, Yu Xia.
      Protein phosphorylation is crucial in many cellular functions. Although the existence of functionally dispensable phosphosites is well recognized, previous estimation of dispensable content in the phosphoproteome has not quantitatively assessed how functional dispensability of a phosphosite is related to the degree of its perturbation specificity, i.e., the number of environmental perturbations where the phosphosite is phosphorylated. Here, we address this question by integrating a high-quality, perturbation-specific yeast phosphoproteome with site-specific evolutionary rate relative to adjacent residues of the site in the protein sequence (denoted "relative evolutionary rate"), a proxy for functional dispensability. We observe extreme heterogeneity in perturbation specificity among phosphosites, where the majority of phosphosites are phosphorylated either under only a few perturbations (denoted "conditional phosphosites") or across nearly all perturbations (denoted "near-universal phosphosites"), yielding a bimodal distribution of perturbation specificity. Our evolutionary analyses reveal that, in disordered regions, perturbation specificity is a key correlate of functional dispensability of phosphosites. Conditional and near-universal phosphosites exhibit significantly higher and lower average relative evolutionary rate than all other experimental and literature-curated phosphoproteome datasets considered, respectively. These trends remain robust even when residue burial is controlled, suggesting that conditional and near-universal phosphosites contain the highest and the lowest levels of dispensable content in disordered regions respectively among all phosphoproteome datasets considered. Using the near-universal phosphosites and serine/threonine sites not known to be phosphorylated to set the lower and upper bounds of the dispensable content spectrum, we estimate that ∼30%-40% of phosphosites in disordered regions of the yeast phosphoproteome are functionally dispensable.
    DOI:  https://doi.org/10.1016/j.bpj.2026.01.055
  74. Probl Endokrinol (Mosk). 2026 Jan 28. 71(5): 100-109
    [Neuroendocrine regulation of the reproductive system: integration of research of neuropeptide and experimental pathophysiology of amenorrhea of different genesis (literature review)].
    Y S Evseeva, Y S Absatarova, E N Andreeva, V A Ioutsi, S A Roumiantsev, E V Sheremetyeva, O R Grigoryan, G A Melnichenko.
      Neuroendocrine regulation of reproductive function represents a complex system based on the integration of signals between the central nervous system and peripheral organs. In recent years, particular attention has been given to the role of neuropeptides - such as kisspeptin, brain-derived neurotrophic factor (BDNF), and orexins - in the pathogenesis of disorders associated with menstrual irregularities. This review provides a detailed analysis of the molecular mechanisms underlying neuropeptide regulation in functional hypothalamic amenorrhea (FHA), primary ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS).Recent experimental studies are summarized, including stress-induced models of persistent estrous cycle arrest in laboratory animals and simulation of PCOS and POI using dietary and pharmacological interventions, respectively. Additionally, the review highlights publications demonstrating the significant role of impaired neuropeptide signaling in the development of reproductive disorders in women.The integration of fundamental research with clinical practice not only enhances our understanding of the pathophysiology of amenorrhea but also opens promising avenues for the development of novel therapeutic strategies, such as the use of kisspeptin agonists or other agents aimed at restoring reproductive function in women with various forms of menstrual dysfunction.
    DOI:  https://doi.org/10.14341/probl13641
  75. Front Immunol. 2025 ;16 1657131
    Macrophage-targeted PEGylated liposomes ameliorate experimental autoimmune encephalomyelitis.
    Alexander Muselman, Lewis W Yu, Khoa D Nguyen, Mohammed Inayathullah, Qiang Liu, Kyle D Brewer, Andrey V Malkovskiy, Jayakumar Rajadas, Edgar G Engleman.
      Macrophages are the predominant immune cell type found in active multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) lesions, where they contribute to demyelination and axonal damage. Depending on the lesion stage, these cells can exhibit either a pro-inflammatory or neurotoxic phenotype that drives central nervous system (CNS) injury or an anti-inflammatory phenotype that promotes remyelination. Therefore, strategies that modulate macrophage function may offer therapeutic benefits for MS. Polyethylene glycol (PEG) has shown anti-inflammatory and neuroprotective effects in various models of inflammation and neurodegeneration, but the mechanisms involved remain poorly understood. In this study, we investigated the potential of PEG and PEG-based delivery systems to modulate EAE. Although PEG alone did not alter EAE progression, it suppressed the pro-inflammatory phenotype of macrophages in vitro. Given the clinical potential and macrophage-targeting properties of larger PEGylated liposomes, we assessed the impact of large (~700 nm) PEGylated liposomes in EAE. These liposomes selectively targeted activated, CNS-infiltrating macrophages and, when administered to mice either before or after neurological manifestations of EAE had developed, they significantly reduced both clinical signs as well as demyelination in the spinal cord. Mechanistically, this treatment reduced macrophage secretion of pro-inflammatory cytokine IL-1β and decreased macrophage and T cell infiltration into the CNS compared to untreated controls. Together, these findings highlight the therapeutic potential of macrophage-targeted PEGylated liposomes in controlling IL-1β-mediated neuroinflammation in MS and potentially other neurodegenerative diseases.
    Keywords:  experimental autoimmune encephalomyelitis (EAE); liposome; macrophages; multiple sclerosis; neurodegenerative disease; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1657131
  76. J Neuromuscul Dis. 2026 Feb 06. 22143602261422971
    Characteristics of muscle cramps as a prodromal symptom of sporadic amyotrophic lateral sclerosis.
    Shota Komori, Daisuke Ito, Atsushi Hashizume, Shinichiro Yamada, Yoshiyuki Kishimoto, Takahiro Kawase, Ayano Kondo, Masashi Suzuki, Mai Hatanaka, Chisato Oba, Masahisa Katsuno.
       BACKGROUND: Prodromal symptoms of sporadic amyotrophic lateral sclerosis (SALS) including muscle cramps were reported; however, their detailed characteristics have not been sufficiently studied.
    OBJECTIVES: To clarify the detailed profiles of prodromal symptoms in SALS.
    METHODS: Patients with SALS (n = 47) and healthy controls (n = 25) were enrolled. A questionnaire-based survey was conducted to investigate symptoms before and after disease onset, including sensory, autonomic, sleep, cognitive disturbances, and frequent muscle cramps. Frequent muscle cramps were defined as those occurring at least twice per month in the lower limbs, or at least once per month in the upper limbs or trunk. We evaluated the relationship between surveyed symptoms and clinical characteristics.
    RESULTS: Prodromal frequent muscle cramps were observed in 29.8% of SALS patients, most frequently in the lower limbs. With disease progression, the sites with cramps increased, and the frequency of cramps during awakening also increased. The SALS patients with prodromal cramps had greater lean mass than those without (p = 0.023). Multivariate analysis showed that the presence of cramps after disease onset was associated with a slower longitudinal decline in the ALSFRS-R score (p = 0.048). Upper limb-onset SALS patients experienced cramps more frequently before onset than bulbar-onset patients did (p = 0.033).
    CONCLUSIONS: Frequent muscle cramps often precede muscle weakness during the prodromal phase of limb-onset SALS. The frequency of cramps increased with disease progression. Prodromal cramps were associated with lean mass, whereas cramps after disease onset were associated with a slower rate of disease progression.
    Keywords:  amyotrophic lateral sclerosis; body weight; muscle cramp; prodromal symptoms
    DOI:  https://doi.org/10.1177/22143602261422971
  77. Front Aging Neurosci. 2025 ;17 1744415
    Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID.
    Laurence Leclerc, Johanne Poudrier, Christopher Power, Grace Y Lam, Emilia Liana Falcone.
      Long COVID (LC) is a multisystem, post-infectious conditions diagnosed ≥3 months after acute SARS-CoV-2 infection and marked by relapsing, persistent, or progressive symptoms, especially fatigue, post-exertional symptom exacerbation and neuropsychiatric syndromes. We synthesized evidence suggesting that LC arises from intersecting pathways including viral persistence, intestinal dysbiosis and barrier compromise with microbial translocation, innate immune activation with neutrophil extracellular traps (NET) and thromboinflammation, and immune dysregulation with features of exhaustion and autoimmunity. These processes adversely impact blood-brain barrier (BBB) function and lead to neuroinflammation. We propose a mechanistic model in which viral antigens and translocated microbial products amplify pro-inflammatory networks promoting immunothrombosis and tissue hypoperfusion. Hematogenous and gut-brain pathways may then deliver inflammatory mediators to the central nervous system (CNS), resulting in BBB disruption and glial activation that underpin nervous system disorders in LC. Treatment regimens aimed at lowering antigen load, restoring mucosal barrier integrity and modulating myeloid/coagulation pathways may warrant investigation as novel therapeutic strategies to treat LC.
    Keywords:  Long COVID; SARS-CoV-2; gut dysbiosis; intestinal barrier dysfunction; microbial translocation; myeloid activation; neuroinflammation; viral persistence
    DOI:  https://doi.org/10.3389/fnagi.2025.1744415
  78. Neurotoxicology. 2026 Feb 04. pii: S0161-813X(26)00019-7. [Epub ahead of print] 103398
    Neuroprotection via IGF-1 Neuronal Signaling Activation by Melatonin and Edaravone Synergy in Methylmercury-Induced ALS-like Neurotoxicity: Comprehensive Analysis of Brain Regions, Spinal Cord, CSF, and Blood Plasma.
    Gurudev Singh Raina, Sidharth Mehan, Ghanshyam Das Gupta.
      Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5mg/kg (MLT5) and 10mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.
    Keywords:  Amyotrophic Lateral Sclerosis; Melatonin; Methylmercury; Neuroprotection; Neurotoxicity; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.neuro.2026.103398
  79. Neuropharmacology. 2026 Feb 02. pii: S0028-3908(26)00031-6. [Epub ahead of print]289 110858
    Sex-dependent disruption of affective behaviors by GBR 12909: relevance to bipolar disorders.
    Maelle Certon, Bruno Brizard, Catherine Belzung, Alexandre Surget, Arnaud Tanti, Solal Bloch.
      Bipolar disorders (BD) are defined by a chronic recurrence of manic and depressive phases. Along with mood, acute phases are associated with altered emotions. The biological underpinnings of these changes are unresolved, mostly because modeling the cycling nature of BD is still a major challenge in preclinical studies. One pharmacological model is based on GBR 12909 administration, a dopamine transporter inhibitor aiming at mimicking some dimensions of mania. Recent findings indicate that this model generates a mixed phenotype, combining hyperlocomotion with negative hedonic biases and anxiety. These studies have only been performed in male animals, and other behavioral dimensions relevant for BD remain to be explored, in particular recognition of conspecific emotional states and reactivity to danger. The objective of this study is to further characterize the GBR model in mice of both sexes by introducing two novel behavioral assays, the sweeping/looming disk and the negative emotion recognition tasks to evaluate response to threat and emotion discrimination. First, we replicated the previous results in the GBR model: higher anxiety, hyperlocomotion, anhedonia in males. These phenotypes were less pronounced and did not reach significance in females. GBR also induced a hypersensitivity to threat in both sexes in the sweeping/looming disk. GBR abolished preference for the emotional target only in males, suggesting altered emotion recognition. This work introduces new phenotypic dimensions relevant to study BD and highlights the necessity to study both sexes which are not strictly equivalent in their behavioral responses.
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110858
  80. Philos Trans R Soc Lond B Biol Sci. 2026 Feb 05. pii: 20240375. [Epub ahead of print]381(1943):
    The relation between children's shyness and their contingent dialogical actions when reacting to a social robot's instructions.
    Valeriia Tykhonenko, Nils F Tolksdorf, Katharina J Rohlfing.
      Dialogical actions are contingent in humans and also need to be contingent when implemented on intelligent systems such as social robots in order to ease human-robot interaction. Whereas current studies suggest that social robots can support children in different contexts, little is known about individual differences in the way children react to their instructions within an interaction. One dimension of individual differences is temperamental shyness-a tendency to be reluctant in novel social situations. The literature suggests that shyness might influence contingency patterns, and effective robots would need to adapt to this. This study aims to analyse the patterns of dialogical actions in preschoolers (N = 28) in a long-term interaction as a function of their shyness level. In two consecutive sessions in which a robot taught the children novel words, we investigated latencies between the robot's prompt and the child's corresponding action. Results showed that higher levels of shyness were associated with increased action latencies, particularly in the first session. However, this effect diminished over time, because latencies decreased from the first to the second session. The discussion focuses on the findings on the role of shyness in interactions with increasing familiarity, and their implications for a robot's partner modelling. This article is part of the theme issue 'Mechanisms of learning from social interaction'.
    Keywords:  child–robot interaction; contingency; familiarization; shyness; turn-timing
    DOI:  https://doi.org/10.1098/rstb.2024.0375
  81. Neurogastroenterol Motil. 2026 Feb;38(2): e70258
    Epilepsy-Induced Intestinal Barrier Disruption: Protective Effects of Rosa Canina Seed Oil on Duodenal Morphology and Junctional Integrity.
    Nevruz Alis, Onur Onguncan, Sabire Guler, Ebru Yorukoglu, Fusun Sonat, Ender Uzabaci.
       BACKGROUND: Epilepsy is a chronic neurological disorder primarily affecting the central nervous system. However, growing evidence suggests that epilepsy also impacts peripheral organs, including the gastrointestinal tract. The intestinal barrier, essential for maintaining homeostasis and immune defense, is particularly susceptible to oxidative stress, which can disrupt junctional proteins, leading to increased permeability and barrier dysfunction. This study aimed to investigate the effects of epilepsy on duodenal morphology and intercellular junction integrity, as well as to evaluate the potential protective role of Rosa Canina Seed Oil (RSO) in mitigating these alterations.
    METHODS: A pilocarpine-induced rat model of epilepsy was employed in 47 male Sprague-Dawley rats, randomly assigned to eight experimental groups, and treated intragastrically with Rosa canina seed oil (RSO) at doses of 0.125, 0.25, or 0.5 mL/rat/day prior to epilepsy induction. Histomorphometric analysis was conducted to assess villus height, crypt depth, and mucosal surface area. Immunohistochemical staining was used to evaluate the expressions of key junctional and cytoskeletal proteins, including zonula occludens-1 (ZO-1), E-cadherin, and vimentin. Correlation analysis was performed to explore associations between morphological parameters and protein expression levels.
    RESULTS: Epileptic rats exhibited significant reductions in villus height, crypt depth, and absorptive surface area, along with downregulation of ZO-1, E-cadherin, and vimentin, indicating compromised barrier function. RSO treatment demonstrated a dose-dependent protective effect, with moderate and high doses partially restoring intestinal morphology and tight junction integrity. Notably, higher doses of RSO significantly restored ZO-1 levels and preserved vimentin expression, suggesting its role in stabilizing the epithelial barrier and cytoskeletal framework. Correlation analysis confirmed a strong association between epilepsy-induced structural disruptions and barrier dysfunction (p < 0.05), highlighting the potential protective effects of RSO.
    CONCLUSION: These findings demonstrate that epilepsy impairs intestinal barrier integrity by altering epithelial structure and junctional protein expression, leading to increased permeability. RSO treatment partially counteracted these effects, supporting epithelial stability and barrier function in a dose-dependent manner.
    Keywords:   Rosa canina ; E‐cadherin; ZO‐1; epilepsy; intestinal morphology; vimentin
    DOI:  https://doi.org/10.1111/nmo.70258
  82. Eur Radiol Exp. 2026 Feb 04. 10(1): 10
    Visualization of gadolinium transport across the blood-brain barrier along perivascular clearance pathways.
    Svea Seehafer, Yvonne Mrosek, Lars-Patrick Schmill, Schekeb Aludin, Olav Jansen, Carl Alexander Gless, Johanna Rümenapp, Naomi Larsen.
       OBJECTIVE: We investigated the transport of gadolinium-based contrast agent (GBCA) across the blood-brain barrier (BBB) along the perivascular spaces as part of the glymphatic drainage in patients with iatrogenic BBB disruption following digital subtraction angiography (DSA).
    MATERIALS AND METHODS: A retrospective analysis was conducted on patients who underwent DSA for diagnosis and/or treatment of intracranial aneurysms and received a 3-T magnetic resonance imaging (MRI) within the following day. Exclusion criteria included states with a suggested impairment of BBB integrity, such as neurodegenerative diseases or suspected glymphatic impairment. BBB disruption was assessed using a pre- and post-contrast three-dimensional T1-weighted volume-isotropic turbo spin-echo sequence. Patterns of GBCA distributions were described. The localization of GBCA-extravasation was correlated with perivascular spaces visualized on the coregistered T2-weighted sequences. Fisher's exact test and logistic regression were used.
    RESULTS: Out of 43 patients, 30 (69.8%) exhibited visible BBB disruption. BBB disruption was significantly more often observed after therapeutic DSA (p = 0.004). GBCA-enhancement patterns indicated a localized pial enhancement in 96.7% of affected patients, with additional parenchymal enhancement along the perivascular spaces in 56.7%. Enhancement was predominantly located in the downstream territories of probed vessels, suggesting a potential association with glymphatic transport. An illustrative case with serial MRI examinations is presented, demonstrating time-dependent GBCA-enhancement patterns.
    CONCLUSION: The study provides in vivo evidence of GBCA transport patterns following iatrogenic BBB disruption, which may correspond to parts of the proposed glymphatic pathways. Our results indicate a sequential progression of contrast enhancement, initially manifesting at the brain surface and subsequently extending along perivascular spaces to the subarachnoid space.
    RELEVANCE STATEMENT: Understanding BBB disruption and glymphatic transport with MRI imaging methods may improve neurovascular disease management.
    KEY POINTS: BBB disruption post-DSA may facilitate GBCA transport via glymphatic pathways, offering novel and hypothesis-generating insights into brain clearance mechanisms. GBCA enhancement followed a chronological and spatial pattern, suggesting an organized cerebrospinal-interstitial exchange system relevant for brain clearance. Findings highlight potential implications for BBB integrity in neurovascular health with prospective implications for diagnostic imaging.
    Keywords:  Angiography (digital subtraction); Blood-brain barrier; Contrast media; Glymphatic system; Magnetic resonance imaging
    DOI:  https://doi.org/10.1186/s41747-025-00672-0
  83. Anal Bioanal Chem. 2026 Feb 02.
    Towards robust identification of Pleistocene adhesives: a critical review of current analytical approaches.
    Anika Lokker, Pierre-Hugues Stefanuto, Dries Cnuts, Veerle Rots, Jean-François Focant.
      Chemical identification of adhesive remains on prehistoric stone tools is of great interest for archaeologists, as the residues contain interesting information on tool use and the exploitation of natural resources by hominins. Adhesives were used to form a wrapping around the stone tool to protect the hand from the sharp edges and improve grip, or to secure a handle out of organic material to the stone tool. This invention, of adding a handle to a stone tool, marks a fundamental change in prehistoric technology. Adhesives can be manufactured from readily available exudates, like pine resin, but could also be man-made, in the case of birch tar that is obtained by dry distillation of birch bark. The glueing properties of the adhesives could be enhanced with the addition of an additive (e.g. charcoal, ochre, beeswax). Given that adhesive manufacture is considered to indicate planning abilities and complex thought, its identification in archaeological assemblages is important for understanding the evolution of human cognition. However, given long-term burial, organic residues on stone tools are generally significantly degraded, which raises numerous chemical challenges and interpretative difficulties that need to be tackled through close collaboration between archaeologists and chemists. Without this interaction between two vastly different research fields, studies can suffer from an overinterpretation of analytical data or a lack of understanding of the archaeological context. This review discusses the main pitfalls encountered in the chemical analysis of prehistoric adhesives and offers analytical recommendations to avoid them. Applying the analytical practices as proposed here will increase the reliability and credibility of the analytical results and allow a strong chemical foundation for the archaeological interpretations. The main focus is on the use of gas chromatography-mass spectrometry for the chemical identification of prehistoric adhesives; however, other commonly used analytical techniques are also briefly discussed.
    Keywords:  Analytical chemistry; Gas chromatography; Hafting; Prehistoric adhesives; QA/QC; Stone tools
    DOI:  https://doi.org/10.1007/s00216-026-06354-z
  84. Integr Comp Biol. 2026 Feb 05. pii: icag005. [Epub ahead of print]
    Natural Variation Reveals Functional and Genetic Integration of a Polyphenism.
    Rose M Nicholson, Nicholas A Levis, Marc R Allison, Elizabeth A Geis, Erik J Ragsdale.
      Integration and modularity can have a profound impact on the function and evolution of environmentally responsive traits, especially when they result in discrete, alternative forms-that is, developmental polyphenism. An unresolved issue for understanding this impact is the degree to which the genetic architectures of the individual components of a plastic trait permit independent versus coordinated evolution. The association of trait variation with genomic variation can provide a test of whether the same loci influence different components of the same integrated phenotype. An example of a coordinated, plastic trait is in the shark-tooth nematode Pristionchus pacificus, which develops into either a bacterial-feeding or a predatory adult morph, depending on its perception of local food availability. Moreover, this polyphenism, when measured as morph induction in response to a common set of cues, differs across natural isolates of the species. By creating recombinant inbred lines (RILs) from natural isolates that have diverged in their morph-induction bias, followed by quantitative trait locus analysis, we tested whether and the extent to which component traits of this resource polyphenism are linked. We found that RILs with more frequent induction of the predatory morph also produced Eu individuals that were more effective predators. We also found that these two traits are associated with the same major-effect locus, suggesting that their causal genes are physically linked, if not the same, and are therefore likely to experience coordinated selection. In contrast, we found that morphological variation was not linked to these two traits and that such variation within each morph was even independent of variation in the other. Our findings show that the same coordinated plastic trait exhibits a blend of genetic correlation and independence, whose balance shapes the trait's evolutionary potential.
    Keywords:   Pristionchus pacificus ; Nematodes; phenotypic plasticity; predation; quantitative trait loci; recombinant inbred lines
    DOI:  https://doi.org/10.1093/icb/icag005
  85. ACM Trans Internet Technol. 2025 Nov;pii: 22. [Epub ahead of print]25(4):
    Semantically Correct Policy Mining and Enforcement for Attribute based Access Control.
    Gunjan Batra, Samir Talegaon, Vijayalakshmi Atluri, Jaideep Vaidya, Shamik Sural.
      Attribute-Based Access Control (ABAC) is increasingly becoming popular due to its dynamic, flexible, portable, and scalable nature. Under ABAC, security policies (ABAC rules) are stated in terms of the attributes of the subject, the object and the environment. A subject is granted access to an object if their respective attribute values are satisfied against a set of ABAC rules. Typically hierarchical relationships exist among the subjects as well as the objects, where more specific subjects (objects) inherit the attributes from the general ones. As such, if a subject is allowed access to a general object, that subject is allowed to access all of its sub-types. This has been the general understanding and current ABAC enforcement and policy mining approaches follow this approach. However, in this article, we argue that the general understanding of the semantics of the ABAC is not always appropriate. Indeed, under certain semantics, the specific data may be more sensitive than that of its general counterpart. In that situation, if a subject is allowed access to a general type, it should not be allowed access to its sub-type, which is contrary to the current understanding and implementation. This paper is the first attempt in the literature to distinguish these two different ABAC semantics arising from the different semantics of object attributes themselves. We present concrete examples of these two semantics and demonstrate what can go wrong - both anecdotally as well as empirically - if one ignores the underlying semantics and inappropriately uses the existing enforcement and mining algorithms. We then present how existing algorithms can be modified so that no misconfigurations arise and security is ensured.
    Keywords:  ABAC; Attribute based; Policy enforcement; Policy mining; access control; revisit; semantics
    DOI:  https://doi.org/10.1145/3736764
  86. Ther Innov Regul Sci. 2026 Feb 03.
    Hierarchical Transit Compartment Model to Describe Absorption Delay in Orally Administered Drugs in Heterogeneous Populations.
    Abhisek Chakraborty, Anirban Chakraborty.
      Following oral administration of a drug, we observe an absorption delay before the drug enters systemic circulation. This delay is attributed to the time taken for disintegration of the drug delivery system, drug dissolution from the delivery system, migration of the drug to the absorption site, and transfer of the drug through absorption site tissue. Additionally, pharmacokinetic profiles of such drugs frequently exhibit substantial variability among individuals from different sub-populations. In this article, we present a hierarchical transit compartment model that systematically describes absorption delay in orally administered drugs, and explicitly accounts for between sub-population variations. Such a transit compartment model can be regarded as an accurate representation of the underlying physiology, that also accounts for the influence of drug formulation and the physicochemical properties of the drug on the absorption process. Here, we specify non-informative priors on the pharmacokinetic parameters of interest, and develop an efficient computational scheme based on Hamiltonian Monte Carlo algorithm to conduct inference. The proposed joint inferential procedure ensures valid uncertainty quantification, and enables us to conduct simultaneous inference on sub-population specific as well as population parameters. The utility of the methodology is demonstrated through simulation studies, and two case studies.
    Keywords:  Drug absorption delay; Hamiltonian Monte Carlo; Heterogeneous population; Hierarchical models
    DOI:  https://doi.org/10.1007/s43441-025-00876-x
  87. Exp Mol Med. 2026 Feb;58(1): 284-295
    Progressive neuroinflammation and deficits in motor function in a mouse model with an Epg5 pathogenic variant of Vici syndrome.
    Bradley T Thornton, Alexandra G Hardinger, Laramie Pence, Priyanka Prem Kumar, Nikolas Connolly, Scott J Weir, Jay L Vivian.
      Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immune deficits, cardiomyopathy and progressive motor dysfunction. This devastating condition is caused by pathogenic variants in the EPG5 gene, which encodes a regulator of autophagy, leading to the accumulation of toxic intracellular material and widespread cellular dysfunction. Less-severe EPG5 pathogenic variants have recently been linked to rare familial forms of Parkinson's disease, suggesting deficits in EPG5 function drive a range of neurodegenerative disorders. Currently, there are no effective treatments for any disorders associated with pathogenic variants of EPG5. The underlying cellular mechanisms driving the progressive neurological decline in VS remain poorly understood. Previous studies using Epg5 knockout models have demonstrated severe neurological phenotypes; however, these models have not been characterized for molecular and cellular deficits within the central nervous system. Here we report the generation and analysis of novel genetically engineered mice with mutations in Epg5 as models of VS, including a strain harboring a truncating mutation that recapitulates a patient-derived pathogenic variant and a strain with an Epg5 null allele. These novel Epg5 mutant mouse models exhibited partial perinatal lethality. Neurological deficits of surviving were detectable by 6 weeks of age, and worsen over time. Histological analysis revealed widespread expansion of microglia and astrocytes throughout the central nervous system. Transcriptomic profiling of central nervous system tissue revealed robust neuroinflammatory signatures, sharing molecular profiles with disease-associated microglia observed in other models of neurological disease and injury. The analysis of these novel mouse models of VS suggest a critical role for neuroglial activation in the pathogenesis of VS. These novel in vivo models will be an essential platform for preclinical evaluation of therapeutics that target autophagy-related neurodegeneration in congenital disorders of autophagy and EPG5-associated neurodegeneration.
    DOI:  https://doi.org/10.1038/s12276-026-01644-z
  88. Brain Spine. 2025 ;5 104243
    Current and emergent therapies targeting spinal cord injury.
    Giovanni Grasso, Luigi Cusimano, Manfredi Noto, Rosario Maugeri, Domenico Gerardo Iacopino.
      Spinal cord injury (SCI) is a serious condition characterized by high rates of disability. The complexities of SCI repair arise from intricate pathological mechanisms and the challenges of neural regeneration within the central nervous system. In recent decades, researchers have sought to fully understand these mechanisms and develop effective strategies for promoting axon regeneration and reconstructing neural circuits, though outcomes have often fallen short. Surgical techniques have evolved considerably, with options such as early surgical decompression, effective bony decompression, and expansile duroplasty providing favorable results in enhancing neurological recovery for patients. Accordingly, surgical intervention should be undertaken within 24 h when medically feasible. In addition, there has been a concerted effort to improve non-surgical management, particularly in critical care. In pre-clinical settings, a range of innovative therapies is currently being explored, with some showing enough promise to advance to clinical trials. In this regard, the use of riluzole and anti NOGO antibodies has shown promising results from secondary analyses of high quality RCTs. Moreover, technological innovations in biomechanics and bioengineering are playing an essential role in managing SCI with growing emphasis on creating intermediate neural networks to facilitate regeneration and circuit rebuilding. This review presents an overview of SCI, current treatments, and illustrates future avenues for SCI repair and clinical application.
    Keywords:  Biomarkers; Clinical practice guidelines; Neuroprotection; Neuroregeneration; Spinal cord injury; Surgery; Timing of surgery
    DOI:  https://doi.org/10.1016/j.bas.2025.104243
  89. Mol Hum Reprod. 2026 Feb 04. pii: gaag004. [Epub ahead of print]
    Variable partition of non-homogeneous ooplasm sets the stage for divergent potency of 2-cell stage blastomeres.
    Thomas Nolte, Reza Halabian, Steffen Israel, Yutaka Suzuki, Hannes C A Drexler, Wojciech Makalowski, Georg Fuellen, Michele Boiani.
      Following fertilization in mice and humans, the first two blastomeres are not equivalent, but one produces more epiblast than the other (imbalance), therefore, they do not feature equal totipotency. Research into the causes has overlooked that the epiblast imbalance is preceded by a fertilization imbalance, since in nature, the spermatozoon fertilizes the oocyte preferentially in the animal hemisphere near the animal-vegetal midline (equator). We conceived a hypothesis that the two imbalances are linked to each other, and broke it down into testable predictions. If the two imbalances were interdependent, then changing the site of sperm entry into the oocyte should change the extent of the epiblast imbalance. Thus, we evened out the fertilization imbalance, using ICSI to fertilize mouse oocytes also in the vegetal hemisphere and the equator. Resultant embryos were split at the 2-cell stage, and the twin blastocysts originating from the sister blastomeres were analyzed. Against the similarity in mRNA levels of epiblast genes, twin blastocysts differed in epiblast function, as measured by NANOG protein expression and derivation of embryonic stem cells, and the epiblast imbalance was greater after oocyte fertilization at the equator. There is no simple way to explain the positional effect other than through differences in the molecular composition of the ooplasm, which, moreover, should also be apportioned variably at the first zygotic division. We tested these predictions by measuring the orientation of the first zygotic division regarding the ICSI site, and the composition of bisected oocytes' hemispheres using half-cell proteomics. Since we found that the hemispheres have different compositions depending on the bisection axis, and the angle of the first division is variable, we propose that the variable partition of non-homogeneous ooplasm sets the stage for the epiblast imbalance. These results revive the role of the oocyte's molecular architecture on embryogenesis in a mammalian species hitherto considered mostly regulative in development.
    Keywords:  2-cell embryo; ICSI; RNA-sequencing; blastocyst; embryo splitting; epiblast; mass spectrometry; mouse; oocyte bisection; proteome
    DOI:  https://doi.org/10.1093/molehr/gaag004
  90. Saudi Med J. 2026 Jan;47(1): 21-32
    Sphingosine-1-Phosphate Regulation to Alleviate Sickle Cell Disease Severity: A Promising Therapeutic Approach.
    Shahanas Chathoth.
      Sickle cell disease (SCD) is a genetic disorder that affects millions of individuals worldwide. Chronic anemia, hemolysis and vasculopathy are the most common symptoms that arise from hemoglobin (Hb) polymerization, which is the primary event of SCD. The above process can lead to erythrocyte sickling. Therapeutic options for SCD remain limited, and novel therapies are still being evaluated for their effectiveness in particular populations. Sphingosine-1-phosphate (S1P), a significant bioactive sphingolipid, acts as a potent signal mediator, modulating several cellular functions. The potential role of erythrocyte-S1P in enhancing SCD severity has been previously reported by multiple studies. Therefore, the present review article aimed to summarize the effects of S1P on the progression of SCD and provide strategies to modulate this process. More specifically, it focused on erythrocyte-S1P as a potential target for reducing the complications associated with SCD, thus paving the way for the development of novel therapeutic strategies for SCD.
    Keywords:  Adenosine; Hypoxia; Sickle cell disease; Sphingosine kinase-1; Sphingosine-1-phosphate
    DOI:  https://doi.org/10.15537/smj.2026.47.1.20250292
  91. Life Sci Alliance. 2026 Apr;pii: e202503527. [Epub ahead of print]9(4):
    TBK1 activity regulates the directionality of axonal transport of signalling endosomes.
    David Villarroel-Campos, Jose Norberto S Vargas, Martin Wallace, Kai Sun, James N Sleigh, Pietro Fratta, Giampietro Schiavo.
      The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.
    DOI:  https://doi.org/10.26508/lsa.202503527
  92. ArXiv. 2026 Jan 29. pii: arXiv:2601.22233v1. [Epub ahead of print]
    Zero-information limit of a collective olfactory search model.
    Francesco Boccardo, Simone Di Marino, Agnese Seminara.
      We address the problem of how individuals can integrate efficiently their private behavior with information provided by others within a group. To this end, we consider the model of collective search introduced in [https://doi.org/10.1103/PhysRevE.102.012402], under a minimal setting with no olfactory information. Agents combine a private exploratory behavior and a social imitation consisting in aligning to their neighbors, and weigh the two contributions with a single ``trust" parameter that controls their relative influence. We find that an optimal trust parameter exists even in the absence of olfactory information, as was observed in the original model. Optimality is dictated by the need to explore the minimal region of space that contains the target. An optimal trust parameter emerges from this constraint because it it tunes imitation, which induces a collective mechanism of inertia affecting the size and path of the swarm. We predict the optimal trust parameter for cohesive groups where all agents interact with one another. We show how optimality depends on the initialization of the agents and the unknown location of the target, in close agreement with numerical simulations. Our results may be leveraged to optimize the design of swarm robotics or to understand information integration in organisms with decentralized nervous systems such as cephalopods.
  93. Front Psychol. 2025 ;16 1631855
    The power of the group: How neuroscience supports expanding the therapeutic dyad through group psychotherapy.
    Patrice Duquette.
      Group psychotherapy represents a therapeutic modality that provides unique affordances for patients, allowing layers of engagement by the patient in the psychotherapeutic process that are not available in dyadic psychotherapeutic treatment. This article considers psychodynamic group psychotherapy through the lens of current neuroscientific concepts. In doing so, we offer a framework for clinicians to consider how beliefs and habits that are originally adaptive become maladaptive and persist, and why patients hold on to maladaptive beliefs about the world and their own agency that are not reflective of the present-day moment. Neuroscientific proposals describing how early-life adaptations may result in longstanding false inferences regarding cause and effect in the world and within their emotional experiences will be evaluated alongside related psychological concepts. We will present and define the importance of neuroscientific concepts to the practicing psychotherapist, such as predictive processing, active inference, and the mentalization of interoception, as applicable to psychological and behavioral processes evidenced by the patient. The value that group psychotherapy specifically adds to processes needed to generate meaningful change will be explored in depth. How the milieu of group psychotherapy presents epistemic affordances to the patients in the group, which can then be leveraged in multiple ways to increase therapeutic benefit, will be addressed. Affordances in the group that offer patients unique interpersonal opportunities to address intrapersonal experiences such as mentalization of interoception and the activation of inference processes, creating lasting change, will be examined. The means by which interactions among group members decrease epistemic vigilance, increase epistemic trust, and facilitate epistemic foraging, thereby supporting necessary changes in mentalization capacity for patients, will be described. A case example will bring to light the elements, both neuroscientifically based and psychologically based, that are presented regarding the power of the group. Through access to and engagement with the process opportunities the group presents, patients can be supported by both therapists and other group members, affecting meaningful changes and ongoing present-moment adaptations over time for the individuals.
    Keywords:  Bayesian inference; active inference; epistemic trust; group psychotherapy; mentalization; mentalization of interoception; psychodynamic psychotherapy; psychotherapy
    DOI:  https://doi.org/10.3389/fpsyg.2025.1631855
  94. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Feb 03. 1-3
    Limited data capture on reproductive medicine use in amyotrophic lateral sclerosis: implications for monitoring access.
    Shanice Allen, Jade Howard, Christopher J McDermott, Felicity Boardman, Alisdair McNeill.
      There is very limited evidence around the use of reproductive genetic testing in individuals with amyotrophic lateral sclerosis (ALS)-linked gene variants. This study aimed to identify the use of reproductive genetic testing in these individuals to understand patterns of (under)utilization and to identify barriers to equitable access. Freedom of information requests were sent in January 2025 to the 22 regional clinical genetics centers across the UK around reproductive services for individuals with, or at risk for, ALS and Huntington's disease. Limited data were available with only six trusts answering in full. The data that our study yielded raises significant concerns and inconsistencies regarding clinical recording and reporting of reproductive genetic counseling and testing. The absence of standardized retrievable data limits the ability to assess utilization and may point toward a systemic issue in data capture of reproductive genetic services for individuals at risk of ALS, and by extension, those affected by other genetic conditions.
    Keywords:  ALS; Huntington’s disease; MND; reproductive genetic counseling; reproductive genetic testing
    DOI:  https://doi.org/10.1080/21678421.2026.2618124
  95. Med J Armed Forces India. 2026 Jan-Feb;82(1):82(1): 6-15
    Exploring the therapeutic potential of beta-3 adrenergic agonists in overactive bladder: A comprehensive review.
    Veena Nayak, Sadhana N Holla, Smita Shenoy, Harshini H, Aditya Vinayak Raveendran.
      Overactive bladder (OAB) is characterized by urinary urgency, frequency, and incontinence. The primary medications used for OAB treatment include antimuscarinics and beta-3 adrenergic agonists. The objective of this review was to understand the beta-3 signaling mechanisms in OAB and analyze the results of studies comparing mirabegron either as monotherapy or in combination with antimuscarinics for OAB treatment. A literature search for comparison studies on beta-3 adrenergic drugs and antimuscarinic medications for OAB from different databases was conducted. Although the antimuscarinic class of medications has been reported to be an effective therapy for the symptomatic management of OAB, dose-limiting adverse effects continue to be the reason for discontinuation in the elderly population. Due to the high efficacy of mirabegron and the possible unavoidable side effects associated with antimuscarinic drugs, OAB can be treated with oral beta-3-agonists. In patients who are resistant to monotherapy, a combination therapy consisting of antimuscarinic agents and beta-3-agonists may be attempted. Primarily, this review emphasizes the role of beta-3 agonists in OAB in terms of their mechanism, safety, and efficacy in comparison with those of antimuscarinic drugs.
    Keywords:  Antimuscarinic drugs; Beta-3 stimulation; Mirabegron; Urinary incontinence; Vibegron
    DOI:  https://doi.org/10.1016/j.mjafi.2025.03.003
  96. mSphere. 2026 Jan 30. e0083825
    Use of a human immortalized microglia cell line to study recognition, phagocytosis, and intracellular survival of Cryptococcus neoformans.
    Robbi L Ross, Kassandra Arias-Parbul, Zane M Douglass, Katrina L Adams, Felipe H Santiago-Tirado.
      Cryptococcus neoformans, the etiological agent of cryptococcal meningitis (CM) is a globally distributed environmental yeast that mainly causes infections in immunocompromised individuals. Particularly in low-resource countries, the mortality rate of CM can reach 81% and accounts for ~19% of HIV/AIDS-related deaths each year. In immunocompromised individuals, once inhaled, C. neoformans escapes from the lungs and disseminates with special predilection for the central nervous system (CNS). Once in the brain, C. neoformans interacts with microglia, the tissue-resident macrophages of the CNS. Previous studies indirectly showed that microglia are ineffective at controlling this fungal infection. The mechanisms underlying this fungal survival and proliferation within the CNS, however, remain unclear. In this study, we use and validate the C20 immortalized human microglia cell line to study cryptococcal-microglia interactions. We show that microglia have limited phagocytic activity that is specific to C. neoformans and partly dependent on cryptococcal antiphagocytic proteins that alter cell size and cell wall structure. We also show that human microglia respond to cryptococcal strains differently than peripheral macrophages. Further, we show that human microglia are ineffective at killing phagocytosed C. neoformans, and that this could be due to the ability of this yeast to disrupt phagosome maturation and induce phagosome membrane damage in these cells. These findings provide us with fundamental knowledge regarding cryptococcal pathogenesis in the CNS, specifically the insight into how C. neoformans is recognized by microglia under different conditions and demonstrate the usefulness of C20 cells to further study how this yeast survives and replicates within the CNS environment.
    IMPORTANCE: While Cryptococcus neoformans is acquired through inhalation, the fatal pathology of cryptococcal infection occurs when the yeast disseminates to the central nervous system (CNS) and causes cryptococcal meningitis. Microglia are the first immune cells that C. neoformans will encounter once it reaches the CNS, and they are the largest population of macrophages in the brain. While microglia are professional phagocytes, they are unable to control C. neoformans infection. The mechanisms behind uncontrolled growth of C. neoformans within the CNS remain understudied, partly due to incomplete knowledge regarding microglia-cryptococcal interactions. This study provides fundamental knowledge into these interactions and establishes a powerful model to specifically study how C. neoformans is recognized by microglia and how cryptococcal phagosomes mature in these phagocytes. This work opens new avenues of research to further our understanding of cryptococcal-host interactions, which can be leveraged to develop more effective therapeutics for cryptococcal meningitis.
    Keywords:  C20 cells; Cryptococcus neoformans; cryptococcal meningitis; microglia
    DOI:  https://doi.org/10.1128/msphere.00838-25
  97. Probl Endokrinol (Mosk). 2026 Jan 18. 71(6): 56-66
    [Features of bioenergetic metabolism in physiological and pathological conditions: focus on oncogenesis].
    A S Zhdanova, Z E Belaya, G A Melnichenko.
      The basis of the vital activity of each cell of the body is energy metabolism, necessary for the implementation of physiological needs in norm and pathology. The most important pathways for the synthesis of adenosine triphosphate are glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. Glucose, free fatty acids and amino acids can be used as a substrate for obtaining energy. As the disease develops, reprogramming occurs in cells with the ability to switch between energy pathways and the choice of its sources, forming a specific metabolic phenotype that ensures cell survival and the formation of clinical characteristics of the disease. The availability of information on pathophysiological changes at the level of cell metabolism is of scientific and practical interest in relation to the development of methods for accurate diagnosis and the choice of personalized tactics in each specific case. This review describes the characteristics of energy metabolism in normal and tumor cells. It also provides information on modern methods for assessing energy metabolism in the body.
    DOI:  https://doi.org/10.14341/probl13648
  98. Immun Inflamm Dis. 2026 Feb;14(2): e70310
    Reducing Neuroinflammation via Inhibition of Fibrinogen Deposition and Microglial Activation as an Underlying Mechanism of Paning I Decoction in Ameliorating Parkinson's Disease Symptoms.
    Yan-Jun Chen, Jing-Wen Chen, Ming-Rong Xie, Rui-Zhen Wang, Yu-Ling Wan, Jie Zeng, Bing-Wu Zhong, Sheng-Qiang Zhou, Fang Liu.
       BACKGROUND: Parkinson's disease (PD) is a major neurodegenerative disorder. Some patients show limited response to standard therapies, driving the need for new complementary treatments. Paning I decoction (PNID), a traditional herbal formula, has shown the potential to alleviate PD symptoms, but its exact mechanisms remain unclear.
    METHODS: We tested PNID in a mouse model of PD induced by a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice received different PNID doses to evaluate symptom alleviation. We used behavioral tests and laboratory analyses to study brain changes, including neuron damage assessment, dopamine and tyrosine hydroxylase (TH) measurements, blood-brain barrier (BBB) integrity and microglia evaluation, and inflammatory marker analysis.
    RESULTS: PNID treatment alleviated PD symptoms in a dose-dependent manner. High-dose PNID performed similarly to Madopar. Neuron protection: increased dopamine and TH expression. BBB repair: less leakage and fibrinogen accumulation. Regulation of polarization: shifted microglia from M1 to M2 states. Inflammation control: lowered pro-inflammatory factors (IL-6, IL-1β, and TNF-α) while increasing anti-inflammatory factors (IFN-β, IL-10, and IL-4).
    CONCLUSIONS: PNID may serve as a promising complementary therapy for PD. Benefits may come from the repair of the BBB, reduction of fibrinogen deposition, and decline in neuroinflammation by modulating microglial polarization.
    Keywords:  Paning I decoction; Parkinson's disease; fibrinogen; microglia; neuroinflammation
    DOI:  https://doi.org/10.1002/iid3.70310
  99. Comput Biol Med. 2026 Feb 04. pii: S0010-4825(26)00080-6. [Epub ahead of print]204 111519
    A semi-automated modelling pipeline to predict the mechanics of multiple sclerosis lesion afflicted brains from magnetic resonance images.
    Adam C Szekely-Kohn, Diana Cruz De Oliveira, Marco Castellani, Michael Douglas, Zubair Ahmed, Daniel M Espino.
      Multiple Sclerosis (MS) is a demyelinating and degenerative autoimmune disease that affects the brain and spinal cord. Its causes, mechanisms, and outcomes are yet to be fully understood. One relatively unexplored area is the understanding of changes in brain biomechanics during MS disease progression, despite the likelihood that demyelination significantly alters the overall mechanical structure of the brain. Such changes have the potential to hinder the propagation of nerve signals essential for cognition and motor function. The aim of this work was to create a computational model to explore the mechanics of brains with MS, separating the brain into grey matter, white matter and lesions. Changes were observed when the surface of the brain was subjected to a ramped uniform pressure tangential to the faces of a finite element model, generated from patient- and time-specific MRI scans. The resulting displacements, stresses and strains can all be gauged using the model. The key benefit of this study was to observe the impact of changes in tissue morphology in real brains using non-invasive methods. Ensuring the accuracy of the axiomatic input tissue parameters of the models was critically important, as exploring the range of values from literature, adjusted by their error margins, revealed a significant variability in outcomes, especially in the case of volumetric strain of lesions. The model has the potential to track changes in mechanical tissue properties assuming the availability of a longitudinal dataset, and if further developed, has the potential to serve as the foundation for creating a digital twin. This could enhance medical practice and provide a non-invasive approach to advancing the understanding of MS and its progression on a patient-specific basis.
    Keywords:  Brain; Finite element analysis (FEA); Hyperelasticity; Lesions; Magnetic resonance imaging (MRI); Mechanical behaviour; Multiple sclerosis (MS); Tissue analysis; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.compbiomed.2026.111519
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